Infectious Diseases, Second Edition (EXPERT GUIDE SERIES- AMERICAN COLLEGE OF PHYSICIANS)

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Infectious Diseases

Tan File Salata Tan

Second Edition

• Features new chapters on antimicrobial agents and prosthetic joint infections. • Includes individual chapters on HIV, herpes virus, Lyme disease, and malaria. • Puts key information at your fingertips with diagnostic and treatment tables throughout the text. • Reviews the clinical manifestations of each infection as well as recent advances in clinical microbiology. • Focuses on the common and uncommon diseases most often seen in primary care practices. Infections comprise a sizable proportion of the conditions encountered in the office setting. Manage them easily and effectively with this thorough, yet practical, guide.

Infectious Diseases

• Examines infections of the central nervous system, heart and blood vessels, gastrointestinal tract, genitourinary system, respiratory tract, skeletal system, and skin.

Second Edition

Find the expert guidance you need to evaluate, diagnose, and treat the most commonly encountered infections in the primary care setting. Infectious Diseases, 2nd Edition keeps you current with new etiologic agents, the most appropriate diagnostic tests, and the most effective management options. This New Edition:

ACP

Infectious Diseases Second Edition

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Expert Guide to

INFECTIOUS DISEASES SECOND EDITION

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Expert Guide to

INFECTIOUS DISEASES SECOND EDITION Edited by James S. Tan, MD, MACP Professor and Vice Chairman, Department of Internal Medicine Northeastern Ohio Universities College of Medicine Head, Infectious Diseases Section Chairman, Department of Internal Medicine Summa Health System

THOMAS M. FILE, JR., MD, MSC, MACP Professor, Department of Internal Medicine Head, Infectious Diseases Section; Master Teacher Northeastern Ohio Universities College of Medicine Chief, Infectious Diseases Service Summa Health System

ROBERT A. SALATA, MD, FACP Professor and Vice-Chair, Department of Medicine Chief, Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center

MICHAEL J. TAN, MD, FACP Assistant Professor, Department of Internal Medicine Northeastern Ohio Universities College of Medicine Clinical Physician, HIV and Infectious Diseases Summa Health System

ACP Press American College of Physicians • Philadelphia

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Clinical Consultant: David R. Goldmann, MD Associate Publisher and Manager, Books Publishing: Tom Hartman Developmental Editor: Victoria Hoenigke Production Supervisor: Allan S. Kleinberg Senior Editor: Karen C. Nolan Editorial Coordinator: Angela Gabella Indexer: Kathleen Patterson Copyright © 2008 by the American College of Physicians. All rights reserved. No part of this book may be reproduced in any form by any means (electronic, mechanical, xerographic, or other) or held in any information storage and retrieval systems without written permission from the publisher. Manufactured in the United States of America Composition by SPI, India Printing/Binding by Versa Press Inc. ISBN: 978-1-930513-85-3

The authors have exerted reasonable efforts to ensure that drug selection and dosage set forth in this volume are in accord with current recommendations and practice at the time of publication. In view of ongoing research, occasional changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This care is particularly important when the recommended agent is a new or infrequently used drug. ACP is not responsible for any accident or injury resulting form the use of this publication.

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In Memoriam James S. Tan, MD, MACP

O

ur renowned colleague, James Tan, died May 25, 2006, in Akron, Ohio. He was 67. Jim was the editor of the first edition of Expert Guide to Infectious Diseases, and through his efforts it was a great success. At the time of his death, he was coordinating this second edition, which we dedicate to him. Jim graduated in 1965 from the University of the Philippines College of Medicine, and he trained in infectious diseases at the University of Cincinnati College of Medicine. In 1974, he moved from a faculty position at the University of Cincinnati to Akron, Ohio to be the first Head of Infectious Diseases at Akron City Hospital (now Summa Health System). He was the first infectious diseases specialist to bring clinical expertise to the community setting in northeastern Ohio. In 1979, he was named Chairman of the Department of Medicine at Akron City Hospital, a position he held until his death. At that time, he had completed the longest term as program v

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In Memoriam

director of an internal medicine residency program in the nation and was involved in the training of countless physicians. He was also the first Chairman of the Infectious Diseases Section of Northeastern Ohio Universities College of Medicine (NEOUCOM) in Rootstown, Ohio and he held this position since 1977. Through his leadership, he organized the development of the infectious diseases curriculum for medical students at the College of Medicine. Jim will be forever remembered as a consummate infectious diseases clinician and educator. Jim was a Master of the American College of Physicians. He was former Governor of the Ohio Chapter of the American College of Physicians, and further served the College in many additional capacities. He was also a Fellow of the Infectious Diseases Society of America (IDSA) and served as the secretary-treasurer (aka, ‘executive director’) of the Infectious Diseases Society of Ohio for five years. He was a member of the IDSA Clinical Guideline Panel for the Diagnosis and Treatment of Diabetic Foot Infections. Jim was exceptionally active in research. He was particularly interested in the evaluation of the pharmacokinetics of antimicrobials: one of his significant achievements in this field was his improvement of a skin window technique to measure the interstitial fluid concentrations of antimicrobials. This work has been published in numerous journal articles and textbook chapters. His many awards include the Liebelt/Wheeler Award from NEOUCOM for faculty excellence and the American College of Physicians Ohio Chapter Laureate and Master Teacher Awards. He received the Watanakunakorn Clinician of the Year Award at the annual meeting of the Infectious Diseases Society of America meeting in San Francisco in October 2005. Twice he was named teacher of the year by the house staff of Akron City Hospital (Summa Health System). He authored and co-authored more than 180 scientific publications. Throughout Jim’s distinguished career, the care of patients was always his primary interest. Even while he excelled at research, teaching medical students, residents, and colleagues, and administering at a large teaching medicine program, patient care remained his passion. His friendly personality and warm smile endeared him to his patients. He truly improved the lives of thousands with his compassionate care. Jim Tan is survived by his wife, June; his children, Stephanie Tan, MD, Rowena Tan, PhD, and Michael Tan, MD (co-editor of this edition of Expert Guide to Infectious Diseases); and his grandchildren, Drew, Allison, Hannah, Nicholas, and Jameson. TMF Jr. RAS MJT

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Contributors

Keith B. Armitage, MD, FACP Professor of Medicine Vice Chair for Education, Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

David Bobak, MD Associate Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

Manmeet S. Ahluwalia, MBBS Department of Medicine Fairview Hospital Cleveland, OH

Hector Bonilla, MD Assistant Professor of Internal Medicine Northeastern Ohio Universities College of Medicine Summa Health System Akron, OH

Johan S. Bakken, MD, PhD, FACP Associate Professor Department of Family Medicine Duluth School of Medicine University of Minnesota Duluth, MN

Robert A. Bonomo, MD Associate Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Section Chief, Louis Stokes VA Medical Center Case Western Reserve University Cleveland, OH

Richard H. Beigi, MD, MSc Assistant Professor of Reproductive Biology Department of OB/GYN University of Pittsburgh Medical Center Pittsburgh, PA

Rebecca A. Brady, PhD Research Associate Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore, MD

Anthony Berendt, MD Medical Director & Consultant Physicianin-Charge Bone Infection Unit Nuffield Orthopaedic Centre Headington, Oxford, United Kingdom

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Contributors

Itzhak Brook, MD, MSc Professor of Pediatrics & Medicine Georgetown University Georgetown University School of Medicine Washington, DC Jason H. Calhoun, MD J. Vernon Luck Distinguished Professor Chair, Department of Orthopaedics University of Missouri Columbia, MO Rafael E. Campo, MD Associate Professor of Medicine Leonard M. Miller School of Medicine University of Miami Associate Director for Inpatient Services Infectious Diseases Research Unit Jackson Memorial Hospital Miami, FL David Canaday, MD Assistant Professor of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH Joseph C. Chan, MD Associate Professor of Medicine Leonard M. Miller School of Medicine University of Miami Mt. Sinai Medical Center Miami Beach, FL Jason W. Chien, MD Assistant Professor of Medicine University of Washington Fred Hutchinson Cancer Research Center Seattle, WA Gordon Christensen, MD, FACP Professor of Medicine University of Missouri-Columbia School of Medicine Columbia, MO Catherine Markin Colecraft, MD Dorn VA Medical Center Primary Care/Subspecialty Medicine Columbia, SC Blaise L. Congeni, MD Professor of Pediatrics Professor of Microbiology & Immunology

Northeastern Ohio Universities College of Medicine Children’s Hospital Medical Center Akron, OH Curtis J. Donskey, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Louis Stokes VA Medical Center Cleveland, OH J. Stephen Dumler, MD Professor of Pathology Department of Pathology Division of Medical Microbiology The Johns Hopkins University School of Medicine Baltimore, MD Jack Ebright, MD, FACP Associate Professor of Internal Medicine Wayne State University School of Medicine Detroit, MI James Fanning, DO Chairman, Department of Obstetrics & Gynecology Medical Director, Women’s Health Services Summa Health System Akron, OH Bradford W. Fenton, MD, PhD, FACOG Faculty, Department of Obstetrics & Gynecology Summa Health System Northeastern Ohio Universities College of Medicine Comprehensive Women’s Specialty Physicians Akron, OH Thomas M. File, Jr., MD, MSc, MACP Professor of Internal Medicine Northeastern Ohio Universities College of Medicine Chief, Infectious Diseases Service Summa Health System Akron, OH Robert F. Flora, MD, MBA Residency Program Director Head, Urogynecology & Reconstructive Pelvic Surgery

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Contributors

Summa Health System Associate Professor of Obstetrics & Gynecology Vice Chair, Clinical Associate Professor of Urology Northeastern Ohio Universities College of Medicine Akron, OH Scott A. Fulton, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH William G. Gardner, MD, MACP Consulting Professor in Community and Family Medicine Duke University Director of Internal Medicine Duke Southern Regional AHEC Family Medicine Residency Durham, NC K.V. Gopalakrishna, MD, FACP Chair, Department of Medicine Chief, Infectious Diseases Fairview Hospital Associate Clinical Professor Case Western Reserve University Clinical Professor & Chairman Ohio State University Department of Medicine Chief, Infectious Diseases Fairview General Hospital Cleveland, OH Barbara M. Gripshover, MD Associate Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH Daniel P. Guyton, MD Professor and Chairman, Department of Surgery Northeastern Ohio Universities College of Medicine Chairman, Department of Surgery

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Akron General Medicine Center Akron, OH Jennifer A. Hanrahan, MD Assistant Professor of Medicine Division of Infectious Diseases Case Western Reserve University MetroHealth Medical Center Cleveland, OH John L. Johnson, MD Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine Tuberculosis Research Unit Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH Warren S. Joseph, DPM, FIDSA VA Medical Center - Coatesville, PA Huntingdon Valley, PA Carol A. Kauffman, MD, FACP Chief, Infectious Diseases Veterans Affairs Ann Arbor Professor of Internal Medicine University of Michigan VA Medical Center Ann Arbor, MI Charles H. King, MD, FACP Associate Professor of International Health Center for Global Health and Diseases Case Western Reserve University School of Medicine Cleveland, OH Richard B. Kohler, MD, MACP Vice Chair for Education Professor of Medicine Department of Medicine Indiana University School of Medicine Indianapolis, IN Donald P. Levine, MD, FACP Professor of Medicine Chief, General Internal Medicine Wayne State University Health Center Detroit, MI Michelle V. Lisgaris, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases & HIV Medicine

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Contributors

Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

Carlos R. Ramírez-Ramírez, MD Infectious Diseases Consultant Pavia Hospital San Juan, PR

Scott Mahan, MD Assistant Professor of Medicine Department of Medicine Division of Infectious Diseases Case Western Reserve University MetroHealth Medical Center Cleveland, OH

Carlos H. Ramírez-Ronda, MD, MACP Professor of Medicine University of Puerto Rico School of Medicine Department of Medicine San Juan VA Medical Center San Juan, PR

Thomas J. Marrie, MD, MACP Dean, Faculty of Medicine & Dentistry University of Alberta Edmonton, Alberta Canada

Allan R. Ronald, MD, FRCPC, MACP Section of Infectious Diseases St. Boniface General Hospital Winnipeg, Canada

Farid F. Muakkassa, MD, FACS Professor of Surgery Northeastern Ohio Universities College of Medicine Chief, Trauma/Surgical Critical Care Akron General Hospital Akron, OH

Heather Rupe, DO Chief Resident Department of Obstetrics & Gynecology Summa Health System Northwestern Ohio Universities College of Medicine Akron, OH

Joseph P. Myers, MD, FACP Chair, Department of Medicine Summa Health System Professor of Internal Medicine Infectious Diseases Section Northeastern Ohio Universities College of Medicine Akron, OH

Robert A. Salata, MD, FACP Professor and Vice Chair Department of Medicine Chief, Division of Infectious Diseases & HIV Medicine Case Western Reserve University University Hospitals Case Medical Center Cleveland, OH

Michael S. Niederman, MD, FACP Professor of Medicine SUNY at Stony Brook Chairman Department of Medicine Winthrop University Hospital Mineola, NY

Louis D. Saravolatz, MD, MACP Chair, Department of Internal Medicine St. John Hospital & Medical Center Detroit, MI

William C. Papouras, MD, FACS Clinical Assistant Professor of Surgery Director of Surgery Clerkship Northeastern Ohio Universities College of Medicine Akron General Medical Center Akron, OH

Mark E. Shirtliff, PhD Assistant Professor, Department of Biomedical Sciences Dental School Adjunct Professor Department of Microbiology and Immunology School of Medicine University of Maryland-Baltimore Baltimore, MD

Timothy R. Pasquale, PharmD Clinical Lead, Infectious Diseases Department of Pharmacy Summa Health System Akron, OH

Gary I. Sinclair, MD Assistant Professor of Medicine The University of Texas Southwestern Medical Center Dallas, TX

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Contributors

Lavinia F. Smultea, DO Infectious Disease Fellow Case Western Reserve University Cleveland, OH Jack D. Sobel, MD, FACP Professor of Medicine Chief Division of Infectious Diseases Wayne State University School of Medicine Harper Hospital Detroit, MI Dennis L. Stevens, MD, PhD, FACP Professor, Department of Medicine University of Washington, Seattle Chief, Infectious Diseases Section VA Medical Center Boise, ID James S. Tan, MD, MACP Professor and Vice Chairman of Internal Medicine Head, Infectious Diseases Section Northeastern Ohio Universities College of Medicine Chairman and Residency Director Department of Internal Medicine Summa Health System Akron, OH Michael J. Tan, MD, FACP Assistant Professor of Internal Medicine Northeastern Ohio Universities College of Medicine Summa Health System Akron, OH

Richard B. Thomson, Jr., PhD Professor of Pathology Director, Microbiology & Virology Laboratory Northwestern University Feinberg School of Medicine Evanston Hospital Evanston, IL Jose A. Vasquez, MD, FACP, FIDSA Professor of Medicine Henry Ford Hospital Senior Staff Wayne State University School of Medicine Detroit, MI Arjun Venkataramani, MD, MPH Assistant Professor of Internal Medicine Northeastern Ohio University College of Medicine Akron, OH Kathryn Wright, MD Resident Summa Health System Akron City Hospital Akron, OH Mohamed Yassin, MD, MBBS Attending Physician Maryland General Hospital Internal Medicine Department Infectious Diseases Section University of Maryland Baltimore, MD

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Preface to the First Edition

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he purpose of this newest volume in the ACP Expert Guide series is to provide up-to-date information on common infectious diseases encountered in the office of the primary care physician. Infections comprise a sizable proportion of the common, and less common, diseases seen in the office as well as in the hospital. Physicians are expected to know not only the basic clinical manifestations of each infection but also the names of the etiologic agents, the new diagnostic tests, and the new therapies. With the number of new antimicrobial agents increasing yearly, it has been ever more difficult for practicing physicians to distinguish and master all the treatments and therapies that could be useful to their patients. Many physicians have not kept up with advances in clinical microbiology since their graduation from medical school. The first chapter introduces the proper use of clinical microbiology and discusses some of the recent advances in diagnostic techniques. The most appropriate and practical diagnostic tests for the more commonly encountered diseases are reviewed. Richard Thomson, a clinical microbiologist with extensive experience, was asked to write this chapter because of his ability to clearly convey clinical microbiology information to the practicing physician. The discussion of individual diseases begins with common central nervous system infections, with emphasis on bacterial infections such as meningitis and brain abscess. Two chapters are then devoted to heart and vascular infections. The first, on endocarditis, was written by Chatrchai Watanakunakorn, one of the most active researchers in this field. Sadly, this close friend and colleague passed away in July 2001. Because of the increased use of vascular devices, the second chapter in this section considers native vascular and device-associated infections. Infections in the gastrointestinal tract, including diarrhea, hepatitis, and surgical diseases, continue to be commonly encountered in the primary care practice, and five chapters are devoted to them here. The following xiii

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section focuses on genitourinary infections, including sexually transmitted diseases and papillomavirus, the latter meriting a separate chapter because of its increasing importance in the detection of cervical cancer. Respiratory tract infections are one of the most common reasons for prescription of antimicrobial agents in the United States. Itzhak Brook, Thomas Marrie, and Thomas File, all members of guidelines committees of important medical societies, were among the contributors to this section, the longest in the book. Bone infections and skin infections are commonly seen in patients; however, diagnosis does not always come easy. Without intending to be exhaustive, the chapters in these two sections provide important principles that will guide physicians in their management of these problems. HIV infection is one of leading causes of death in the world. Because of rapid advances in the diagnostic and therapeutic fields, the clinician is urged to consult the most recent literature and specialists in treating HIV patients. Our purpose herein has been to give the basic information the physician needs to manage the patient with this infection. Opportunistic fungal, mycobacterial, viral, and Pneumocystis infections are next reviewed. The final two chapters discuss Lyme disease (included because of its prevalence in certain geographic areas of the United States) and malaria (representing the parasitic infections). The authors have written with clarity and conciseness. For the convenience of the reader, helpful tables on diagnosis and treatment recommendations have been provided throughout the text. Expert Guide to Infectious Diseases cannot be the final word on a subject so vast. Its aim is more modest but of equal importance: to be the best source for the essential information sought by the primary care physician. James S. Tan, MD

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Preface to the Second Edition

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s co-editors of the Expert Guide to Infectious Diseases, second edition, we are honored to contribute to an update of the first edition that was so expertly edited by James Tan, MD, MACP. Sadly, Jim passed away in May 2006; a brief description of some of his many accomplishments is included on the In Memoriam page. At the time of his passing, Jim was actively supervising this second edition, and he kindly asked us to assist with its completion. We are pleased and privileged to have done so, and believe we have preserved Jim’s desire for a concise, complete guide for the primary care physician. As stated in the Preface to the first edition, the primary purpose of this volume of the ACP Expert Guide series is to provide up-to-date information on common infectious diseases encountered within the office and hospital setting by the practicing primary care physician. We have added Key Learning Points to every chapter, and separate New Developments boxes highlighting important changes and advances within each subject area that have particular relevance for the primary care provider. Additionally, we have created a large Appendix that summarizes, in convenient table form, recommended antimicrobial therapy for the most common pathogens and infections discussed within this book. The compilation of this table was largely done by one of the contributing authors, Tim Pasquale, PharmD, to whom we are very grateful. We feel this appendix provides an easy-to-use, quick reference for all practitioners in primary care practice. We thank all of the contributing authors for their expertise and excellent discussions. We are confident that this new edition of Expert Guide to Infectious Diseases will be a useful source of essential infectious disease

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information for primary care practitioners and help them provide the best care for their patients. We wish to thank Betty Loucks for her administrative assistance for this, as well as the first edition. TMF, Jr. RAS MJT

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Contents

PA R T I

ANTIMICROBIALS AND L A B O R AT O R Y T E S T S

1. Antimicrobial Agents for the Primary Care Physician. . . . . . . . . . 3 Timothy R. Pasquale and James S. Tan 2. Use of Microbiology Laboratory Tests in the Diagnosis of Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . 15 Richard Thomson, Jr.

PA R T I I

CENTRAL NERVOUS SYSTEM INFECTIONS

3. Bacterial Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Carlos H. Ramírez-Ronda and Carlos R. Ramírez-Ramírez 4. Viral Meningitis and Viral Encephalitis . . . . . . . . . . . . . . . . . . . 80 K.V. Gopalakrishna and Manmeet S. Ahluwalia 5. Brain Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Scott A. Fulton and Robert A. Salata

PA R T I I I

HEART

AND

VA S C U L A R I N F E C T I O N S

6. Infective Endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Jack Ebright and Donald P. Levine 7. Vascular Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Louis D. Saravolatz

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PA R T I V

GASTROINTESTINAL INFECTIONS

8. Infectious Diarrhea and Gastroenteritis . . . . . . . . . . . . . . . . . 143 Keith B. Armitage and Robert A. Salata 9. Biliary Tract Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 Lavinia F. Smultea and Curtis J. Donskey 10. Viral Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 Hector Bonilla and Arjun Venkataramani 11. Peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204 Jennifer A. Hanrahan and Robert A. Bonomo 12. Intra-Abdominal Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Farid F. Muakkassa, William C. Papouras, and Daniel P. Guyton

PA R T V

GENITOURINARY INFECTIONS

13. Urinary Tract Infections in Adults . . . . . . . . . . . . . . . . . . . . . 245 Allen R. Ronald 14. Prostatitis and Epididymitis . . . . . . . . . . . . . . . . . . . . . . . . . 266 Keith B. Armitage and Catherine Markin Colecraft 15. Common Sexually Transmitted Diseases . . . . . . . . . . . . . . . . 284 Richard Beigi and Barbara M. Gripshover 16. Pelvic Inflammatory Disease . . . . . . . . . . . . . . . . . . . . . . . . 313 Robert F. Flora, Heather Rupe, and James Fanning 17. Vaginitis and Cervicitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 J. D. Sobel 18. Papilloma Virus and Cervical Cancer . . . . . . . . . . . . . . . . . . 352 James Fanning, Kathryn Wright, Bradford W. Fenton, and Robert F. Flora

PA R T V I

R E S P I R AT O R Y T R A C T I N F E C T I O N S

19. Pharyngotonsillitis, Peritonsillar, Retropharyngeal, and Parapharyngeal Abscesses, and Epiglottitis . . . . . . . . . . . . . . 365 Itzhak Brook

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20. Sinusitis and Otitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 David H. Canaday and Robert A. Salata 21. Acute Bronchitis and Exacerbations of Chronic Bronchitis . . . 401 Richard B. Kohler and James S. Tan 22. Influenza and Other Viral Respiratory Tract Infections. . . . . . 417 Jason W. Chien and John L. Johnson 23. Community-Acquired Pneumonia . . . . . . . . . . . . . . . . . . . . . 450 Thomas J. Marrie 24. Nosocomial Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 Thomas M. File, Jr. and Michael Niederman 25. Tuberculosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495 Scott Mahan and John J. Johnson

PA R T V I I

DEEP FUNGUS INFECTIONS

26. Blastomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 Carol A. Kauffman 27. Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527 Carol A. Kauffman 28. Coccidioidomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 Carol A. Kauffman 29. Histoplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Carol A. Kauffman 30. Aspergillosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559 Jose A. Vasquez

PA R T V I I I

SKIN, BONE INFECTIONS

AND

JOINT

31. Septic Athritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581 William G. Gardner 32. Prosthetic Joint Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . 599 Anthony R. Berendt

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33. Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 Jason H. Calhoun, Rebecca A. Brady, and Mark E. Shirtliff 34. Superficial Skin Infections (Pyodermas) . . . . . . . . . . . . . . . . 629 Thomas M. File, Jr. and Dennis L. Stevens 35. Necrotizing Soft Tissue Infections. . . . . . . . . . . . . . . . . . . . . 643 Thomas M. File, Jr. and Dennis L. Stevens 36. Foot Infections in Patients with Diabetes Mellitus . . . . . . . . . 663 Warren S. Joseph and James S. Tan 37. Bite-Wound Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680 Joseph P. Myers 38. Viral Exanthems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699 Blaise L. Congeni

PA R T I X

I M M U N O C O M P R O M I S E D - R E L AT E D INFECTIONS

39. HIV Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723 Joseph C. Chan and Rafael E. Campo 40. Opportunistic Infections in Patients with AIDS . . . . . . . . . . . 760 Michael J. Tan 41. Opportunistic Infections in the Immunocompromised Host . . 777 David A. Bobak and Robert A. Salata 42. Herpes Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800 Michelle V. Lisgaris and Gary I. Sinclair

PA R T X

MISCELLANEOUS INFECTIONS

43. Tick-Borne Infections: Lyme Borreliosis, Ehrlichiosis and Anaplasmosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833 Johan S. Bakken and J. Stephen Dumler

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Contents

44. Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853 Keith B. Armitage and Charles H. King Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909

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Part I

Antimicrobials and Laboratory Tests

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Chapter 1

Antimicrobial Agents for the Primary Care Physician TIMOTHY R. PASQUALE, PHARMD JAMES S. TAN, MD

Key Learning Points 1. Several reports have described the association of patients receiving inappropriate antimicrobial therapy with increased morbidity and mortality. 2. Goal of antibiotic prophylaxis in surgical patients is to have drug concentrations in the serum and tissue exceeding the MIC of the organism likely to be encountered for the duration of the operation. 3. Appropriate empirical antimicrobial usage requires consideration of a number of factors, including knowledge of the most likely pathogens. 4. Pharmacokinetics is simply what the host does to the drug. 5. Pharmacodynamics is the relationship between concentration and pharmacological/toxicological effects of a drug. 6. A drug must not only reach the site of infection, but achieve adequate concentration in order for an optimal effect to occur. 7. The minimal inhibitory concentration (MIC) is a good predictor of the potency of an antimicrobial agent against an infecting organism, but does not always equate to treatment success. 8. The goal for optimal dosing in time-dependent agents (i.e., penicillins, cephalosporins, vancomycin, etc.) is to achieve drug concentration above the MIC for at least 40-50% of the dosing interval. 9. The goal for optimal dosing in concentration-dependent agents is to maximize the AUC/MIC ratio (i.e., fluoroquinolones) or the peak/MIC ratio (i.e., aminoglycosides). 3

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Expert Guide to Infectious Diseases

New Developments in Antimicrobial Therapy • An advisory statement from the National Surgical Infection Prevention Project recommends the first antimicrobial prophylactic dose should be given within 60 minutes before surgical incision, and the prophylactic antimicrobial should be discontinued within 24 hours after the end of surgery. • A recent review found that bactericidal antimicrobials are not considered superior to bacteriostatic agents except in certain infections such as endocarditis, meningitis, and neutropenia.

Antimicrobial Therapy Empirical Antimicrobial resistance is an ongoing problem that has plagued institutions over the last several decades. In addition, awareness of antimicrobial resistance in the community is increasing with the emergence of communityacquired methicillin-resistant Staphylococcus aureus infections. Over the last decade several reports described the association of patients receiving inappropriate antimicrobial therapy with increased morbidity and mortality (1-5). Inappropriate antimicrobial therapy is defined as failure to provide an antimicrobial agent with activity against the causative pathogen based on the results of in-vitro susceptibility testing (3). Considering these two significant factors, the issue of appropriate antimicrobial therapy has emerged to the forefront for clinicians. An appropriate empirical antimicrobial regimen requires a clinician to consider a number of factors. First, the antimicrobial agent chosen is based on the likelihood of a specific infection. Second, the clinician must have knowledge regarding the most likely pathogens that are encountered in the specific infection. Third, the clinician must have awareness to the most likely predicted susceptibility patterns of the pathogen. A fourth factor to consider is the characteristics of the host (e.g., site of infection, age, renal and hepatic function, pregnancy, and drug interactions). Finally, the characteristics of the drug—concentration-dependent killing, time-dependent killing, bactericidal versus bacteriostatic, route of administration, and halflife—should be taken into consideration. Recommended antimicrobial regimens for adults for specific infections are listed in the Appendix. These recommendations were obtained from the chapters within this edition of the Expert Guide to Infectious Diseases.

Antimicrobials for Surgical Prophylaxis Surgical site infections remain a common cause of nosocomial infections and are associated with increased morbidity and mortality. Primary care physicians often have patients that have surgery and require preventative

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antimicrobial therapy. The goal of antibiotic prophylaxis in surgical patients is to have drug concentrations in the serum and tissue exceeding the MIC of the organism likely to be encountered for the duration of the operation (6). Appropriate selection and timing of antimicrobial prophylaxis in surgical patients is crucial. Recommendations for antibiotic prophylaxis in patients undergoing common surgical procedures are listed in Table 1-1.

Table 1-1 Recommendations for Antibiotic Prophylaxis for Common Surgical Procedures (6, 25-27). Type of Surgery

Common Pathogens

Prophylaxis1

Cardiothoracic Surgery

Prosthetic valve, coronary Staphylococcus aureus artery bypass, other Staphylococcus epidermidis open-heart surgery, pacemaker, or defibrillator

Cefazolin 1-2 g IV2 or cefuroxime 1.5 g IV2 or vancomycin 1 g IV3 or clindamycin 600-900 mg IV

Gastrointestinal Surgery

Esophageal, gastroduodenal6 Biliary tract Colorectal

Appendectomy, nonperforated

Enteric gram-negative bacilli, Cefazolin 1-2 g IV4 gram-positive cocci Enteric gram-negative bacilli, Cefazolin 1-2 g IV5 enterococci, clostridia Enteric gram-negative bacilli, Oral: neomycin plus enterococci, anaerobes erythromycin base7 Parenteral: cefoxitin or cefazolin 1-2 g IV + metronidazole 500 mg IV Enteric gram-negative bacilli, Cefoxitin 1-2 g IV enterococci, anaerobes

Gynecologic and Obstetric

Vaginal or abdominal hysterectomy Cesarean section

Enteric gram-negatives, Cefazolin 1-2 g IV or anaerobes, group B cefoxitin 1-2 g IV or streptococcus, enterococci cefotetan 1-2 g IV Enteric gram-negatives, High risk only8: cefazolin anaerobes, Group B 1-2 g IV after cord

clamping Abortion

Streptococcus, enterococci Enteric gram-negatives, First trimester, high risk9: anaerobes, group B penicillin G 2 million streptococcus, enterococci units IV or doxycycline 300 mg PO10 Second trimester: cefazolin 1 g IV

Head and Neck Surgery

Incisions through oral or pharyngeal mucosa

S. aureus, enteric gramClindamycin 600-900 mg negative bacilli, anaerobes IV + gentamicin 1.5 mg/kg IV or cefazolin 1-2 g IV Continued

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Table 1-1 Continued Type of Surgery

Common Pathogens

Prophylaxis1

Neurosurgery

Craniotomy, cerebrospinal S. aureus, S. epidermidis fluid shunting

Cefazolin 1-2 g IV or vancomycin 1 g IV3

Ophthalmic Surgery

S. epidermidis, S. aureus, Topical gentamicin, streptococci, enteric gramtobramycin, ciprofloxacin, negative bacilli, ofloxacin, or neomycinPseudomonas species gramicidin-polymyxin B (multiple drops topically over 2 to 24 hours) or cefazolin 100 mg subconjunctivally Orthopedic Surgery

Total joint replacement, internal fixation of fractures

S. aureus, S. epidermidis

Cefazolin 1-2 g IV or vancomycin 1 g IV3

S. aureus, S. epidermidis

Cefazolin 1-2 g IV or cefuroxime 1.5 g IV or vancomycin 1 g IV3 + gentamicin 3 mg/kg IV

S. aureus, S. epidermidis, Streptococci, enteric gram-negative bacilli

Cefazolin 1-2 g IV or cefuroxime 1.5 g IV or vancomycin 1 g IV3

Spine Surgery

Thoracic (noncardiac)

Pulmonary surgery

Vascular Surgery

Arterial surgery S. aureus, S. epidermidis involving a prosthesis, enteric gram-negative the abdominal aorta, bacilli or a groin incision Lower extremity S. aureus, S. epidermidis amputation for ischemia enteric gram-negative bacilli, Clostridia

Cefazolin 1-2 g IV or vancomycin 1 g IV3

Cefazolin 1-2 g IV or vancomycin 1 g IV3

Urologic Surgery

High-risk patients only: Enteric gram-negative Urine culture positive bacilli, enterococci or unavailable, presence of preoperative urine catheter, or transrectal biopsies

Ciprofloxacin 500 mg PO or 400 mg IV

Contaminated Surgery11

Ruptured viscus

Enteric gram-negative bacilli, Cefoxitin 1-2 g q 6 h IV or anaerobes, enterococci cefotetan 1-2 g q 12 h IV ± gentamicin 1.5 mg/kg q8h Continued

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Table 1-1 Continued Type of Surgery

Traumatic wound

Common Pathogens

S. aureus, group A streptococcus, Clostridia

Prophylaxis1

IV or clindamycin 600 mg q 6 h IV + gentamicin 1.5 mg/kg q 8 h IV Cefazolin 1-2 g IV q 8 h

Abbreviations: IV, intravenous; PO, orally; q, every. 1. Recommended for prophylactic antibiotics to be given as a single intravenous dose completed 30 minutes or less before operation. Additional intraoperative doses should be given every 4 to 8 hours for the duration of the operation. 2. An additional dose when patients are removed from bypass during surgery is recommended. 3. Recommended only when methicillin-resistant S. aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) are a frequent cause of wound infection. 4. Recommended for high-risk patients such as those with morbid obesity, esophageal obstruction, decreased gastric acidity, or gastrointestinal motility. 5. Recommended for high-risk patients such as those older than 70 years of age, or with acute cholecystitis, nonfunctioning gallbladder, obstructive jaundice, or common duct stones. 6. Placement of percutaneous endoscopic gastrostomy (PEG) tube. 7. After appropriate diet and catharsis, one gram of each at 1 p.m., 2 p.m., and 11 p.m. the day before an 8 a.m. operation. 8. Active labor or premature rupture of membranes. 9. Patients with previous pelvic inflammatory disease, previous gonorrhea, or multiple sex partners. 10. Divided into 100 mg 1 hour before the abortion and 200 mg 30 minutes after. 11. Antimicrobial agents for these operations are considered therapy rather than prophylaxis and should be continued postoperatively for several days.

Pharmacokinetics and Pharmacodynamics Over the past several decades, knowledge of the interactions between antimicrobial agents and the microbes in the host has become clearer. In order for an antimicrobial agent to exert its effect on the bacterial cell, the antimicrobial must have the ability to reach the target site, achieve adequate concentration at the site, and remain there for a sufficient time to accomplish its mission. This drug-host-microbe system is very complex and involves the interaction of multiple factors. Two distinct components of this drug-host system are pharmacokinetics and pharmacodynamics. Pharmacokinetics involves the absorption, distribution, metabolism, and excretion of a drug or simply what the host does to the drug. Pharmacodynamics encompasses the relationship between serum concentrations as well as tissue concentrations and the pharmacological and toxicological effects of the drug on the host and microbe. In simple terms, pharmacodynamics is what the drug does in the host to the bacteria. The integration of these principles can be used to optimize dosing to maximize the clinical efficacy of antimicrobials and minimize any potential adverse toxicities. A brief review of the general principles of pharmacokinetics and pharmacodynamics and their clinical application will be provided.

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Pharmacokinetics Absorption Absorption of a drug is a dynamic process that occurs at different sites of administration (e.g., intramuscular, subcutaneous, topical, rectal, or oral) other than a physiologic fluid component (e.g., intravenous). The rate and extent of absorption can vary among different drugs and different formulations of the same drug. The percentage of the total amount of drug that reaches systemic circulation is the drug bioavailability. The route of administration can have a significant affect on the bioavailability of a medication. A drug administered via intravenous tends to have a 100% bioavailability, although drugs administered via other routes such as oral, intramuscular, subcutaneous, and rectal have reduced bioavailability (<100%). Other factors affecting the bioavailability of a drug include the nature of the drug (e.g., solubility), physiologic environment (e.g., pH, gastrointestinal motility), first-pass effect, drug-metabolizing enzymes in the gastrointestinal tract, induction/inhibition of transport proteins in the gastrointestinal tract, drug interactions with other compounds or food, or disease state (e.g., diarrhea, ileus). First-pass effect is the process when an orally administered drug must pass through the intestinal epithelium, portal venous system, and the liver prior to entering the systemic circulation. At each of these sites, drug bioavailability can be reduced. Medications administered via other routes (such as intramuscular or intravenous) usually are not associated with firstpass effect. Volume of Distribution After a drug reaches systemic circulation, the drug is distributed throughout the body. Volume of distribution (Vd) is the theoretical value that relates drug concentration in the body to the amount of drug present in the body, depending on the fluid measured. In a typical patient weighing 70 kg (154 lb), the approximate plasma volume is 3 L, blood volume is 5.5 L, extracellular fluid volume outside the plasma is 12 L, and the volume of total body water is 42 L (7). The volume of distribution is an important pharmacokinetic term in determining appropriate drug dosing regimens including the loading doses of medications and half-life. Although Vd lacks a physiologic significance, it can indicate the extent of drug distribution in the body. Drugs that have small Vd, that is 10 to 20 L, such as aminoglycosides, indicate distribution into extracellular fluid (8). Drugs such as linezolid, fluoroquinolone, macrolide, ketolides, and rifampin that have large Vd, that is, more than 40 L, indicate that they have wide tissue distribution, however, it does not indicate specific tissues to which the drug has distributed (8). Generally, the dosing is considered to be proportional to the Vd. The larger the Vd, the larger dose that is required to achieve target concentrations. Several factors influence the Vd of a drug including lipid solubility, pH, and binding to biological material, for example, plasma proteins. Protein

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binding can be an important factor that can affect the pharmacokinetics of a medication. When clinical or reference laboratories report the drug concentration, this represents the total concentration of the antimicrobial whether it is free drug or bound to plasma proteins (9). The free or unbound drug is the pharmacologic active portion that is responsible for the antimicrobial microbiologic activity. For most antimicrobials, the issue of protein binding is not significant because either they are not highly protein bound or the binding is dissociable.

Clearance Another important pharmacokinetic parameter is clearance. Clearance can be defined as the removal from plasma per unit of time (9). Drugs can be cleared from the plasma by many different mechanisms, pathways, or organs including hepatic metabolism and renal and/or biliary excretion. Hepatic metabolism involves phase I and phase II reactions. Phase I reactions have the ability to inactivate, activate, or convert an active compound into another active compound with activity that is higher, lower, or equal to the parent compound. Phase I reactions involve the cytochrome P-450 system. Cytochrome P-450 enzymes (CYPs) are affected by many factors that can stimulate or inhibit their ability to metabolize drugs (8). These factors include genetic or polymorphism, indicating that individuals can vary in their genetic ability to metabolize CYP substrates. Other factors can include sex, age, disease state, food, and drugs (8). Certain drugs can have a significant impact on the metabolism of other medications by either inhibiting (e.g., amiodarone, clarithromycin, erythromycin, fluconazole, itraconazole, isoniazid, HIV protease inhibitors) or inducing (e.g., rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital) their metabolism. This can have a significant impact on antimicrobial therapy as it can lead to failure of therapy, development of resistance, or potential toxic effects. Phase II reactions involve conjugation of the parent compound with large molecules, and the end result increases the polarity of the parent compound for excretion (8). Elimination of a drug from the host occurs via two main mechanisms, renal and nonrenal excretion. Renal excretion can involve several pathways through the kidney including glomerular filtration, tubular secretion, and passive diffusion. Excretion can occur via one or more of these pathways depending on the saturation of another pathway by the drug. For example, some factors that can enhance or decrease the renal excretion of some drugs include kidney function, dialysis, disease states, and age. Nonrenal clearance generally involves the sum of pathways that do not include the kidney. Examples of nonrenal clearance include ceftriaxone via the biliary tree and azithromycin via the intestines. Half-Life The general definition of the half-life of a drug is the amount of time required for the plasma concentration of the drug to decrease by half.

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Half-life is dependent on the clearance and volume of distribution and can vary with each drug and from patient to patient. The half-life of a drug can be as short as minutes or as long as days. It is suggested that steady-state concentration of a drug has been achieved when the drug has been administered for a period equal to at least five to seven half-lives of the drug. However, a drug is considered to have been eliminated when five to seven half-lives have passed since the final dose of the drug. Factors that can affect the half-life of a drug include renal and hepatic function and protein binding.

Pharmacodynamics Antimicrobial Activity There are several factors that can be used to quantify the antimicrobial activity or potency of antimicrobial agents. First, antimicrobials can be categorized arbitrarily as bacteriostatic or bactericidal. The generally accepted definition for an agent to be considered bactericidal is that a greater than or equal to 99.9% reduction in the colony-forming units in an 18- to 24-hour period must occur (10). Any agent that achieves less reduction is considered static. Agents can be cidal to certain bacteria and static to another bacteria. Agents can be considered bactericidal or bacteriostatic depending on their mechanism of action (8). For example, agents that typically interfere with the development of the bacterial cell wall or membrane (e.g., penicillins, cephalosporins, carbapenems, vancomycin, and daptomycin) result in cell lysis and death. Agents that interfere with nucleic acid (e.g., quinolones) or protein synthesis (e.g., aminoglycosides, macrolides-azalides-ketolides) also lead to cell death. Agents that interfere with folic acid synthesis (e.g., sulfonamides) can only inhibit bacterial growth. Antimicrobials can produce a static effect at a low concentration, but produce a cidal effect at higher concentration (8). However, there is no antimicrobial agent that is considered bactericidal that kills every microorganism, nor is there an antimicrobial agent that is considered bacteriostatic that doesn’t kill bacteria. Agents with in-vitro bactericidal activity are not considered to be superior to those agents with in-vitro bacteriostatic activity except in certain clinical situations (such as endocarditis, meningitis, and neutropenia) where a cidal agent would be preferred (10). A second factor that plays a role in quantifying the activity of an antimicrobial agent is the MIC. The MIC that is most commonly reported for bacterial organisms is MIC90, which is the minimal concentration that is required to inhibit 90% of the bacterial isolates for that particular bacterial organism. The MIC is a good predictor of the potency of an antimicrobial agent against an infecting organism, but not the time course of activity (11). It is important to consider the limitations of using the MIC as a gauge of antimicrobial action. First, MIC is determined in an in-vitro environment with a standard bacterial inoculum (105 colony-forming unit [CFU]/mL) that cannot correspond to bac-

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terial inoculum at the site of infection, nor the phase of growth of the bacterial organism (12). Second, a consistent drug concentration throughout the incubation period is used, and the various pharmacokinetic issues that can affect the drug concentration at the site or the varying drug concentrations occurring in vivo are not considered (12). Susceptibility does not always equate to treatment success, however, resistance can predict failure. A third factor that can be considered in determining the activity of an antimicrobial agent is postantibiotic effect (PAE), which is considered when there is a persistent suppression of bacterial growth following the removal of the antimicrobial agent. PAE is observed with most antimicrobial-bacteria combinations and is dependent on the antimicrobial agent and the bacteria. For example, long-term PAEs are induced against susceptible bacteria by protein and nucleic acid synthesis inhibitors, such as aminoglycosides, fluoroquinolones, tetracycline, clindamycin, and rifampin (12). Agents that are active against the cell wall, such as beta-lactams and vancomycin, induce a PAE of approximately 2 hours against staphylococci, and do not induce or induce a very short PAE against most gram-negative bacilli (12). Another factor to consider in the antimicrobial activity is the inoculum effect. The rate and extent of bactericidal action, the MIC, and the duration of PAE can be dependent on the bacterial density that is present (12). The inoculum effect is greater for some antimicrobials than others. For example, beta-lactam agents are known to have a bactericidal effect on organisms that are rapidly dividing. In more established or advanced stages of infections the bacteria density is high, and the bacteria are in a stationary phase of growth; the bacteria are generally less susceptible to beta-lactams because they are not actively multiplying (stationary phase). As for fluoroquinolones, they display bactericidal activity against organisms that are rapidly growing as well as in the stationary phase of growth.

Types of Antibacterial Killing Antimicrobial agents can be classified as to whether they exhibit timedependent killing or concentration-dependent killing. Time-dependent killing refers to the amount of time it takes to kill a pathogen by exposure to an antimicrobial agent. As a rule, time-dependent agents include penicillin, cephalosporins, carbapenems, aztreonam, vancomycin, macrolides, linezolid, and clindamycin (8,13,14). The major pharmacodynamic parameter that correlates with clinical and bacteriologic efficacy is time greater than minimum inhibitory concentration (T > MIC) (11). These agents are most effective when the serum drug concentrations remain greater than the MIC of the infecting bacteria (11). The efficacy of these agents is not greatly enhanced by increasing drug concentrations above the minimal bactericidal concentration (11). However, when drug concentrations at the site of infection fall below the MIC, residual bacterial populations can regrow quickly (especially for beta-lactams because they lack or have no PAE) (11). The

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rate and extent of killing stays essentially constant once the concentration is approximately four times the MIC of the pathogen. The efficacy of these agents can be maximized by the dosing to ensure the optimal duration of drug exposure. The optimal time to be above the MIC is variable depending on the pathogen, infection site, and drug. Studies done in animal infection models show that antibiotic concentrations do not have to exceed the MIC for 100% of the dosing interval. It is generally accepted that the T > MIC be at least 40% to 50% of the dosing interval for optimal effect (13,15). The relationship between efficacy and the T > MIC in clinical situations was assessed. The bacteriologic cure for beta-lactam antibiotics against Streptococcus pneumoniae and Haemophilus influenzae was evaluated in patients with acute otitis-media infections. These studies demonstrated a T > MIC of greater than 40% was necessary to achieve an 85% to 100% bacteriologic cure rate (11,16-19). The principle in using timedependent killing agents is to maintain levels above the MIC for at least 40% to 50% of the time between dosing intervals. This can be achieved with continuous infusion, extended infusion (e.g., extending the infusion time of the agent given intermittently from 30 minutes to 3 hours), or using drugs with long half-lives. Agents that exhibit concentration-dependent killing include aminoglycosides, fluoroquinolones, azalide, ketolides, and metronidazole. The goal of therapy for these agents is to maximize the concentration and attain the highest concentration possible at the site of infection without producing toxicity. The greater the concentration above the MIC, the greater killing these agents produce. Two good parameters to indicate the extent of antibiotic exposure or maximal concentration are the area under the serum concentration curve (AUC) and peak drug concentration as they are dependent on dose, absorption, and clearance of a drug. The pharmacodynamic parameters that correlate with clinical and bacteriologic efficacy are the 24-hour AUC to MIC ratio (AUC:MIC), or peak drug concentration to MIC ratio (peak:MIC). There are two pharmacodynamic parameters associated with the aminoglycosides. Animal and in-vitro models show the 24-hour AUC to MIC ratio as an important parameter (20). The 24-hour AUC:MIC ratio of 80:100 produced maximum effects against a strain of Escherichia coli (20). Although, the pharmacodynamic parameter generally accepted to be associated with aminoglycosides is the peak:MIC ratio. Several studies supported the correlation between peak:MIC ratio and clinical efficacy. Kashuba and others demonstrated in patients with nosocomial pneumonia caused by gram-negative bacteria that a peak:MIC ratio of 10 or greater within the first 48 hours of aminoglycoside therapy was associated with a 90% probability of a therapeutic response by day 7 (21). The aminoglycosides are also associated with adaptive resistance (22). A short-term decrease in drug uptake and bactericidal activity of bacteria occurs when it is initially exposed to low drug concentrations. Thus, the

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goal of aminoglycosides is to optimize the dosage to produce higher drug concentrations. The 24-hour AUC:MIC ratio is the best pharmacodynamic parameter associated with efficacy of fluoroquinolones. The targeted AUC:MIC ratio for fluoroquinolones varies for gram-positive and gram-negative pathogens. For gram-negative pathogens, the accepted AUC:MIC ratio is greater than or equal to 125. Forrest and others demonstrated that a 24-hour AUC:MIC ratio of greater than or equal to 125 was associated with a satisfactory outcome for seriously ill patients treated with intravenous ciprofloxacin (23). Lower values resulted in clinical and bacteriologic cure rates at less than 50% (22). In addition, AUC:MIC ratios of less than 100 are associated with the development of antimicrobial resistance (24). For gram-positive pathogens (specifically Streptococcus pneumoniae), an AUC:MIC of 30 is the breakpoint that is generally accepted to maximize killing and minimize the development of resistance (12,14,15). The principle in using concentration-dependent killing agents is to give a high-dose bolus of the agent at a twice- or once-a-day interval depending on the drug.

Summary The information to date suggests that the dose is not a good predictor of outcome. Pharmacokinetic and pharmacodynamic characteristics are probably a better predictor of outcomes as they play a vital role in the efficacy of antimicrobial therapy. Over the past several decades, knowledge of antimicrobials’ pharmacokinetic and pharmacodynamic properties has increased significantly and has provided a better understanding of the complex drug-host interaction that occurs. Pharmacokinetics and pharmacodynamics are two distinct components of this complex interaction, but go hand in hand with each other. A drug must not only reach the site of infection, but achieve adequate concentration at the site of infection for an optimal effect to occur. Most of the pharmacodynamic data available has been generated through the use of in-vitro models. More patient experience is warranted to validate the information that has been obtained from experimental models. REFERENCES 1. Leone M, Bourgoin A, Cambon S, Dubuc M,Albanèse J, Martin C. Empirical antimicrobial therapy of septic shock patients: adequacy and impact on the outcome. Crit Care Med. 2003;31:462-7. 2. Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, Matera J, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest. 1997;111:676-85. 3. Kollef MH, Sherman G,Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115:462-74. 4. Ibrahim EH, Sherman G,Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146-55.

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5. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36:53-9. 6. Surgical Infection Prevention Guidelines Writers Workgroup. Antimicrobial prophylaxis for surgery: an advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis. 2004;38:1706-15. 7. Wilkinson GR. Pharmacokinetics: The dynamics of drug absorption, distribution and elimination. In: Hardman JG, Limbird LE, Gilman AG, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001:3-30. 8. Amsden GW, Ballow CH, Bertino Jr. JS, Kashuba ADM. Pharmacokinetics and pharmacodynamics of anti-infective agents. In: Mandell G, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Disease. 5th ed. New York: Churchill Livingstone; 2000:271-81. 9. Nicolau DP, Quintiliani R, Nightingale CH. Antibiotic kinetics and dynamics for the clinician. Med Clin North Am. 1995 May;79(3):477-95. 10. Pankey GA, Sabath LD. Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of Gram-positive bacterial infections. Clin Infect Dis. 2004;38:864-70. 11. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-10; quiz 11-2. 12. Levison ME. Pharmacodynamics of antibacterial drugs. Infect Dis Clin North Am. 2000 Jun;14(2):281-91. 13. Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect. 2001;7:589-96. 14. Gunderson BW, Ross GH, Ibrahim KH, Rotschafer JC. What do we really know about antibiotic pharmacodynamics? Pharmacother. 2001;21(10 pt 2):302S-18S. 15. Craig WA. Does the dose matter? Clin Infect Dis. 2001;33(suppl 3):S233-7. 16. Howie V. Eradication of bacterial pathogens from middle ear infections. Clin Infect Dis. 1992;14(suppl 2):S209-11. 17. Klein JO. Microbiologic efficacy of antibacterial drugs for acute otitis media. Pediatr Infect Dis J. 1993;12:973-5. 18. Dagan R,Abramson D, Leibovitz E, et al. Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin. Pediatr Infect Dis. 1996;15:980-5. 19. Hoberman A, Paradise JL, Block S, Burch DJ, Jacobs MR, Balanescu MI. Efficacy of amoxicillin/clavulanate for acute otitis media: relation to Streptococcus pneumoniae susceptibility. Pediatr Infect Dis J. 1996;15:955-62. 20. Vogelman B, Gudmundsson S, Leggett J,Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis. 1988;158:831-47. 21. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43:623-9. 22. Rodvold KA. Pharmacodynamics of antiinfective therapy: Taking what we know to the patient’s bedside. Pharmacother. 2001;21(11 pt 2):319S-30S. 23. Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother. 1993;37:1073-81. 24. Schentag JJ, Gilliland KK, Paladino JA. What have we learned from pharmacokinetic and pharmacodynamic theories? Clin Infect Dis. 2001;32(suppl 1):S39-46. 25. Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther. 2001;43:92-7. 26. ASHP Therapeutic Guidelines on Antimicrobial Prophylaxis in Surgery. American Society of Health-System Pharmacists. Am J Health Syst Pharm. 1999;56:1839-88. 27. Brown EM, Pople IK, de Louvois J, et al for the British Society of Antimicrobial Chemotherapy Working Party on Neurosurgical Infections. Spine update: Prevention of postoperative infection in patients undergoing spinal surgery. Spine. 2004;29(8):938-45.

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Chapter 2

Use of Microbiology Laboratory Tests in the Diagnosis of Infectious Diseases RICHARD THOMPSON, JR., PHD

Key Learning Points 1. Communication of the suspected diagnosis with the microbiology lab will help the laboratory professional select appropriate media and look for particular organisms. 2. Available testing modalities are constantly changing; there should be open communication between the clinician and the laboratory to ensure appropriate tests are ordered and to explain nuances that are not conveyed through reporting. 3. Specimens submitted to the microbiology laboratory need to be collected on appropriate media and handled correctly while being delivered to the laboratory in a timely fashion. 4. Quality of the results will often depend on the quality of the specimen and clinical information submitted. 5. Interpretation of results by the clinician may vary, and clinical information must be taken into consideration. 6. Antigen detection, serology, and molecular assays can aid with diagnosis but negative results often will not be enough to exclude a diagnosis.

T

he microbiology laboratory has changed in recent years. Automation, the use of molecular testing, new or reemerging infectious diseases, regulation and cost controls, and consolidation of laboratory services has changed the face of microbiology. Medical school education has moved away from teaching lists of microorganisms and diseases that prepare future physicians for laboratory reports. In addition, primary care physicians and other laboratory users are too busy to keep up with the changing science 15

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New Developments in Laboratory Testing and Diagnosis • Many newer methods, including polymerase chain reaction and antigen detection, can aid in the detection of microorganisms. These methods may speed detection and diagnosis; however, they are not 100% sensitive. • Changes to the microbiology laboratory in recent years include more use of automation and molecular testing, more newly available diagnostic tests, and the increasing presence of new or reemerging infectious disease. These changes require the clinician to have open communication with the microbiology lab.

of laboratory testing. All these developments have resulted in widespread misunderstanding of laboratory testing. This chapter serves as a reminder and an update of important clinical microbiology principles that enable full and appropriate use of microbiology tests and test results. The laboratory diagnosis of infectious diseases requires the detection of etiologic microorganisms or antibodies specific for the etiologies. Microorganisms can be detected by staining and recognition of characteristic morphology and tissue histopathology, by culture and identification of the isolate, and by detection of antigens or nucleic acid (RNA or DNA) unique to the pathogen. Serologic testing for specific antibodies can be performed by many different methods, all of which are designed to detect the presence or absence of antibody, the relative amount of specific antibody, and the class of antibody or immunoglobulin (IgM, IgG, etc.) present. Table 2-1 summarizes the use of microbiology tests in the diagnosis of infectious diseases. Regardless of the diagnostic approach used, communication between the laboratory professional and clinician is essential to proper selection and interpretation of tests and results (1). Evolving technology, emerging infec-

Table 2-1 Summary of Laboratory Tests for the Detection of Infectious Diseases Test

Detects

Use

Microscopic examination Histopathologic examination Culture

Inflammatory cells and microorganisms Inflammatory reaction and microorganisms Microorganisms

Rapid etiologic diagnosis

Antigen detection (EIA, FA, latex) Nucleic acid detection (e.g., PCR) Serology

Microorganisms Microorganism DNA or RNA Antibody

Pathologic reaction and microorganism morphology Isolate for definitive identification and antimicrobial testing Rapid etiologic diagnosis Rapid detection or detection of microorganism that does not grow in culture Establish immune status or active disease

Abbreviations: EIA, enzyme immunoassay; FA, fluorescent antibody; Latex, latex agglutination; PCR, polymerase chain reaction.

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tious diseases, and the need to provide rapid, economical testing fuel the need for communication. Communication can be accomplished by wellorganized test requisitions and clearly formatted computer reports but often requires verbal exchange to convey important nuances. The need for a primary care physician to discuss a radiograph with a radiologist or for a surgeon to review a surgical pathology slide and report with a pathologist is a well-established practice that improves the clinician’s understanding of diagnostic and treatment options. Reviewing specific laboratory data with a laboratory pathologist or scientist, beyond checking normal values, is a step in the diagnostic process that has been lost during recent years as laboratories have moved off site and as work schedules have become more hectic. The responsibility for establishing channels of communication lies with both the clinician and the laboratorian. Issues in the laboratory diagnosis of infectious diseases that are enhanced by communication over and above the usual test requisitions and preliminary and final computer reports include the following: ●

●

● ●

●

●

●

Selecting the correct test including those for the detection of unusual pathogens (e.g., Leptospira) Selecting among the available multiple tests (e.g., detecting influenza using rapid culture or PCR testing) Collecting and transporting specimens Choosing the appropriate specimen (e.g., urethral, cervical, or urine specimen for the detection of Chlamydia trachomatis) Ensuring the quality of the specimen (e.g., the results of microscopic screening can indicate an inferior specimen) Interpreting the results (e.g., determining if the positive result represents contaminating flora or pathogen) Choosing antimicrobial testing of unusual pathogens for which standard methods are not available

Laboratory Processing Laboratory processing, simply speaking, includes performing all the tests ordered. However, laboratory processing also requires the verification of proper labeling of the specimen, the clear indication of the test(s) that have been requested, the clinical diagnosis or diagnosis code according to the International Classification of Diseases, 9th Edition, and complete billing information. All laboratories have protocols that must be followed for unlabeled specimens to ensure compliance with licensing regulations (2). Specimens that are not labeled with patient-identifying characters or have been mislabeled cannot be processed. Additionally, it is illegal for laboratories to perform tests that have not been requested. Improper test requests cannot be changed without a physician’s written order.

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The clinical diagnosis helps the laboratory technician select appropriate media for a requested culture. Although standard media with inocula from a specific site grow pathogens typical for that site, unusual or fastidious microorganisms can be missed unless specific tests for them are requested or are indicated by the clinical diagnosis. Enterohemorrhagic Escherichia coli, Vibrio species, and Cyclospora cayetanensis are examples of causes of enterocolitis that can go undetected if clinical suspicion is not conveyed to the laboratory.

Principles of Culture Culture represents the century-old gold standard for detecting microorganisms and remains essentially unchanged except for nutritional modifications that allow for growing a wider variety of bacterial species. Bacteria grow by binary fission, with average strains requiring 30 to 60 minutes for one cell to become two or for the total organism count to double. This process, which cannot be accelerated, results in at least an overnight delay before growing bacteria are detected by colony formation. Some microorganisms, such as the mycobacteria, have doubling times that approach 24 hours, resulting in detection times of many weeks. Viruses grow only within other living cells and therefore are isolated in cell cultures that consist of living cells. Cell cultures serve as hosts for the propagation and detection of pathogenic viruses. The average times to detection of microbial colonies (turn-around times) for common microbial cultures and viruses in cell culture are listed in Table 2-2. Table 2-2 Average Turnaround Times for Microbial Cultures and Virus Isolation* Test

Average Time to Detection

Aerobic bacterial culture

16–24 hours

Anaerobic bacterial culture

24–48 hours

Mycobacterium tuberculosis and other slowly growing mycobacteria Mycobacteria—rapidly growing (e.g. M. fortuitum)

1–2 days 3–14 days 3–6 weeks 2–7 days

Fungi—yeasts and molds Fungi—dimorphic pathogens (e.g. Histoplasma, Blastomyces, Coccidiodes) Virus detection

1–5 days 3 days–3 weeks

1 day 1–7 days 2–4 weeks

Comment

Longer if antimicrobials in specimen slow growth Actinomyces spp., can require 1–2 weeks before growth is detected Molecular methods Broth culture methods Solid medium methods Can grow on bacterial culture media (e.g., Mycobacterium fortuitum) (e.g., Histoplasma, Blastomyces, Coccidioides) Molecular methods Virus isolation Some CMV and VZV strains

Abbreviations: CMV, Cytomegalovirus; VZV, varicella-zoster virus. * For culture, time until colonies appear or virus replication in cell culture can be detected.

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Although culture and virus isolation tests can delay the detection or confirmation of an infectious disease, they have many important advantages. Positive cultures provide the following: definitive proof of the presence of a pathogen, organisms for typing in cases of suspected outbreaks, and, most importantly, isolates for antimicrobial testing. Non–culture-based tests for the presence of pathogens (e.g., antigen detection by enzyme or fluorescence methods, and antibody detection in serum) are subject to misleading false-positive and false-negative results. Diagnosis by molecular methods (e.g., detection of pathogen DNA or RNA by PCR) provides results similar to those of culture but cannot provide antimicrobial susceptibility test results. It is for these reasons that culture remains essential for the diagnosis of most infectious diseases.

Specimens for Culture Specimens for culture require specific clinical material collected, stabilized, and transported according to exacting specifications to ensure valid results (3). Table 2-3 lists appropriate and inappropriate microbiology specimens

Table 2-3 Selection of Common Clinical Specimens Disease

Appropriate

Inappropriate

Bronchitis and pneumonia Sinusitis

Sputum (expectorated mucus and inflammatory cells) Secretions, washes, curettage and biopsy material collected during endoscopy procedure Midstream, straight catheterization, suprapubic, and cystoscopy urine Aspiration of pus or local irrigation fluid (nonbacteriostatic saline). Swab of purulence from beneath the dermis Freshly passed stool. Washes and feces collected during endoscopy

Saliva (oropharyngeal material) Nasal or nasopharyngeal secretions, sputum and saliva

Urinary tract infection

Wound infection

Diarrhea

Bacteremia/sepsis

Two to three blood specimens collected from separate venipunctures, before initiation of antibiotics, each containing 20 mL of blood

Urine from Foley catheter collection bag Swab of surface material or specimen contaminated with surface material Rectal swab. Specimen for bacterial culture if diarrhea developed after patient hospitalization for >3 days Clotted blood. One or more than three blood specimens collected within 24 h period. Volume of blood <10 mL per culture

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Table 2-4 Specimen Holding and Transportation Conditions Specimen

Appropriate

Inappropriate

Sputum

Transport to laboratory within 1 h Refrigerate specimen for longer delays Use sterile or clean container with leak-proof top Keep moist in sterile container Use holding medium to maintain viability and halt overgrowth of normal flora or contaminants Keep at room or refrigeration temperatures Same as for swab, except holding medium in vial rather than swab holder Use anaerobic transport, if appropriate Hold at room temperature if anaerobes are suspected Transport to laboratory within 1 h Refrigerate specimen for longer delays or use boric acidcontaining transport tube to stabilize bacterial quantities Transport to laboratory within 1 h Use holding medium for longer transport Inoculate culture bottle directly with venipuncture blood Hold in incubator or at room temperature. Or, collect into sterile tubes containing SPS anticoagulant

Keep at room temperature >1 h Freeze during transport Expose to sunlight

Purulence or secretions (swab)

Fluid or purulent aspirate

Urine

Stool

Blood for culture

Blood for serology tests

Clotted blood in sterile tube Refrigerate for delays of 1-4 h Separate serum within 4 h

Use dry container No holding medium Delay >48 h Expose to temperature extremes Do not send to lab in syringe with needle. No anaerobic transport if anaerobes are suspected Delay >48 h before culture

Room temperature holding and transport without using boric acid preservative Expose to temperature extremes No holding medium used Temperature extremes Blood transported in syringe Clotted blood Blood in collection tube containing anticoagulant other than SPS Expose to temperature extremes Blood in nonsterile tube Blood hemolyzed Expose to temperature extremes

Abbreviation: SPS, sodium polyanetholesulfonate.

for the diagnosis of different types of diseases. Table 2-4 lists specimen holding and transportation conditions that are required to maintain viable microorganisms in the relative quantities in which they are found at the time of collection. Poor specimen quality is the single greatest obstacle to the accurate diagnosis of infectious diseases. Diagnoses are missed, and over-diagnoses are made from inaccurate culture reports that stem from improper specimen collection methods or transport conditions. In general, specimens for culture should be collected as soon as possible after the onset of acute disease and before the initiation of antibiotic

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therapy. Collecting a second specimen for culture can be necessary because of poor specimen quality or inadequate transport conditions that affect a first specimen, but it is rarely required in other situations. Exceptions include the collection of multiple blood specimens for culture, additional stool cultures from patients with chronic diarrhea, and additional specimens if unusual or fastidious pathogens need to be added to the list of suspected causes.

Screening to Ensure Specimen Quality Most specimens that are submitted for bacterial culture can be screened to check for quality (4). Table 2-5 lists common specimens and results of

Table 2-5 Screening Specimens to Ensure Quality Specimen

Screening Method

Sputum

Acceptable

Unacceptable

Microscopic

<25 SEC/10 × field

>25 SEC/10 × field

Endotracheal aspirate

Microscopic

Bronchoalveolar lavage

Microscopic

<25 SEC/10 × field and bacteria in at least 1 of 20 fields <1% of cells are SEC

>25 SEC/10 × field and no bacteria detected in 20 fields >1% of cells are SEC

Urine

Superficial wound Stool for bacterial pathogens

Other specimens

Action if Unacceptable

Do not culture without consultation Do not culture without consultation

Culture results can represent oropharyngeal contamination Urinalysis <3+ SEC with >3+ SEC with Recollect urine. LE+ and/ LE and Infection less or NIT+ NIT − likely Gram stain Leukocytes 3+ or predom- Recollect urine if and bacteria inant SEC infection suspected present present Gram stain <2+ SEC, >2+ SEC, no Culture results can leukocytes leukocytes represent present contamination Patient Outpatient or In hospital Consider Clostridium location, inpatient >3 days and difficile testing duration of <3 days diarrhea hospitaldeveloped in ization hospital Screen methods unavailable or unproven

Abbreviations: SEC, squamous epithelial cells; LE, leukocyte esterase; NIT, nitrite; +, positive test result; −, negative test result.

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screens performed to ensure quality. The following are important questions in such screening: 1. Does the material originate from the site of inflammation/ infection? 2. Is the material likely to contain a suspected pathogen without the confounding presence of contaminating flora? An ideal specimen is full of inflammatory cells (usually polymorphonuclear leukocytes) and is devoid of squamous epithelial cells that indicate superficial contamination. For example, sputum (lower respiratory tract inflammation and secretions) should have no or very few squamous epithelial cells, indicating little contamination with saliva, and many polymorphonuclear leukocytes indicating that the specimen came from the source of acute inflammation. Specimens that fail a screening examination for quality should be discarded and replaced with acceptable specimens whenever possible. Reporting bacterial isolates from unacceptable specimens contributes to excessive laboratory work and encourages antimicrobial treatment of contaminating flora.

Interpreting Culture Results Because there are no normal values for most microbial culture results, interpretation of positive cultures is a challenge. Methods used to review the significance of results are, as a rule, not standardized or evidence based. Circumstances in which scientific evidence, common sense, and understanding of the pathogenesis of infection can be used to guide the interpretation of culture results are listed in Table 2-6 (5). The proper interpretation of culture results requires an understanding of laboratory information and the patient’s clinical presentation. Critical values for microbiology tests include those results that are likely to have an immediate effect on patient care, such as positive blood and cerebrospinal fluid cultures, and those that require rapid but not immediate communication such as unusual antimicrobial resistance patterns. Critical values can be unique to individual medical centers and require laboratories to consult with medical staff representatives before compiling a specific call list.

Principles of Rapid and Non–Culture-Based Testing Although culture remains the gold standard for detecting most microorganisms, non–culture-based detection methods offer more rapid results, and in some cases are more sensitive than culture-based methods. However, non–culture-based methods suffer most from the inability to provide information about antimicrobial susceptibility. Non–culture-based detection methods can be divided into the following categories: microscopic exami-

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Table 2-6 Interpretation of Bacterial Culture Results

Specimen

Potential Pathogen

Not Potential Pathogen

Sputum and endotracheal aspirate

Isolate predominates in Gram stain and culture. Neutrophils abundant

Isolate does not predominate in Gram stain or culture

Bronchoalveolar lavage

Isolate in every field of Gram stain and >105 CFU/mL in quantitative culture

Isolate not seen in Gram stain and <104 CFU/mL in quantitative culture

Urine— midstream, female with cystitis Urine— midstream, female with pyelonephritis

Isolate >102 CFU/mL Urine LE positive

Isolate equal to or less than contaminating flora

Urine— midstream, patient with asymptomatic bacteriuria Urine— midstream, male with UTI

Urine—“straight” catheter, all patients Urine—Foley catheter, all patients Superficial wound

Isolate >105 CFU/mL Urine LE positive

Additional Data Suggesting Isolate Is a Pathogen

Gram stain shows potential pathogen within leukocytes (intracellular bacteria) Gram stain shows potential pathogen within leukocytes (intracellular bacteria). For patients with prior antimicrobials, clinical judgment rather than quantitative counts Gram stain shows potential pathogen within leukocytes and/or casts Confirm by repeating urine culture

Isolate <104 CFU/ mL and equal to or less than contaminating flora (when present) Isolate < 105 CFU/ Gram stain shows Isolate >105 CFU/mL LE positive or negative mL and equal to potential pathogen or less than conwithin leukocytes taminating flora and/or casts (when present) Isolate <103 CFU/ Gram stain shows Isolate >103 CFU/mL Urine LE positive mL and equal to potential pathogen or less than conwithin leukocytes taminating flora and/or casts (when present) Isolate <103 CFU/ Gram stain shows Isolate >103 CFU/mL and LE positive in mL and LE potential pathogen symptomatic patients negative within leukocytes and/or casts Isolates detected Do not culture if Isolate >103 CFU/mL; multiple pathogens in asymptomatic patient can be present patients asymptomatic Urine LE positive Isolate predominates SEC present and Gram stain shows in Gram stain and neutrophils potential pathogen culture absent within leukocytes Neutrophils abundant, (intracellular no SEC bacteria) Continued

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Table 2-6 Continued

Specimen

Potential Pathogen

Fluids (e.g., CSF) and deep tissue biopsy

Neutrophils present Isolate in Gram stain and culture If Gram stain is negative, multiple colonies of isolate present on culture plates Isolate in one or more cultures

Blood

Not Potential Pathogen

Additional Data Suggesting Isolate Is a Pathogen

Neutrophils absent. Gram stain shows If Gram stain is potential pathogen negative, single within leukocytes colony on plate or growth in broth only

Detection of Pathogen coagulasematching blood negative isolate detected staphylococci, at primary site Corynebacteof infection (e.g., rium, Bacillus, urinary tract) and saprophytic Neisseria in one culture only

Abbreviations: CFU, colony forming units; CSF, cerebrospinal fluid; LE, leukocyte esterase; SEC, squamous epithelial cells.

nation of stained smears; microbial antigen detection by fluorescent antibody staining, or enzyme immunoassay or latex agglutination (LA); and detection of microbial genes by molecular methods such as nucleic acid probing or amplification (e.g., PCR) (6).

Microscopic Examination Microscopic examination of wet mounts and stained smears is the easiest and one of the quickest non–culture-based detection methods. Bacterial infection is detected best with the Gram stain; mycobacterial infection with the auramine–rhodamine fluorescent acid-fast stain; fungal infections with the potassium hydroxide (KOH)/calcofluor wet mount; and parasitic infections with Giemsa stain for intracellular and blood parasites, iodine wet mount for helminths, trichrome stain for protozoans, and Kinyoun acid-fast stain for stool coccidians (Cyclospora and Cryptosporidium). Table 2-7 summarizes the common morphologies reported using the Gram stain and the specific bacteria or yeast corresponding to each morphology. These are especially important when interpreting Gram stains for empiric antimicrobial selections.

Fluorescent Antibody Staining Microbial antigen detection is nearly as quick as microscopic examination and is more specific, because microorganisms can be identified by unique

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Table 2-7 Interpretation of Gram Stained Smears Morphology Observed/Reported

Interpretation

Gram-positive Gram-positive Gram-positive Gram-positive Gram-positive Gram-positive Gram-positive

Staphylococci Streptococci/Enterococci Pneumococci Corynebacterium/Propionibacterium Bacillus/Clostridium Nocardia/Actinomyces Lactobacillus, Listeria, and other Gram-negative bacilli Neisseria/Moraxella catarrhalis Haemophilus, Bacteroides Enteric and Pseudomonas-like Gram-negative bacilli Yeast (e.g., Candida and Cryptococcus) Molds (filamentous fungi, e.g., Aspergillus)

cocci, clusters cocci, chains cocci, diplococci/lancets bacilli, diphtheroid bacilli, boxcar bacilli, filamentous-branching bacilli, other

Gram-negative diplococci Gram-negative coccobacilli Gram-negative bacilli Yeast cells with and without pseudohyphae Hyphae

antigens. However, microbial antigen detection does not allow the examination of specimen cellularity (e.g., neutrophils, contaminating epithelial cells) that is inherent in conventional microscopy. Fluorescent antibody stains require the use of an expensive fluorescence microscope and a trained microscopist. Moreover, smear preparation for fluorescent staining can require centrifugation to concentrate the specimen as well as specimen washing to eliminate nonspecific fluorescence. Fluorescent stains are less sensitive than culture but require only 2 to 4 hours for completion.

Enzyme Immunoassays Enzyme immunoassays (EIAs) are available as conventional and membrane (handheld) tests. Conventional tests formatted for microtiter trays must be performed by trained personnel, can require expensive instrumentation, and are best for testing large batches of specimens at one time. Membrane tests, such as the rapid Streptococcus tests available for detecting Streptococcus pyogenes, can be performed by personnel with minimal training and are designed for individual rather than batch use. Common EIAs are 50% to 90% sensitive with turnaround times of hours for conventional formats and minutes for handheld formats.

Latex Agglutination Latex agglutination (LA) testing, a less common method for antigen detection, is limited to testing for bacterial antigens in body fluids such as cerebrospinal fluid. Bacterial antigens that can be detected include those of Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae (group B Streptococcus). After decades of use, it has been concluded that bacterial antigen testing has little usefulness in

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the diagnosis of serious disease. Laboratory evaluations show antigen-testing results to be equivalent to those of the Gram stain, and clinical evaluations show that no change in antibiotic therapy occurs until culture results are available. In a climate of limited testing resources, bacterial antigen tests should be used infrequently, if at all (7). An approach to limiting the use of antigen tests is to test only specimens from patients who have taken antibiotics that might interfere with culture results.

Molecular Assays Molecular methods for detecting pathogenic organisms have emerged as essential components for the diagnosis of many infectious diseases (8). Common molecular methods include detection without target amplification using probes, and detection with target amplification using the PCR or related assays. Probes detect specific microbial genes (DNA sequences). The higher the concentration of specific microorganism present in the specimen, the more copies of the target gene there will be, and the more sensitive the probe detection test. Detection of papilloma viruses in skin biopsies is an example of a DNA probe assay. Although PCR and related assays also detect specific genes, detection occurs after amplification or multiplication of the gene up to 1 million times, increasing significantly the sensitivity of detection. PCR methods allow detection of DNA and RNA, the latter is necessary for viruses with RNA genomes. Currently, molecular methods are used for the detection of microorganisms in cases in which culture methods are not available, not sensitive, or relatively slow. Table 2-8 summarizes molecular tests used for the diagnosis of infectious diseases. Table 2-8 Molecular Tests for the Diagnosis of Infectious Diseases Microorganism Detected

Method

Specimen

Methicillin-resistant Staphylococcus aureus (MRSA) Neisseria gonorrhoeae Chlamydia trachomatis Bordetella pertussis Mycobacterium tuberculosis Herpes simplex virus Varicella-Zoster virus Other herpes viruses (EBV, HHV 6-8) Human immunodeficiency virus (HIV)

PCR

Nasal swab

PCR, molecular probe PCR, molecular probe PCR PCR, molecular probe PCR PCR PCR PCR and others

Hepatitis C virus (HCV)

PCR and others

Parvovirus Human papilloma virus

PCR Molecular probe

Genital Genital Nasopharyngeal Respiratory/CSF Skin/CSF Skin/CSF Skin/Blood/CSF Blood (detection and viral load) Blood (detection and viral load) Amniotic fluid Skin

Abbreviations: CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; HHV 6-8, human herpes viruses 6-8; MRSA, methicillin-resistant S. aureus; PCR, polymerase chain reaction (for the detection of RNA and DNA).

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Principles of Identification Bacteria Isolated bacteria are identified by immunologic testing, which reveals the presence of unique antigens, and biochemical testing, in which a characteristic pattern of substrate utilization is obtained (9). Identification by immunologic methods, such as LA, can be accomplished in minutes but is restricted to Staphylococcus aureus, beta-hemolytic streptococci, the Salmonella and Shigella groups, and a few other organisms. Biochemical testing is the mainstay of bacterial identification, and is accomplished by spot, same-day, or overnight testing. Spot testing requires only minutes to complete, and involves rubbing the unknown microorganism on a substrate-impregnated paper. Large amounts of preformed bacterial enzyme degrade the substrate, which is signaled by a colored indictor. Spot testing is inexpensive and rapid (usually minutes to complete) but works only with bacteria that produce excessive amounts of enzyme and have unique substrate patterns. The advantage of same-day testing is the relative speed of identification. More than 80% of bacteria detected in the usual hospital clinical laboratory can be identified using LA and rapid spot testing. Overnight testing is required for bacteria that produce small quantities of enzyme or whose enzymes require induction before detectable substrate degradation occurs. Overnight testing is, in general, costly and time consuming but more comprehensive and accurate than is same-day testing. Automated identification of bacterial isolates is accomplished by biochemical testing that uses unique signals to identify substrate utilization. For example, the Vitek System (bioMerieux Vitek, Hazelwood, Missouri) detects early growth and substrate utilization through the use of colorimetry and nephelometry (light scattering). The Microscan System (Dade Microscan, Inc., West Sacramento, California) uses colorimetry and spectrophotometry (light transmission) to detect growth and reactions that involve a color change. In both instruments, identification is accomplished by computer software that matches the substrate-utilization profiles of unknown organisms with databases of known utilization profiles (10). Identification by automated methods can require as little as 2 hours or can need overnight incubation. Terminology used to characterize bacteria in preliminary reports, before definitive identification has been completed, is not standardized among all microbiology laboratories and can be confusing. It is helpful for the clinician to understand this terminology to better interpret preliminary culture results. For example, an oxidase-positive, gram-negative rod growing from a blood culture will not be an E. coli or related enteric-type gram-negative rod, because all of the Enterobacteriaceae are oxidase-negative. The most common oxidase-positive, gram-negative rod in blood cultures is Pseudomonas aeruginosa. Empiric therapy needs to cover P. aeruginosa and other oxidasepositive pathogens in this example. In other preliminary reports, one can

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encounter a lactose-fermenting, gram-negative rod. The most common lactose fermenters encountered are E. coli and Klebsiella and Citrobacter species. None of the opportunistic, nonfermenting gram-negative rods, such as Acinetobacter, Stenotrophomonas, and Pseudomonas, are lactose fermenters. Tables 2-9 through 2-12 organize common and important bacteria according to official classification schemes using laboratory jargon.

Table 2-9 Classification and Terminology Used to Describe Gram-Positive Aerobic and Facultative Bacteria Gram-Positive Cocci (GPC)

GPC pairs and chains (streptococci, enterococci, Abiotrophia) Beta-hemolytic streptococci Group A (S. pyogenes) Group B (S. agalactiae) Group C Group G Group F (S. milleri/anginosis group) Streptococcus pneumoniae (pneumococcus with more than 80 serotypes) Enterococci (contains Group D antigen) E. faecalis E. faecium Viridans streptococci S. milleri/anginosis group S. mitis group S. mutans group S. salivarius group S. sanguinis group Nutritionally variant streptococci (satelliting streptococci) Abiotrophia defectiva Granulicatella adiacens Streptococcus bovis group S. gallolyticus (formerly S. bovis I) S. infantarius (formerly S. bovis II 1) S. pasteurianus (formerly S. bovis II 2) GPC clusters (staphylococci) S. aureus (coagulase-positive) Coagulase-negative staphylococci S. epidermidis S. capitis S. hominis S. haemolyticus S. saprophyticus Many others Gram-Negative Bacilli (GNB)

Arcanobacterium haemolyticum Bacillus species (produce endospores, many species) B. anthracis B. cereus Continued

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Table 2-9 Continued Gram-Negative Bacilli (GNB)

Corynebacterium species (aerobic diphtheroid, many species) C. diphtheriae C. jeikeium C. urealyticum Erysipelothrix rhusiopathiae Lactobacillus species (lactobacilli, many species) Listeria monocytogenes

Table 2-10 Classification and Terminology Used to Describe Gram-Negative Aerobic and Anaerobic Bacteria Gram-Negative Cocci

Neisseria species (many species, including) N. gonorrhoeae (gonococci) N. meningitides (meningococci) Moraxella catarrhalis Gram-Negative Bacilli

Glucose-fermenters, oxidase-negative Enterobacteriaceae Lactose-fermenters E. coli K. pneumoniae Non-lactose fermenters Proteus mirabilis Salmonella species Shigella species Lactose or non-lactose fermenters Enterobacter species Serratia species Citrobacter species Glucose-fermenters, oxidase-positive Vibrio cholerae V. parahaemolyticus V. vulnificus Vibrio (many other species) Aeromonas hydrophilia A. caviae Aeromonas (many other species) Glucose non-fermenters, oxidase-negative Acinetobacter species A. baumannii A. lwoffii Stenotrophomonas maltophilia Glucose non-fermenters, oxidase-positive Pseudomonas aeruginosa Pseudomonas, other species Continued

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Table 2-10 Continued Gram-Negative Bacilli

Alcaligenes species Burkholderia cepacia Burkholderia, other species Gram-Negative Bacilli—Fastidious (fastidious means no growth on selective Gramnegative media such as MacConkey Agar)

Haemophilus influenzae (H. flu) HACEK group (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella) Bordetella pertussis Pasteurella multocida Legionella pneumophila

Table 2-11 Classification and Terminology Used to Describe Bacteria That Are Uncultivable or Difficult to Cultivate Bartonella henselae (cat scratch bacillus) Chlamydia trachomatis Chlamydophila (formerly chlamydia) pneumoniae Coxiella burnetii (Q-fever bacterium) Ehrlichia/Anaplasma species Rickettsia species Spirochetes Borrelia burgdorferi (Lyme disease spirochete) Borrelia recurrentis Leptospira species Treponema pallidum (syphilis spirochete) Tropheryma whippelii (Whipple disease bacterium)

Mycobacteria The mycobacteria are identified by molecular probe technology, substrate utilization studies that are similar in principle to those used with the common bacteria discussed earlier, and sequencing of certain mycobacterial genes. Commercially available nucleic acid probes can be used to rapidly identify Mycobacterium tuberculosis, M. avium, M. kansasii, and M. gordonae. Once in-vitro growth occurs, probe identification requires 2 to 4 hours. Some mycobacteria are identified by biochemical utilization studies, which can require 2 weeks or longer to complete. The number and diversity of mycobacteria have increased so greatly in the past 20 years that accurate identification of some isolates is accomplished only by gene sequencing. This technology requires 1 to 2 days following growth. Terminology used to classify clinically significant mycobacteria is summarized in Table 2-13 (11).

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Table 2-12 Classification and Terminology Used to Describe Anaerobic Bacteria Gram-Positive Bacilli (non-spore-forming)

Gram-Negative Bacilli

Actinomyces species Propionibacterium (anaerobic diphtheroid) Eubacterium species Lactobacillus species Bifidobacterium species

Bacteroides fragilis group B. fragilis B. thetaiotaomicron B. vulgatus B. distasonis B. uniformis B.ureolyticus Bilophila species Porphyromonas species Prevotella species Fusobacterium species

Gram-Positive Bacilli (spore-formers)

Clostridium perfringens C. septicum C. difficile C. botulinum C. tetani Clostridium, many other species Cocci

Gram-positive cocci Peptostreptococcus species Peptococcus species Gram-negative cocci Veillonella species

Table 2-13 Classification and Terminology Used to Describe the Mycobacteria Category

Mycobacterium

Mycobacterium tuberculosis complex

M. tuberculosis M. bovis M. kansasii M. marinum M. scrofulaceum M. szulgai M. thermoresistable M. xenopi M. avium complex (MAC) M. genavense M. haemophilum M. fortuitum M. chelonei M. abscessus M. leprae

Photochromogens (colony pigment following exposure to light) Scotochromogens (colony pigment in light and dark)

Nonchromogens (no colony pigment)

Rapid Growers (colonies in <7 days)

Not able to cultivate in vitro Abbreviation: MAC, M. avium-intracellulare complex.

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Fungi The fungi are identified by morphologic analysis and, occasionally, by physical or biochemical tests. The fungi are divided into yeasts (singlecelled organisms that reproduce by budding) and molds or filamentous fungi (organisms that grow by producing multicellular filaments and aerial growth). Identification can be completed on the same day on which growth occurs but can require weeks in circumstances in which identifying characteristics are not produced readily during growth on agar plates. Colonies that represent common yeasts, such as Candida albicans and C. (Torulopsis) glabrata, can be identified with rapid tests that require only 1 to 3 hours. Terminology used to classify the clinically significant fungi is summarized in Table 2-14 (12).

Parasites Parasites are identified by morphologic studies and, in cases of intestinal infection with Giardia, Cryptosporidium, or Entamoeba histolytica, by enzyme immunoassay. Terminology used to classify human parasites is summarized in Table 2-15 (13).

Table 2-14 Classification and Terminology Used to Describe Fungi Yeast-Like Fungi

Filamentous Fungi (Molds)

Dimorphic Fungi

Candida albicans C. tropicalis C. parapsilosis C. tropicalis C. krusei

Septate Hyphae—no pigment Aspergillus fumigatus A. flavus A. niger A. terreus

Histoplasma capsulatum Blastomyces dermatitidis Coccidioides immitis Sporothrix schenckii Paracoccidioides brasiliensis

C. (Torulopsis) glabrata Fusarium species Cryptococcus neoformans Pseudallescheria species Malassezia furfur Nonseptate Hyphae Trichosporon species Rhizopus species Mucor species Septate Hyphae—brown pigment Curvularia species Phialophora species Exophiala species Alternaria species Dermatophytes Trichophyton species Microsporum species Epidermophyton floccosum

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Table 2-15 Classification and Terminology Used to Describe Parasites Protozoa

Intestinal Helminths

Tissue Helminths

Intestinal and Urogenital Amoebae Blastocystis hominis Entamoeba histolytica Ciliates Balantidium coli Flagellate Dientamoeba Giardia lamblia Trichomonas vaginalis Coccidia Cryptosporidium Cyclospora Isospora Microsporidia Encephalitozoon Enterocytozoon Nosema Pleistophora Septata Blood and Tissue Babesia Leishmania Plasmodium Toxoplasma Trypanosoma Free-Living Ameba Acanthamoeba Hartmannella Naegleria

Cestodes (Flat Worms) Diphyllobothrium latum Hymenolepis Taenia (beef/pork tapeworm) Nematodes (round worms) Ancylostoma (hookworm) Ascaris lumbricoides Enterobius (pinworm) Strongyloides stercoralis Trichuris (whipworm) Trematodes (flukes) Clonorchis (liver) Fasciola (liver) Fasciolopsis (intestinal) Metagonimus (intestinal) Opisthorchis (liver) Paragonimus (lung) Schistosoma (blood)

Cestodes (Flat Worms) Cysticercus (T. solium) Echinococcus Nematodes (round worms) Ancylostoma (dog/cat hookworm) Anisakis Brugia (lymphatic filaria) Dirofilaria (dog heartworm) Dracunculus (Guinea worm) Loa loa (eye filaria) Mansonella (dermal filaria) Onchocerca (tissue filaria) Strongyloides (hyperinfection) Toxocara (dog/cat Ascaris) Trichinella (muscle) Wuchereria (lymphatic filaria) Trematodes (flukes) Clonorchis (liver) Fasciola (liver) Paragonimus (lung) Schistosoma (blood)

Viruses The standard for identifying viruses in clinical specimens is cell culture (14). Viruses cannot grow on or in artificial media (e.g., agar); they require living cells for their growth. The viral infectious cycle, which represents the sequence of events that begins with viral recognition of a susceptible cell and ends with the release of tens of thousands of new infectious virions, results in dead and dying cells in cell culture. Although viruses are too small to be seen with bright-field microscopy, the morphologic changes they produce in dying cells can be recognized and are referred to as cytopathic effect (CPE). The presence of virus in a cell culture can be recognized by the presence of CPE. In fact, the CPE of each virus is unique and can be used to identify the infecting virus. CPE can require days or weeks before appearing. To overcome this delay inherent in conventional cell culture, the rapid cell culture (or shellvial culture) was developed. Rapid cell culture uses the same principle of

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viral detection as does conventional cell culture, the infection of living cells by a virus. However, rather than await the development of CPE, the cell monolayer is stained after 24 to 48 hours with an antibody directed at early protein produced by the suspected infecting virus. Once the virus has infected a cell, viral genes direct the production of viral gene-encoded early proteins. The advantage of the rapid shell-vial cell culture is the rapid production and detection of viral antigen as compared with the more timeconsuming detection of a CPE. Viruses can be detected directly in clinical specimens within hours by EIA and fluorescent antibody (FA) staining. These methods are especially useful for viruses that do not grow in cell culture. Although direct enzyme or FA detection of viruses is rapid, these methods lack sensitivity, generally detecting only 50% to 90% of the viruses that can be detected by cell culture. Molecular methods (such as PCR) are fast becoming the gold standard for the detection of many viruses (8). Table 2-16 summarizes the classification and terminology used to describe viruses.

Table 2-16 Classification and Terminology Used to Describe Viruses DNA Viruses

RNA Viruses

Family

Viral Members

Family

Viral Members

Adenoviridae

Human adenoviruses

Arenaviridae

Hepadnaviridae

Hepatitis B virus

Astroviridae

Herpesviridae

Herpes simplex virus 1 and 2; VaricellaZoster virus; cytomegalovirus; Epstein-Barr virus; human herpes viruses 6, 7, 8

Bunyaviridae

Papillomaviridae

Human papilloma (wart) viruses Parvovirus B-19

Caliciviridae

Lymphocytic choriomeningitis virus; Lassa fever virus Gastroenteritiscausing astroviruses Arboviruses including California encephalitis, La Crosse virus; Nonarboviruses including sin nombre and related hantaviruses Noroviruses, hepatitis E virus Coronaviruses including SARS coronavirus

Parvoviridae

Coronaviridae

Continued

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Table 2-16 Continued DNA Viruses

RNA Viruses

Family

Viral Members

Family

Viral Members

Polyomaviridae

BK virus; JC virus

Filoviridae

Poxviridae

Variola virus, vaccine virus, orf virus, molluscum contagiosum virus, monkeypox virus

Flaviviridae

Hemorrhagic viruses including Ebola and Marburg viruses Arboviruses including yellow fever, dengue, West Nile, Japanese encephalitis, St. Louis encephalitis viruses; Nonarboviruses including hepatitis C virus Influenza A, B, C viruses Parainfluenza viruses, mumps virus, measles virus, respiratory syncytial virus, metapneumovirus Polio viruses, coxsackie A and B viruses, ECHO viruses, enteric viruses 68-70, enterovirus 72 (hepatitis virus), rhinoviruses Rotavirus, Colorado tick fever virus Human immunodeficiency virus (HIV-1 and HIV2), human Tlymphotropic viruses (HTLV-1, HTLV-2) Rabies virus Eastern, Western, and Venezuelan equine encephalitis viruses; rubella virus

Orthomyxoviridae Paramyxoviridae

Picornaviridae

Reoviridae Retroviridae

Rhabdoviridae Togaviridae

Abbreviation: SARS, severe acute respiratory syndrome.

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Principles of Serologic Tests Serologic tests, which detect antibody in serum, can be used to establish either immunity or susceptibility to infectious disease, and to diagnose such disease (15). Table 2-17 lists the common serology tests that are used to detect immunity and diagnose disease. In general, infection with a microor-

Table 2-17 Serologic Tests Used to Detect Immunity and Active Disease Disease

Etiologies

Amoebic dysentery Entameba histolytica Cytomegalovirus Cytomegalovirus disease

Antibody Detected/Specimen Tested

Disease: IgG/Acute Immune status: IgG/Any Disease: IgM/Acute Disease: IgG/Acute and convalescent Immune status: IgG/Any Immune status: IgG/Any Immune status: IgG/Any Disease: IgM/Acute Disease: IgG/Acute and convalescent Disease: IgG/Acute and convalescent

Gastritis/Ulcer HIV Disease Mononucleosis

Helicobacter pylori HIV Epstein-Barr Virus

Fungal disease

Histoplasma capsulatum Blastomyces dermatitidis Coccidioides immitis Hepatitis A virus Immune status: IgG/Any Disease: IgM/Acute Hepatitis B virus Immune status: IgG/Any Disease: IgG/Acute Hepatitis C virus Immune status: IgG/Any Disease: IgG/Acute Leptospira Disease: IgG/Acute and convalescent Borrelia burgdorferi Disease: IgG/Acute and convalescent Measles virus Immune status: IgG/Any Disease: IgM/Acute Mycoplasma Disease: IgM/Acute or IgG/Acute pneumoniae and convalescent

Hepatitis

Leptospirosis Lyme disease Measles Mycoplasma— atypical pneumonia Parvovirus disease

Parvovirus B19

Rubella

Rubella virus

Syphilis

Treponema pallidum

Chickenpox

Varicella-Zoster virus

Immune status: IgG/Any Disease: IgM/Acute or IgG/Acute and convalescent Immune status: IgG/Any Disease: IgM/Acute or IgG/Acute and convalescent Disease: IgG/Acute and convalescent (non-treponemal RPR/VDRL and treponemal FTA-ABS tests) Immune status: IgG/Any Disease: IgM/Acute

Abbreviations and Definitions: Acute, serum specimen collected within 1-2 weeks of onset of disease; Any, serum specimen collected irrespective of timing, generally in the absence of active/symptomatic disease; Convalescent, serum specimen collected 3 or more weeks after the onset of disease; Disease, detect presence of active or current disease; FTA-ABS, fluorescent treponemal antibody absorption syphilis serology test; HIV, human immunodeficiency virus; Immune status, detect presence of past disease; RPR/VDRL, rapid plasma reagin/venereal disease research laboratory syphilis serology tests.

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ganism is followed within 1 to 2 weeks by the formation of acute-phase IgM and lifelong IgG antibodies. These antibodies are specific to the infecting microorganism and continue to increase in titer for weeks to months, depending on the microorganism, the severity of disease, and the patient’s immune status. As the patient convalesces, the titer of microorganismspecific IgM antibody wanes and, as a rule, becomes undetectable from 1 to 4 months after the onset of infection. Although the titer of microorganismspecific IgG antibody also wanes, it is usually detectable for the remainder of that patient’s life. Reinfection by an antigenically similar microorganism results in a spike in the titer of this specific IgG and occasionally a spike to detectable levels of specific IgM. Titers then once again diminish to undetectable levels of IgM and detectable but lower levels of IgG. Serum specimens are collected by venipuncture into a sterile tube that contains no anticoagulant. Specimens should be stored on ice or refrigerated until clots are removed. Clots should be removed as soon as possible, preferably within hours, to prevent hemolysis and subsequent interference with assays. Serum separator tubes can be stored for longer periods without drawing off the serum. Serum can be stored for days to years before testing. Storage for a few days should be at refrigeration temperatures (4˚C). Storage for longer periods should be at freezer temperatures (colder than −12˚C). Prolonged storage (>1 month) should be at −70˚C. Serum specimens should not be stored in frost-free freezers with repeated freezing and thawing because this can aggregate IgM-type antibodies and denature all antibodies resulting in false-negative tests. Specimens that are frozen and need to be transported to another office or laboratory for analysis should be sent in the frozen state. Immunity, especially to viral diseases, can be established by detecting antibody—an indication that infection has occurred sometime in the past. Serologic tests for immunity must be performed with sensitive methods that detect IgG-type antibodies (e.g., enzyme-based assays rather than complement fixation-type assays). Serologic diagnosis of disease can be accomplished by detecting either pathogen-specific IgM or a rise in the titer of pathogen-specific IgG. IgM can be detected as early as 1 week after the onset of disease. The presence of pathogen-specific IgM in a single serum specimen suggests current or very recent infection by that particular pathogen. Rising IgG titers are detected by collecting and assaying acute and convalescent serum specimens. The acute specimen is collected as soon as possible after the onset of disease, and the convalescent specimen is collected 3 to 6 weeks later. A significantly greater antibody titer in the convalescent specimen than that detected in the acute specimen suggests current infection by the specifically infecting pathogen. In some clinical situations, both convalescent and postconvalescent serum specimens are collected. In such instances, a significant decrease in serum antibody titer from the convalescent to the postconvalescent specimen can indicate recent infection. This approach and interpretation should be

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confirmed with the laboratory performing the test. Serologic diagnosis of infection by detection of IgM or IgG antibody is more effective for some infectious agents than for others. Drawbacks to serologic testing include the persistence of IgM for months after acute infection, the need to wait for a convalescent specimen when testing for IgG, and interference with diagnostic antibody levels after vaccination. In general, serological testing is not practical for the initial management of an acute infectious disease because of the delay between onset of disease and appearance of diagnostic antibodies.

Interpreting Biopsy Specimens Microorganisms can be detected in thin sections of biopsy tissue through characteristic histopathologic reactions and by identifying microbial morphologies with histologic stains. In either case, unfixed tissue from the same biopsy specimen as that submitted for microscopic examination by the pathologist should be aseptically dissected and submitted to the microbiology laboratory for culture. Detecting microorganisms in culture is more sensitive than is microscopic examination, serves to confirm morphologic findings and to provide more complete identification of an organism, and provides organisms for antimicrobial susceptibility testing or microbial typing in epidemiologically related cases. Histopathologic inflammatory responses to infection depend on both the pathogenic properties of the infectious agent and the immune status of the host, and can be divided into the following categories as reviewed by Woods and Walker (16). The microorganisms responsible for each inflammatory category also are listed. ●

●

●

●

Acute inflammation characterized by an exudative and suppurative response, which can result in abscess formation is caused by pyogenic bacteria such as Nocardia species, Candida species, Aspergillus species; and Zygomycetes, such as Rhizopus species. Caseating granulomatous inflammation is caused by Mycobacterium tuberculosis, nontuberculous mycobacteria (especially Mycobac-terium marinum, Mycobacterium szulgai, and Mycobacterium leprae), Histoplasma capsulatum, Coccidioides immitis, and Cryptococcus neoformans. Noncaseating granulomatous inflammation is caused by M. tuberculosis, nontuberculous mycobacteria as in the preceding for caseating granulomas, H. capsulatum, Brucella species, Toxoplasma gondii, Coxiella burnetti, Ehrlichia species, cytomegalovirus, Schistosoma species, and Dirofilaria immitis. Mixed suppurative and granulomatous inflammation is caused by nontuberculous mycobacteria, Blastomyces dermatitidis, Sporothrix schenckii, Paracoccidioides brasiliensis, fungal agents

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●

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of chromoblastomycosis and phaeohyphomycosis, Acanthamoeba species, Yersinia species, Francisella tularensis, Bartonella henselae, and C. trachomatis strains causing lymphogranuloma venereum. Nonorganizing, mixed acute and chronic or chronic inflammation is caused by Legionella species, Helicobacter pylori, Cryptosporidium species, microsporidia, and Treponema pallidum. Aggregates or diffuse infiltrates of histocytes are caused by Mycobacterium avium complex, M. genavense, M. leprae, Leishmania species, and Listeria monocytogenes.

Use and Interpretation of In-Vitro Antimicrobial Susceptibility Tests In-vitro antimicrobial susceptibility tests are used to help predict whether a specific antimicrobial agent will eradicate a pathogen from the site of infection. Laboratories perform in-vitro susceptibility tests when they isolate a likely pathogen that has an unpredictable antimicrobial profile, and proven methods exist for determining the pathogen’s susceptibility and resistance. The methods used to test antimicrobial susceptibility are established by the Clinical Laboratory Standards Institute (CLSI), a consensus group composed of representatives from industry, government, clinical laboratories, and appropriate medical specialties. The CLSI publishes annual updated procedures, and all laboratories are required by licensing regulations to follow CLSI methods and interpretations. The antimicrobial agents to be tested by the laboratory should be determined by local resistance patterns, cost, and the preferences of physicians who are knowledgeable in antimicrobial therapy. Physician, pharmacy, and laboratory representatives commonly form the nucleus of the hospital committee responsible for determining the batteries of antimicrobials to be tested. These batteries of tests need to be reviewed and changed on a periodic basis.

The Minimum Inhibitory Concentration Test and the Breakpoint The backbone of in-vitro antimicrobial susceptibility testing is the minimum inhibitory concentration (MIC) test (17), which determines the lowest concentration of an antimicrobial agent needed to inhibit the growth of a microorganism. Reported in micrograms per milliliter (µg/mL) of antimicrobial agent, MIC values are established at concentrations that range from 0.1 µg/mL to as high as 64 µg/mL, depending on the antimicrobial agent being tested. The MIC value is compared with the quantity of antimicrobial agent that can be achieved in the patient at the site of infection. In general,

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when the MIC is lower than the concentration at the infected site, the infecting organism is considered susceptible to the antimicrobial agent being tested. When the MIC is higher, the microorganism is considered resistant. The specific concentration of antimicrobial agent at the infection site that is used to differentiate between susceptible and resistant is referred to as the breakpoint. Antimicrobials are used in various dosages and dosing schedules because they have different pharmacologic properties in the body and, therefore, can have different breakpoints. In practice, the breakpoint for a particular antimicrobial agent is set using many different criteria, such as the results of clinical trials, resistance mechanisms of bacteria, animal studies, pharmacokinetic and pharmacodynamic properties, and concentrations of the agent at important sites of infection (e.g., cerebrospinal fluid). An understanding of the MIC and breakpoint should make it clear that selecting an antimicrobial agent from a list of MIC values is not simply a matter of selecting the drug with the lowest MIC. One must know the breakpoint concentration for each antimicrobial agent to ensure that the MIC value of the agent for a particular pathogen is below this concentration. The goal of antimicrobial therapy is to kill a patient’s pathogen. Can an inhibitory test be used in the laboratory to predict the killing of a pathogen in the patient? The answer is “Yes” (18). Although methods for bactericidal testing (measure killing rather than inhibition) are available to the laboratory, the MIC test has proven to be an accurate predictor of clinical response through decades of clinical use. In most patients, a susceptible MIC test result implies that the pathogen is likely to be eradicated from the site of infection, increasing the likelihood of a favorable outcome. A resistant MIC test result suggests that the pathogen is less likely to be eradicated. A laboratory report indicating an intermediate result means that the concentration of antimicrobial agent at the infected site is at or near the MIC of the infecting pathogen. In most such cases, an alternative drug that yields a susceptible MIC test result is selected. The term intermediate also implies that the infecting organism can be interpreted as susceptible if higher-thannormal doses of the specific antimicrobial agent are used or if the antimicrobial agent is concentrated at the site of infection (e.g., in the urinary tract, where drugs excreted by the kidneys become concentrated). Increasing the dose and concentration of an antimicrobial agent at various body sites increases the breakpoint of the agent for a particular pathogen, transforming intermediate MIC test results into susceptible ones.

Methods Used to Determine the Minimum Inhibitory Concentration Laboratories use many manual and automated methods to determine the MICs of antimicrobial agents for various pathogens. The microbroth dilu-

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tion method is the commonly used gold standard. In this technique, dilutions of antimicrobial agents prepared in microtiter trays are inoculated with a standard concentration of the microorganism which is to be tested for susceptibility. After overnight incubation, quantitative MIC results are determined and reported in micrograms per milliliter (µg/mL), with a qualitative interpretation of susceptible, resistant, or intermediate susceptibility. Commercially available automated methods are adjusted to meet the microbroth dilution standard. Disk diffusion is performed using disks containing the antimicrobial agent to be tested, which are placed on the surface of a standard agar plate that has been inoculated with a carefully adjusted lawn of bacteria. The antimicrobial agent diffuses into and across the agar surface, creating a concentration gradient that mimics the dilutions one uses in the broth microdilution procedure, with a high concentration near the disk and progressively lower concentrations at increasing distances from the disk. Bacteria grow toward the disk until they reach the surrounding region that contains the test antibiotic at their MIC value, producing a circular zone of inhibited growth around the disk. The disk-diffusion test, in effect, is a MIC test performed on the surface of an agar plate. Statistical analysis has been used to determine MIC and breakpoint equivalents for disk diffusion. Results of disk-diffusion testing are reported as being susceptible, intermediate, or resistant, without including the MIC equivalent value. The E-test (AB Biodisk, Piscataway, New Jersey) is an agar-gradient method that uses an antimicrobial agent applied in gradient concentrations to a strip. The strip is marked to show the exact decreasing concentrations of the antimicrobial agent from one end to the other. The strip is placed onto an agar surface that has been inoculated with the bacterium to be tested. Bacterial growth occurs around the strip in an elliptical pattern, with a larger area of growth inhibition at the high-concentration end of the strip and a narrowing area of inhibition toward the low-concentration end. The MIC value is read from the concentration marking on the strip at the point at which the concentration of antimicrobial agent is low enough to permit growth of bacteria right up to the strip. Results are reported as quantitative MIC values with a susceptible, resistant, or intermediate interpretation.

Special Methods Used to Detect Specific Resistance Standard MIC and disk-diffusion methods do not detect all resistant bacteria accurately (19). Supplementary methods are used to ensure accurate results. Table 2-18 lists combinations of bacteria and antimicrobials that require supplementary testing.

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Table 2-18 Bacterial-Antimicrobial Combinations that Require Supplementary Testing to Confirm In-Vitro Susceptibility Microorganism

Antimicrobial

Mechanism of Resistance

Supplementary Test

Gram-Positive Cocci

Staphylococcus aureus

Penicillin

All Staphylococci

Methicillin, and related drugs

Vancomycin

Clindamycin

Enterococci

Vancomycin

Beta-lactamase production Altered penicillinbinding proteins

Beta-lactamase assay Mec-A gene analysis, or a combination of agar and broth dilution testing with increased concentrations of NaCl Broth dilution MIC or agar dilution. Disk diffusion should not be used. D-test

Altered cell wall morphology that binds excess drug Induced by erythromycin or mutation Altered cell wall Broth dilution MIC or morphology agar dilution. Disk that prevents diffusion should not binding of drug be used.

Gram-Negative Bacilli

Escherichia coli/ Klebsiella

Cephalosporins

Haemophilus influenzae

Ampicillin

ExtendedReview overall spectrum antimicrobial beta-lactamase pattern. Compare production cephalosporin (e.g., (ESBL) ceftazidime) MIC or zone diameter to cephalosporin plus clavulanate MIC or zone diameter. Beta-lactamase Beta-lactamase assay production

Gram-Negative Cocci

Moraxella catarrhalis

Ampicillin

Neisseria gonorrhoeae

Penicillin

Beta-lactamase production Beta-lactamase production

Beta-lactamase assay Beta-lactamase assay

Abbreviations: D-test, erythromycin and clindamycin disk approximation test on agar plate that detects inducible clindamycin resistance. A D-test positive Staphylococcus is considered resistant to clindamycin. A D-test negative Staphylococcus is considered susceptible to clindamycin. MIC, minimum inhibitory concentration; mec-A, staphylococcal gene encoding altered penicillin binding protein (referred to as PBP2a) that confers methicillin resistance. Absence of mec-A implies methicillin susceptibility; NaCl, sodium chloride.

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Synergy Testing The term synergy describes an inhibitory or cidal test result representing the combination of two antimicrobial agents that exceeds that expected when individual results of each tested alone are added together. Combinations of antimicrobial agents are commonly used with the expectation that synergy will occur, although laboratory testing is rarely needed to prove that synergy is present (20). Even if synergy does not occur, the two antimicrobial agents in a particular combination can be necessary either to broaden the spectrum of organisms covered by therapy or to ensure that mutant organisms that are resistant to one antimicrobial agent will be inhibited by the second agent. Synergy is expected with the following regimens: ●

●

●

A beta-lactam drug plus an aminoglycoside is used in treating infections caused by many gram-negative bacilli, especially Pseudomonas aeruginosa. An antistaphylococcal beta-lactam drug plus an aminoglycoside is used when treating S. aureus. Ampicillin (or an equivalent drug) or vancomycin plus an aminoglycoside is used when treating enterococci or viridans streptococcus.

Only the combinations of antimicrobials that are needed to treat enterococcal infections require laboratory testing to confirm synergy. Enterococci are not routinely killed by therapy with a single antimicrobial agent. Enterococcal endocarditis requires bactericidal therapy to ensure a high probability of bacteriologic cure. Combinations of inhibitory, cell-wall–active antimicrobials (e.g., ampicillin or vancomycin), plus gentamicin are synergistic because the cell-wall–destroying antimicrobial agent augments the penetration of gentamicin into the cytoplasm where gentamicin binds to ribosomes and kills the bacterial cell. A surrogate test for synergy in this instance is to perform an MIC test at a single concentration of gentamicin. The enterococcus sample to be tested is inoculated onto an agar plate or into broth medium that contains 500 µg/mL of gentamicin, a concentration so high that gentamicin is forced across the enterococcal cell wall and into the cell’s cytoplasm. If the gentamicin is not inactivated by enterococcal aminoglycoside–inactivating enzymes, the organism will be inhibited, that is, it will be susceptible to the 500 µg/mL concentration of the drug, and synergy can be expected. If the gentamicin is inactivated by enterococcal enzymes, growth is not inhibited, the isolate is resistant to the 500 µg/mL concentration of gentamicin, and synergy will not occur. This high-level gentamicin test should be performed whenever combination antimicrobial therapy is used for the treatment of enterococcal infection.

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Antimicrobial Assays Assays of antimicrobial agents are used to measure the concentrations of these drugs in the blood. These assays can be used to document compliance with a prescribed regimen, to ensure that concentrations of a drug are adequate to effectively treat a serious infection, and to document that concentrations are not at toxic levels. In practice, measurements of aminoglycoside and vancomycin concentrations are the only assays needed routinely. Measurements of both drugs are used to ensure therapeutic and nontoxic levels (21,22). The recommended target levels for the aminoglycosides will depend on the dosing schedule (i.e., the previously traditional every 8 hours or the more commonly used once daily dosing for gram-negative bacilli) and whether used for synergy for enterococci (for this latter indication gentamicin peak levels of 3-4 µg/mL are recommended). For the once daily dosing of gentamicin or tobramycin (7 mg/kg), a peak level is usually not required because the peak levels with this dose are relatively high; trough levels of less than 1 µg/mL are usually the target level recommended. For vancomycin, target levels will depend on the site of infection and MIC of the pathogen. Newer recommendations are pending, but many authorities recommend a trough level of 10 to 15 µg/mL, with higher levels (15-20 µg/mL) for selected infections (e.g., a central nervous system [CNS] infection or methicillin-resistant Staphylococcus aureus [MRSA] pneumonia).

Antibiograms Antibiograms are compilations of antibiotic testing results over a defined period (23). In general, antibiograms list the percentage of bacteria susceptible to antimicrobial agents during the preceding 1-year period. Antibiograms are used to assess the overall activity of antimicrobial agents against a pathogen. Every hospital or community has a different antibiogram. Commonly used antibiograms include those for gram-negative bacilli, S. aureus, and enterococci. Focused antibiograms, with data limited to specific microorganism–antimicrobial combinations, are useful in the management of emerging antimicrobial resistance. Antibiograms for vancomycin-resistant enterococci, Viridans group streptococci, coagulase-negative staphylococci, pneumococci, anaerobes, yeasts, and M. tuberculosis also can be useful. Antibiograms for groups of pathogens isolated from various anatomic sites (e.g., community-wide respiratory pathogens and stool pathogens) provide another way of representing antimicrobial susceptibility data. Table 2-19 is an example of a focused antibiogram for the viridans group streptococci.

9 11 38 0 29

0.015

Abbreviation: MIC, minimum inhibitory concentration.

S. milleri/anginosus group (115) S. mitis group (163) S. mutans group (15) S. salivarius group (32) S. sanguinis group (39)

Organism (number of strains tested) 45 26 100 6 28

0.03 94 41 100 31 39

0.06

Susceptible

Table 2-19 Penicillin Antibiogram for Viridans Group Streptococci

98 60 100 47 62

0.12 99 71 100 53 80

0.25 100 78 100 75 90

0.5

100 80 100 88 95

1.0

Intermediate

100 85 100 91 97

2.0

Cumulative Percent Inhibited by Penicillin MIC of:

100 92 100 94 100

100 100 100 100 100

8.0

Resistant

4.0

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REFERENCES 1. Thomson RB, Peterson LR. Role of the clinical microbiology laboratory in the diagnosis of infections. In: Noskin GA, ed. Management of Infectious Complications in Cancer Patients. Boston: Kluwer Academic Publishers; 1998:143-65. 2. College of American Pathologists. Compliance Guidelines for Pathologists. Northfield, IL: College of American Pathologists; 1978:57-61. 3. Wilson ML. General principles of specimen collection and transport. Clin Infect Dis. 1996;22:766-77. 4. Bartlett RC, Mazens-Sullivan M,Tetreault JZ, Lobel S, Nivard J. Evolving approaches to management of quality in clinical microbiology. Clin Microbiol Rev. 1994;7:55-88. 5. Morris AJ, Smith LK, Mirrett S, Reller LB. Cost and time savings following introduction of rejection criteria for clinical specimens. J Clin Microbiol. 1996;34:355-7. 6. Holland CA, Kiechle FL. Point-of-care molecular diagnostic systems—past, present and future. Curr Opin Microbiol. 2005;8:504-9. 7. Kiska DL, Jones MC, Mangum ME, Orkiszewski D, Gilligan PH. Quality assurance study of bacterial antigen testing of cerebrospinal fluid. J Clin Microbiol. 1995;33:1141-4. 8. Espy MJ, Uhl JR, Sloan LM, Buckwalter SP, Jones MF, Vetter EA, et al. Real-time PCR in clinical microbiology: applications for routine laboratory testing. Clin Microbiol Rev. 2006;19:165-256. 9. Forbes BA, Sahm DF,Weissfeld AS. Bailey and Scott’s Diagnostic Microbiology. 11th ed. St. Louis: Mosby; 2002:1148-68. 10. Miller JM, O’Hara CM. Manual and automated systems for microbial identification. In: Murray PR, Baron EJ, Pfaller MA, et al, eds. Manual of Clinical Microbiology. 7th ed. Washington, DC: ASM Press; 1999:193-201. 11. Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, March 1997. Medical Section of the American Lung Association. Am J Respir Crit Care Med. 1997;156:S1-25. 12. McGinnis MR, Rinaldi MG. Some medically important fungi and their common synonyms and obsolete names. Clin Infect Dis. 1997;25:15-7. 13. Garcia LS. Classification of human parasites. Clin Infect Dis. 1997;25:21-3. 14. Forbes BA, Sahm DF,Weissfeld AS. Bailey and Scott’s Diagnostic Microbiology. 11th ed. St. Louis: Mosby; 2002:799-863. 15. Weinstein AJ, Farkas S. Serologic tests in infectious diseases. Clinical utility and interpretation. Med Clin North Am. 1978;62:1099-117. 16. Woods GL,Walker DH. Detection of infection or infectious agents by use of cytologic and histologic stains. Clin Microbiol Rev. 1996;9:382-404. 17. Jorgensen JH, Ferraro MJ. Antimicrobial susceptibility testing: general principles and contemporary practices. Clin Infect Dis. 1998;26:973-80. 18. Jacobs MR. How can we predict bacterial eradication? Int J Infect Dis. 2003;(suppl 1): S13-20. 19. Kiska, DL. In vitro testing of antimicrobial agents. Semin Pediatr Infect Dis. 1998;9:281-91. 20. Eliopoulos GM, Eliopoulos CT. Antibiotic combinations: should they be tested? Clin Microbiol Rev. 1988;1:139-56. 21. Cantú TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis. 1994;18:533-43. 22. Rogers MS, Cullen MM, Boxall EM, Chadwick PR. Improved compliance with a gentamicin prescribing policy after introduction of a monitoring form. J Antimicrob Chemother. 2005;56:566-8. 23. Ernst EJ, Diekema DJ, Boots Miller BJ,Vaughn T,Yankey JW, Flach SD, et al. Are United States hospitals following national guidelines for the analysis and presentation of cumulative antimicrobial susceptibility data? Diagn Microbiol Infect Dis. 2004;49:141-5.

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Part II

Central Nervous System Infections

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Chapter 3

Bacterial Meningitis CARLOS H. RAMIREZ-RONDA, MD CARLOS R. RAMIREZ-RAMIREZ, MD

Key Learning Points 1. Early recognition of meningitis is essential for better prognosis. 2. Blood cultures should be obtained before therapy is started. 3. Cerebrospinal fluid should be sent for examination including gram stain and culture. 4. The common etiologies are Streptococcus pneumoniae and Neisseria meningitides in areas where Haemophilus influenzae vaccine routine used. 5. Antimicrobial therapy should be instituted as soon as possible after blood cultures have been taken. 6. Consider using adjunctive corticosteroids in patients with suspected or proven bacterial meningitis as recommended by IDSA guidelines.

B

acterial meningitis is a relatively infrequent disease with serious consequences. Central nervous system (CNS) infections account for approximately 1% of hospital admissions. Athough bacterial meningitis is a rare disease, it requires prompt diagnosis and treatment. The morbidity and mortality from bacterial meningitis remain unacceptably high. A 1993 report observed that 61% of infants who survived gram-negative bacillary meningitis had developmental disabilities and neurologic sequelae (1). In 493 episodes of bacterial meningitis in adults, the overall case fatality rate was 25% (2). The increased frequency of isolates of Streptococcus pneumoniae that are resistant to penicillin makes the prompt diagnosis and treatment of bacterial meningitis an urgent requirement (3-13).

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New Developments in Bacterial Meningitis • New pathogens are being observed as causes of community-acquired bacterial meningitis including methicillin resistant Staphylococcus aureus. • Recent studies have identified factors associated with a worse outcome in meningitis in adults caused by Streptococcus pneumoniae including Glasgow coma score, cranial palsies, cerebral spinal fluid WBC < 100 cells/mm3, and markedly elevated erythrocyte sedimentation rate. • Molecular diagnostic techniques are becoming available to enable rapid and accurate diagnosis of bacterial meningitis.

Infection of the CNS can present in a great variety of forms, ranging from acute benign forms of viral meningitis to rapidly fatal bacterial meningitis; in other cases CNS infection can present with slow progressive mental deterioration that can be related to fungal, mycobacterial, or persistent viral infection (Figure 3-1). The most common infectious diseases of the CNS are viral and bacterial meningitis, with the cumulative risk for CNS infection through 80 years of age being 2.3% for men and 1.5% for women (14). Prompt treatment is usually effective for many of the severe presentations of CNS infections. The outcome is often determined by the efficacy and appropriateness of the treatment. Most deaths from bacterial infection occur at an early point, and usually within the first 48 hours of hospitalization. Because of its potential lethality, CNS infection must be recognized early and the probable infecting agent determined as rapidly as possible, either through laboratory examination or clinical diagnosis. Proper initial assessment of the patient requires a careful history, with attention to the evolution of the patient’s disease, the history of exposures to infectious agents, and host factors that can result in increased susceptibility to certain infections. The physical examination is directed at localizing the neurologic disease and identifying evidence of systemic infection. These assessments are supplemented by examination of the cerebrospinal fluid (CSF) and imaging studies.

Epidemiology The frequency of meningitis in children caused by Haemophilus influenzae has declined dramatically in the past 5 to 10 years because of widespread vaccination against H. influenzae type b with the protein conjugated vaccine. From 1985 to 1991 there was an 82% reduction in incidence of H. influenzae meningitis in children < 5 years of age (4,15). This reduction means S. pneumoniae and Neisseria meningitidis have become the predominant causes of meningitis in non-neonates. Another important trend is the worldwide increase in infection with antibiotic-resistant strains of S. pneumoniae. Although penicillin-resistant strains of S. pneumoniae were first identified in the late 1960s, and meningitis caused by such strains was first diagnosed

No

Meningitis

Yes

Focal deficit

Meningitis Encephalitis Meningitis Encephalitis Abscess Abscess encephalitis

Absent

Cranial nerve palsy

Alert Obtunded Coma Present

Level of consciousness

Yes

Meningitis

No

Abscess

No

Meningismus

Meningitis encephalitis abscess

Yes

No

Intracranial presion

Figure 3-1 Algorithm for the evaluation and management of community-acquired or nosocomial meningitis. Clinical presentations are those seen in the acute clinic or emergency room or in hospitalized patients. The community-acquired diseases are divided into those that present with and without prior antibiotic treatment. In those with prior treatment, empirical therapy is started in patients with more than 48 hours of pretreatment, irrespective of the CSF findings. If treatment was for less than 48 hours, empirical treatment is started only on those whose CSF examination shows a protein level of ≥150 mg/dL, a glucose level of ≤40 mg/dL, or a leukocyte count of ≥1200 cells/mL.

Meningitis

Yes

Cranial trauma

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in 1974, the incidence of infection with S. pneumoniae resistant to penicillin and other beta-lactam antibiotics has increased worldwide in the past decade (4,16,17). The new findings are in contrast to the 1990 Centers for Disease Control and Prevention (CDC) report of a multistate surveillance study of bacterial meningitis based on data collected in 1986 (18). H. influenzae was the pathogen most commonly identified. The majority of cases were caused by three species of bacteria: H. influenzae (45%), S. pneumoniae (18%), and N. meningitidis (14%). The incidence rates of infection with specific pathogens were most influenced by age. Case fatality rates varied according both to type of bacteria and age group. For example, the overall case fatality rate for infection was higher for S. pneumoniae (19%) than for either N. meningitidis (13%) or H. influenzae (3%), but that for S. pneumoniae meningitis was much lower in children younger than 5 years of age (3%) than in adults older than 60 years of age (31%) (18). Antibiotic-resistant strains of S. pneumoniae have emerged as a major problem in the United States. For example, in metropolitan Atlanta, from January through October 1994, isolates from 25% of patients with invasive pneumococcal infection were resistant to penicillin (5% were highly resistant, with minimum inhibitory concentrations [MIC] > 2 µg/mL), and isolates from 9% were resistant to cefotaxime (4% were highly resistant) (18).

Etiology The most frequent bacterial pathogens of meningitis (S. pneumoniae, N. meningitidis, H. influenzae) were responsible for approximately 80% of reported cases in the United States. Until the 1990s, H. influenzae was the leading cause of bacterial meningitis, accounting for almost 50% of cases. The position of H. influenzae as the chief cause of bacterial meningitis in infants and young children was changed by the widespread use of H. influenzae type b (Hib) conjugate vaccines. As a result, the relative frequencies of S. pneumoniae and N. meningitidis as agents of meningitis have increased among children (5,6,8,10,11,13,19). Other bacterial causes of meningitis are group B streptococci, Listeria monocytogenes, and enteric gram-negative bacilli. L. monocytogenes has become important in bacterial meningitis as the result of the increasing numbers of immunocompromised and otherwise vulnerable persons at risk, such as transplant recipients, patients undergoing hemodialysis, and patients with liver disease. In New York City, cases of Listeria meningitis increased from 0.9% to 3.4% of all reported cases between 1972 and 1979. Similarly, gram-negative bacillary meningitis (excluding cases caused by H. influenzae) increased in New York City from 5.6% to 7.0% of reported cases between 1972 and 1979 (20). The frequencies of the bacterial agents in meningitis are age related. In neonatal meningitis, Escherichia coli and group B streptococci predominate,

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but other streptococci and L. monocytogenes also have significant roles. After the neonatal period in children, the predominant position of H. influenzae as a cause of meningitis in the first few years of life declined dramatically since 1990 in the United States as a result of widespread immunization with Hib-protein conjugate vaccines. N. meningitidis is the second most frequent cause of childhood bacterial meningitis. For adult meningitis, S. pneumoniae is the principal bacterial agent, causing approximately 40% of cases. In adults with bacterial meningitis treated in tertiary care institutions, cases of nosocomial as well as community origin are seen. Among community-acquired cases, S. pneumoniae, N. meningitidis, and L. monocytogenes are the leading causes, accounting for approximately 40%, 15%, and 10% of cases, respectively. Among nosocomial cases, gram-negative bacilli, various streptococcal species, Staphylococcus aureus, and coagulase-negative staphylococci are the principal infecting microorganisms, accounting for approximately 40%, 15%, and 10% of cases, respectively. Gram-negative bacillary meningitis is commonly a postneurosurgical (nosocomial) complication, but can be spontaneous (in hospitalized patients or in the community setting) (11,13,21). S. aureus is the pathogen in 1% to 9% of cases of bacterial meningitis overall. Cases occur in several categories, based on predisposing circumstances: CNS disorders (usually involving prior neurosurgery) in approximately 50%, endocarditis in approximately 20%, and bacteremia from other sites of infection (often in the setting of diabetes, cancer, or alcoholism) in approximately 25% (22). Obligate anaerobic bacteria rarely cause meningitis. Approximately 1% of cases of bacterial meningitis are polymicrobial infections. The common predisposing factors for mixed bacterial meningitis have become cerebrospinal fluid (CSF) fistulae; neoplasms in proximity to the CNS, such as carcinoma of the rectosigmoid colon eroding through the sacrum to the subarachnoid space; and contiguous sites of infection (23).

Pathogens and Pathophysiology A common feature among the bacterial meningeal pathogens is their polysaccharide capsules. These are present on S. pneumoniae, H. influenzae, N. meningitidis, E. coli K1, and Streptococcus agalactiae (group B streptococcus). Such encapsulation inhibits phagocytosis by neutrophils and antibody-independent, complement-mediated bactericidal activity in different ways. The capsular sialic acid of N. meningitidis seems to facilitate binding of complement factor H to C3b, and this interferes with the binding of factor B and activation of the alternative pathway (24). In the case of S. pneumoniae, factor B binds poorly to C3b on the capsular surface of the organism, and the poly-ribosyl phosphate capsule of Hib cannot serve as an acceptor for covalent C3 deposition (24).

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The initial site of entry of H. influenzae into the CNS is the vascular choroid plexus, which shows the earliest histopathologic evidence of inflammation. After exiting the inflamed plexus capillaries, the organisms enter the lateral ventricles and the subarachnoid space. Once infection is introduced into the CSF, bacteria multiply rapidly because of inadequate local defenses in the form of lack of complement-mediated lysis, opsonizing antibody, and neutrophil phagocytosis. A number of pathophysiologic changes develop as a consequence of bacterial meningitis, and involve the brain, its lining, cranial nerves, meningeal and other intracranial blood vessels, and the spinal cord (24). In experimental animal models, specific bacterial subcapsular components (in the case of S. pneumoniae, peptidoglycan or lipoteichoic acid; in the case of Hib, lipopolysaccharide) are the major inducers of the meningeal inflammation that follows bacterial entry and multiplication in the CSF. Ampicillin-induced lysis of pneumococci in the CSF results in a transient increase in polymorphonuclear cell pleocytosis, consistent with the release of cell-wall debris (24). This inflammatory response is caused by the release into the subarachnoid space of various proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF) from meningeal cells. By inducing the expression of several families of adhesion molecules on endothelium that interact with corresponding leukocytic receptors, these cytokines promote increased adherence and transendothelial movement of neutrophils (24). A leukocyte adhesion of molecule (AM-1) belonging to the selectin family mediates adhesion to endothelium even under conditions of flow; its binding affinity for its endothelial receptor is increased by exposure to cytokines (TNF, granulocyte-macrophage colony-stimulating factor), thus furthering neutrophil trafficking into the subarachnoid space. Once within the subarachnoid space, activated neutrophils release prostaglandins and toxic oxygen metabolites that increase vascular permeability and can cause direct neurotoxicity. Early in the course of meningitis, as observed in animal models, changes take place in meningeal and cerebral capillaries. These vessels, by virtue of their tight intercellular endothelial junctions and their meager rate of pinocytosis, constitute the blood-brain barrier (BBB). They undergo morphologic changes (opening of tight junctions, enhanced pinocytosis) and become permeable to proteins. In experimental Hib meningitis, the increase in permeability in the BBB seems to correlate principally with the bacterial titer in the CSF, but is augmented by increasing pleocytosis. A variety of mediators of the inflammatory response, such as IL-1, IL-6, TNF, complement components, and arachidonate metabolites probably contribute to the breakdown of the BBB and the cerebral manifestations of bacterial meningitis. The major physiologic consequence of altered vascular permeability is (vasogenic) cerebral edema (24). This edema can also have cytotoxic and interstitial components. Increased intracranial pressure (ICP) caused by cerebral edema and reduced reabsorption of CSF produces vomiting and obtundation (24).

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Cerebral blood flow (CBF) seems to be enhanced in the early stages of bacterial meningitis, but it subsequently declines in accordance with the severity of the inflammatory process. Focal areas of marked hypoperfusion (attributable to local vasculitis or thrombosis) can occur in patients with normal overall CBF. In some patients, impaired autoregulation of CBF can contribute to the development of cerebral edema or ischemia or altering cerebral perfusion pressure (24). With the spread of meningeal inflammation over the cerebral hemispheres and into the basal cisterns, superficial pial arteries and veins can be subject to thrombosis. Decreased CBF caused by cerebral edema or vascular thrombosis, plus any element of hypoxia caused by pneumonia or respiratory insufficiency results in enhanced glucose metabolism via the anaerobic glycolytic pathway, with ensuing lactate accumulation in the brain and CSF. This central lactic acidosis can contribute considerably to the obtundation and coma of patients with severe meningitis (24).

Diagnosis Clinical Evaluation Figure 3-2 summarizes the steps in the diagnosis and management of bacterial meningitis.

General Manifestations Headache or backache and fever are common, but not universal, indications of bacterial meningitis. Fever can accompany acute meningitis but can be absent. The initial physical evaluation should include evaluation for level of consciousness, cranial nerve palsy, focal deficits, meningismus, increased ICP and critical trauma (14). Antecedent upper-respiratory tract infection is common in bacterial meningitis (40% of cases), and another 10% to 15% of patients have an illdefined prior illness (often diagnosed as otitis media). Between 25% and 75% of patients have a headache, lethargy, and confusion (meningeal symptoms) of rapid onset (within 24 hours). Other patients have more prolonged (1 to 7 days) respiratory tract or otic symptoms, with meningeal symptoms that develop and progress more slowly. In patients with L. monocytogenes meningitis, the prodromal symptomatic period tends to be longer than in patients with other types of pyogenic meningitis (12,25,26). Kerning and Brudzinski signs, along with fever, vomiting, irritability, lethargy, and headache, are features found on physical examination in most patients. Neck stiffness is a symptom in less than half of patients, but nuchal rigidity of some degree is noted as a sign in more than 80%. Myalgias (especially in meningococcal diseases) and backache occur less frequently. Reduced cognitive function is also seen. Photophobia is more often associated with viral meningitis.

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Headache, Fever, Confusion, Vomiting, Lethargy, Irritability, ± Nuchal rigidity, + Kerning signs, + Brudzinski signs, etc.

Community

Nosocomial Hx:

Neurosurgery Head trauma Sepsis Other site

Neurologic localizing signs or Papilledema

< 48 hrs CSF Exam Protein Glucose WBC count WBC differential Gram-Stain Culture or gluc < 40 + glucose < 40 protein > 150 WBC > 1200 observe Gram stain + −

+ Neurology/ Neurosurgery Consult

> 48 hrs

Localizing signs321 −

+

CSF Exam Empiric Rx 3rd Gen CPS

Repeat Empiric Rx CSF exam CPS 3rd or in 8–24 hrs CPS 4th* ± Vancomycin ± Aminoglycoside

*If Listeria possible Ampicillin, if using dexamethasone consider rifampin.

< 48 hrs CSF Prot > 150

All with > 48 hrs

Ampicillin

Empiric Rx or WBC > 1200

CT

−

Not pre-treated

Antibiotics for

No localizing signs

Empiric Antibiotic Therapy CPS3 3rd Gen AP/ CPS4 4th Gen ± ± Vancomycin ± Aminoglycoside

CT

Pre-treated

+ Neurology

−

+

− Observe

Repeat CSF exam in 8–24 hrs

− Observe

+

Figure 3-2 Algorithm for the patient who presents with granulomatous meningitis.

A petechial or purpuric rash, predominantly on the extremities, in a patient with meningeal signs carries the high probability of a meningococcal cause, and requires immediate treatment because of the rapidity with which this type of infection can advance. Approximately 50% of patients with meningococcal meningitis have such skin lesions. In more severe meningococcal infections, large purpuric areas develop, usually accompanying hypotension or shock and evidence of disseminated intravascular coagulation (DIC). Petechial and purpuric skin lesions sometimes occur in

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patients with acute S. aureus endocarditis who have meningeal signs and CSF pleocytosis (either from staphylococcal meningitis or cerebral embolic infarction). In this setting, one or two of the purpuric lesions often contain a purulent center, and aspirated material reveals gram-positive cocci in clusters (Staphylococci) on Gram-stain examination. Macular and petechial skin lesions accompanied by meningeal signs can occur with enteroviral aseptic meningitis in summer outbreaks (12). Infections of the leptomeninges can present with signs and symptoms of meningeal irritation and altered mental status. Inflammation of the meninges causes reflex paraspinous muscle spasm, which is reflected in an opisthotonic posture as nuchal rigidity, inability to straighten a raised leg, and flexion of the leg when the neck is flexed, or opisthotonic posture. Most patients with acute bacterial meningitis after the neonatal period have signs of meningeal irritation at the time of presentation (14). Those without such signs are more likely to be elderly and to have gram-negative meningitis. Neonates usually exhibit listlessness but no clear CNS signs. Seizures are common. Disease within the brain parenchyma can result in seizures, altered states of consciousness, acute changes in personality or behavior, or focal neurologic deficits. The hypothalamic–pituitary axis can be involved, causing severe hypothermia and diabetes insipidus. The evidence of CNS infection in meningitis can be masked in elderly persons by other disease processes. Fever can be attributed to a recognized infection elsewhere, such as pneumonia, cellulitis, endocarditis, otitis, or sinusitis, and altered CNS function can be blamed on alcoholism, head trauma, stroke, brain tumor, subarachnoid hemorrhage, or metabolic abnormalities. Treatable CNS infection, particularly bacterial meningitis, must be ruled out in such patients. This is usually done by careful neurologic examination, including lumbar puncture.

Neurologic Manifestations In adults the most frequent neurologic complications of bacterial meningitis are cerebrovascular, occurring in approximately 37% of patients with intracranial complications, followed in frequency by brain swelling, which is detected by computed tomography (CT) (in 34% of cases, and hydrocephalus in 29%) (27). BRAIN SWELLING As noted earlier, cerebral edema can occur in acute bacterial meningitis. Manifestations include obtundation and coma, palsies of cranial nerve VI, abnormal reflexes, hypertension, decerebrate posturing, an abnormal respiratory pattern, and bradycardia. Brain edema causes increased ICP, which in older infants has been shown to reduce cerebral blood flow velocity. The resulting decrease in cerebral perfusion is another potential cause of brain injury. Papilledema is rare because of the relatively brief duration of the meningeal process and increased CSF pressure.

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A markedly increased ICP from meningitis can lead to herniation. The following are signs of herniation: bradycardia and an abnormal respiratory pattern; midposition, nonreactive pupils; unequally sized or dilated, nonreactive pupils; a skew deviation or dysconjugate movements of the eyes; decorticate or decerebrate posturing (12). Marked hyperpnea sometimes occurs in patients with severe bacterial meningitis; in this condition, CSF acidosis, caused mainly by increased lactic acid levels, provides much of the respiratory drive.

FOCAL CEREBRAL SIGNS Focal cerebral signs (hemiparesis, quadriparesis, visual field defects, disorders of conjugate gaze, dysphasia) occur in 10% to 20% of patients with meningitis, more frequently with pneumococcal than with other types of meningitis. These signs can appear early in the course of meningitis, or, less frequently, later in the course of the disease as a result of cortical arteritis or phlebitis. CRANIAL NERVE DYSFUNCTION Cranial nerve dysfunction has been reported in 10% to 20% of patients with bacterial meningitis. Cranial nerves III, VI, and VIII are most often involved. The highest frequency of involvement is associated with S. pneumoniae meningitis. Vasculitis-induced infarction of cranial nerve VIII and necrosis of cells in the organ of Corti can be responsible for permanent deafness. Involvement of the inner ear is not a result of direct extension of infection from the middle ear to the inner ear, even when otitis media precedes meningitis (12,28). SEIZURES Seizures in meningitis can be focal or generalized. Early seizures occur in 15% to 30% of cases of bacterial meningitis. In a study of adults with meningitis, S. pneumoniae was the cause of seizures in a greater percentage of those patients who had them, but alcoholism was a confounder. Seizures that occur early in hospitalization do not herald the onset of a permanent seizure disorder, but those that persist beyond the first few days or that develop later during hospitalization can do so (29). Non-Neurologic Complications SEPTIC COMPLICATIONS Because of the early treatment of acute bacterial meningitis, endocarditis is an uncommon complication of the bacteremia associated with such meningitis. In the rare instance in which endocarditis develops, it usually involves the aortic valve. Pyogenic arthritis caused by the common agents of meningitis can complicate the presentation early in the course of CNS infection. COAGULOPATHIES In patients with meningitis, coagulation disorders (thrombocytopenia, DIC) can complicate bacteremia and hypotension. The coagulopathy can be mild and consist only of thrombocytopenia, but in patients with more profound bacteremia the clinical features and laboratory findings can be typically those of DIC.

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SHOCK Shock can develop early in the course of acute bacterial meningitis as a consequence of intense bacteremia, and this can also occur in meningococcemia-meningitis or in pneumococcal bacteremia in asplenic patients. PROLONGED FEVER Most patients with the common types of bacterial meningitis become afebrile within 2 to 5 days of initiation of appropriate antimicrobial therapy. Occasionally, fever persists for 8 to 10 days or longer, or recurs after initial defervescence. Such a febrile course, accompanied by persisting headache, a stiff neck, a depressed sensorium, and focal cerebral signs, suggests that antimicrobial therapy has been inadequate or that a neurologic complication (e.g., cortical vein thrombophlebitis and arteritis, ventriculitis, ventricular empyema, subdural effusion or empyema, sagittal sinus thrombosis) has supervened. Reevaluation of CSF findings, particularly Gramstained smears and cultures, is of paramount importance; the appearance of new focal cerebral signs would be an indication for cranial CT. (Examination of CSF is described in the following section, Laboratory Diagnosis.) Drug fever or a serum sickness-like syndrome should be considered in a patient with persistent fever whose clinical course and CSF findings show continued improvement.

Laboratory Diagnosis CSF Examination Examination of CSF is the basis of the diagnostic approach to CNS infection. Normally, CSF is crystal clear, contains less than five mononuclear cells per cubic millimeter; has a protein content of less than 4.5 g/L, of which 14% or less is g-globulin; has a glucose concentration approximately two thirds that of the blood; and is under a pressure of less that 180 mm H2O (21). CNS infection usually produces changes in the CSF. These can include an increased number of cells, increased protein concentration, and decreased glucose concentration. Total and differential cell counts should be made. Mononuclear cells usually predominate in nonbacterial (mycobacterial, fungal, rickettsial, and viral) infections; predominance of polymorphonuclear leukocytes (PMN) is typical of bacterial infections, but can also be seen in amebic infections and early in viral infections. One PMN or more than five mononuclear cells in an uncentrifuged CSF specimen are abnormal. Early in any of these diseases there can be no increase in the cell number. Repeated examination of the CSF after 8 to 24 hours in patients suspected of having a viral process is often useful. A pleocytosis can be found in subacute bacterial endocarditis, after severe seizures, and during systemic viral infections such as measles. Large numbers of erythrocytes can be found in the CSF in herpes virus infection and in postinfectious and amebic encephalitis (12,19,30,31). A CSF specimen should be stained and cultured for the possible infecting organism in meningitis. Because CNS infection is frequently a complication of

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systemic diseases, other body fluids (e.g., blood, stool, throat scrapings, sputum, and urine) should also be cultured. Short-term antibiotic treatment before hospital admission does not significantly alter the total or differential cell count or CSF protein or glucose values; however, it does reduce the frequency of positive cultures and diagnostic Gram stains (12). Some fungal and bacterial antigens (e.g., Cryptococcus, Haemophilus, pneumococcus, and meningococcus) can be detected by immunodiagnostic techniques, providing a rapid clue to diagnosis and a potential mechanism for identifying the infecting organism in previously treated persons. The polymerase chain reaction (PCR) is increasingly useful for the diagnosis of viral infections of the CNS (32-35). The CSF protein level increases with most infections, and in chronic infections an increased proportion of this protein can consist of locally synthesized immunoglobulin. The increase in protein concentration can be slight with viral infections, but is usually greater with bacterial, fungal, or tuberculous infections. An increased protein value can be the only CSF abnormality in brain abscess or parameningeal infection. The immunoglobulin present is often directed against the infecting agent. The CSF glucose value is usually low in untreated bacterial meningitis, and is often also low in fungal, tuberculous, and amebic meningitis. The CSF glucose value can best be interpreted if a plasma glucose level is also available from a sample taken at approximately the same time. The CSF glucose value can be depressed in some encephalitides of viral meningitis (mumps, lymphocytic choriomeningitis viruses, herpes virus infection), and CNS sarcoid, tumors, and subarachnoid hemorrhage (36). Infection at the site where the puncture will be performed is a contraindication to lumbar puncture. The major risk in performing a lumbar puncture occurs when there is evidence of increased ICP from a mass lesion in the brain. With removal of CSF, the ICP dynamics can be altered, and the brain can shift and herniate through the tentorial notch or foramen magnum. If a mass lesion is suspected on the basis of the history or physical examination, or if increased ICP is evident on funduscopic examination, an imaging technique such as CT or magnetic resonance imaging (MRI) should be used before lumbar puncture. If this occurs after culture, empiric antibiotic therapy should be begun. In other situations, lumbar puncture should not be delayed, because the information gained from examining the CSF is crucial for the differential diagnosis and early institution of treatment (19,37).

Other Laboratory Studies Blood cultures from patients with meningitis often reveal the pathogen, disclosing 90% of H. influenzae, 80% of S. pneumoniae, and 90% of N. meningitidis (34).

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Bacteremic skin lesions associated with highly invasive organisms can reveal the agent on a Gram-stained smear. Thus, for example, aspiration of the whitish center of one of the cutaneous purulent purpura associated with S. aureus or N. meningitides bacteremia can reveal the pathogen. The purely petechial lesions of the skin in bacterial meningitis, however, are unlikely to be revealing on Gram-stain examination. Gram-stain examination and a culture of fluid aspirated from a middleear effusion can provide a clue to bacteriologic diagnosis when the findings of CSF smear examination are equivocal. The peripheral leukocyte count is commonly increased in patients with bacterial meningitis, ranging from 14,000 to 24,000 cells/mm3, and is generally higher in pneumococcal and meningococcal than in H. influenzae disease (12). Hyponatremia in the course of bacterial (or tuberculous or fungal) meningitis is commonly caused by either the complicating syndrome of inappropriate antidiuretic hormone secretion (SIADH) or by inappropriate fluid administration.

Radiologic Studies Chest radiographs should be made in cases of bacterial meningitis to discover any predisposing pulmonary portal of infection. Films of the air sinuses and mastoids should be made at an appropriate time after commencing antimicrobial therapy if the history or findings suggest infection of these structures. When the history, clinical setting, or physical signs (papilledema, focal cerebral findings) suggest a suppurative intracranial fluid collection, cranial CT should be done without delay, and before lumbar puncture (but after blood for cultures has been taken, and therapy with appropriate antimicrobials for meningitis of unknown bacterial cause has been instituted) (12). Patients with bacterial meningitis rarely have clinically significant CT findings without concomitant focal neurologic abnormalities. A CT done during the second week of meningitis is most sensitive for cerebral infarction. In the course of meningitis in children, CT is most valuable when focal neurologic findings persist, when CSF cultures remain positive, or when meningitis is recurrent (38,39). In approximately 30% of adults with meningitis, CT shows abnormalities related to meningitis or its complications. Cerebral edema and dural enhancement are abnormalities seen on scans done within 72 hours of admission, whereas cerebral infarcts are seen on later scans. Ventriculomegaly is the most common CT abnormality in adult meningitis, occurring in 15% of all cases, of which 15% require a shunting procedure. In the study of adult meningitis in which this was found, 19 (49%) of the 39 patients who exhibited focal

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neurologic deficits or seizures had CT abnormalities related to meningitis. In contrast, of the 48 patients with nonfocal findings, only eight (17%) had CT abnormalities. Thus, CT in meningitis should not be routine, but should be employed as indicated by the clinical setting, neurologic findings, and clinical course (12,21).

Differential Diagnosis The clinical manifestations of meningeal inflammation in bacterial meningitis (headache, fever, stiff neck, obtundation) are common to various other types of meningitis (viral, fungal mycobacterial, treponemal, borrelial, parasitic, hypersensitivity), as well as to acute pyogenic bacterial meningitis and to parameningeal infections. Analysis of CSF findings is central to development of the differential diagnosis.

Nonbacterial Meningitis A retrospective analysis of the predictive value of initial clinical and laboratory observations was performed with 422 patients who had meningitis seen at one hospital between 1969 and 1980 (4). Five CSF values were found to be individual predictors of bacterial infection with 99% or greater certainty: 1. 2. 3. 4. 5.

The CSF glucose level is less than 1.9 mmol/L (34 mg/dL). The CSF/blood glucose ratio is less than 0.23. The CSF protein level is more than 2.2 g/L. There is more than 2000/mm3 CSF. There is more than 1180 CSF neutrophils per mm3.

Although any one of the foregoing tests could rule in bacterial meningitis with a high likelihood, none could exclude it. However, a logistic multiple regression model, utilizing the following parameters: patient age, month of onset, total CSF neutrophil count, and CSF/blood glucose ratio could be used to exclude acute bacterial meningitis with more than 95% confidence in patients whose CSF Gram stains were negative. Aseptic enteroviral meningitis usually can be distinguished from bacterial meningitis by its epidemiology, more gradual onset, rare occurrence of outbreaks, accompanying macular or petechial rash, and lymphocytic pleocytosis without hypoglycorrhachia (9). Aseptic echovirus meningitis can present with an initial pleocytosis of up to 1000 cells per mm3 and neutrophil predominance, which shifts in the following 12 to 36 hours to a predominance of lymphocytes. In nonbacterial meningitis, the CSF glucose level is usually greater than 40 mg/dL, but can be slightly reduced in occasional patients if the pathogen is the virus of lymphocytic choriomeningitis,

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mumps, or herpes simplex. Aseptic meningitis can be associated with the acute human immunodeficiency virus (HIV) mononucleosis-like syndrome. Acute aseptic herpes simplex virus type 2 (HSV-2) meningitis occurs in sexually active persons, and can be distinguished from bacterial meningitis by the presence of clustered vesicular lesions in the genital area or inguinal lymphadenopathy and by its lymphocytic pleocytosis. The aseptic meningitis of neuroborreliosis can be distinguished from acute pyogenic meningitis by its more subacute onset, exposure of the patient to an area endemic for Lyme disease, positive serologic test result for Lyme disease, lymphocytic pleocytosis, and history of erythema chronicum migrans. Leptospiral meningitis might be suggested by a biphasic illness, conjunctivitis, and lymphocytic pleocytosis occurring in a person exposed to rodents, dogs, or cows. Diagnosis of this disease is usually made by serologic testing. Tuberculous meningitis occurs in a setting of either past tuberculous infection (breakdown of an old meningeal tuberculoma) or recently acquired infection with miliary dissemination to the meninges in an immunocompetent or immunocompromised (e.g., HIVinfected) patient. The onset of tuberculous meningitis tends to be less abrupt than that of acute pyogenic meningitis. The characteristic CSF changes are lymphocytic pleocytosis, hypoglycorrhachia, and an increased protein concentration. Bilateral palsies of cranial nerve VI suggest a basilar meningitis, and with the CSF algorithm described earlier, strongly suggest tuberculous meningitis. Fungal meningitides are almost always more subacute in onset than is bacterial meningitis, produce a lymphocytic pleocytosis with hypoglycorrhachia, and are suggested by epidemiologic clues. Fungal meningitides— such as Cryptococcus neoformans—most commonly present the clinical picture of chronic meningitis, and are diagnosed by culture and antigen detection in the CSF, or by antibody determination in the CSF and serum. Rarely, chronic meningitis can be characterized by a predominantly neutrophilic CSF according to the algorithm previously described, for which any of several bacterial and mycotic agents can be responsible. Parameningeal infections (particularly brain abscess, subdural empyema, and cranial and spinal epidural abscess) should be considered in the differential diagnosis of acute bacterial meningitis. These processes might be suspected in a patient with features of meningeal inflammation who also has a chronic ear, sinus, or lung infection. Focal cerebral signs and neurologic symptoms antedating the onset of the acute meningitis suggest a space-occupying intracranial infection, such as a brain abscess. In a patient with presumed bacterial meningitis whose CSF algorithm shows an atypical neutrophilic pleocytosis, a normal glucose level, and no demonstrable organisms on a Gram-stained smear, parameningeal infections warrant particular attention in the differential diagnosis. Isolation of anaerobic bacteria from CSF, especially in mixed culture, suggests parameningeal infection.

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Naegleria fowleri can rarely produce a fulminant, acute, and usually fatal purulent meningitis. This diagnosis would be considered for a patient who had recently swum in warm freshwater. Early symptoms can include an altered sense of smell and taste. In addition to a neutrophilic pleocytosis with a low to normal glucose level, the CSF often contains numerous erythrocytes. The diagnosis is made by finding motile amoebic trophozoites in fresh preparations of uncentrifuged CSF. The clinical picture of acute meningitis can develop in bacterial endocarditis. It can represent true bacterial meningitis caused by a pyogenic organism (e.g., S. pneumoniae, S. aureus), or it can result from cerebral embolic infarction from endocarditis caused by a nonpyogenic organism. The CSF findings of cerebral infarction in this latter situation include a pleocytosis of several hundred cells, with varying numbers of neutrophils, a normal glucose level, and absence of bacteria. In occasional patients with meningeal symptoms caused by small cerebral embolic infarctions from acute S. aureus endocarditis, the diagnosis can be made by examining Gram-stained smears of purulent cutaneous purpura lesions.

Chemical Meningitis Chemical meningitis occasionally results from leakage into the subarachnoid space of debris from an intracranial tumor, commonly a craniopharyngioma or an epidermoid tumor of the posterior fossa. This can produce the picture of recurrent meningitis. The CSF findings include an initial neutrophilic (or lymphocytic) pleocytosis, with or without hypoglycorrhachia. Birefringent material (keratinized debris) from an epidermoid tumor or a craniopharyngioma can be observed under polarized light microscopy (40). Another rare, noninfectious cause of meningitis is systemic lupus erythematosus. The CSF in such cases usually shows a lymphocytic pleocytosis with a normal glucose concentration, although rarely, numerous neutrophils and hypoglycorrhachia are features. Antinuclear antibodies are present in high titers. Rarely, unusual acute, recurrent episodes of nonbacterial meningitis of unknown cause are part of the course of Behçet syndrome, Mollaret meningitis (believed to be caused by recurrent herpes meningitis), or familial Mediterranean fever. Hypopyon, oral and genital lesions, and pathergic skin changes would be indicative of Behçet syndrome.

Hypersensitivity Meningitis Occasionally, meningitis is the principal manifestation of hypersensitivity to drugs such as sulfonamides and nonsteroidal antiinflammatory agents. The pleocytosis in such cases can be predominantly neutrophilic or lymphocytic, and some eosinophils can be present, but the glucose level in CSF is normal. Mollaret meningitis, characterized by self-limited episodes of fever, meningeal

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findings, mononuclear pleocytosis (sometimes neutrophilic at inception), and the presence in the CSF of unusual cells variously described as epithelial or endothelial, has been associated in some instances with underlying Herpes simplex virus type 1 (HSV-1) infections or with epidermoid cysts of the CNS (6,8,12,13,19,30,41-43).

Treatment The efficacy of antimicrobial therapy in bacterial meningitis depends on a variety of factors, including the antimicrobial susceptibility of the organism, bactericidal activity of the antimicrobial agent, capacity of the antimicrobial agent to penetrate BBB, and effectiveness of various modes of antimicrobial drug administration in achieving desired concentrations of the drug in the CSF. Because there is a lack of intrinsic opsonic and antibacterial activity in the CSF early in bacterial meningitis, bactericidal rather than bacteriostatic agents are needed for treatment (44). The CSF concentration of beta-lactam antibiotics, vancomycin, or aminoglycosides must be 10 to 20 times higher than the minimal bactericidal concentration for the infecting organism if optimal bactericidal effects are to be achieved. The low pH and abundance of nucleic acids in purulent CSF inhibit rapid bacterial killing by aminoglycosides. Most antimicrobial agents used in treating bacterial meningitis, with the exception of chloramphenicol, do not penetrate well through the normal BBB. Beta-lactam antibiotics penetrate only to the extent of 0.5% to 2.0% of their peak serum concentrations, although higher concentrations are achieved when the meninges are inflamed. Clindamycin, erythromycin, and first- and second-generation cephalosporins should not be used to treat bacterial meningitis because effective bactericidal levels in the CSF cannot be obtained with these drugs. For antimicrobial drugs such as beta-lactam drugs, aminoglycosides, and vancomycin, which poorly penetrate even inflamed meninges, intermittent bolus parenteral administration is preferred because higher peak levels are achieved (19). The Infectious Diseases Society of America (IDSA) has prepared recently the treatment guidelines for bacterial meningitis, which we recommend to be used as reference (45).

Why Bactericidal Activity in Cerebrospinal Fluid? “Bacterial meningitis is an infection in an area of impaired host resistance” (19). Specific antibody and complement are frequently absent from the CSF in patients with this disease, resulting in inefficient phagocytosis and in rapid bacterial multiplication (to concentrations of 10 million or more colonyforming units per milliliter of CSF (46). Optimal antimicrobial treatment requires that the drug being used have a bactericidal effect in the CSF.

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Patients with pneumococcal and gram-negative bacillary meningitis who are treated with bacteriostatic antibiotics have poor clinical outcomes (12,19,47).

Factors Influencing Bactericidal Activity in Cerebrospinal Fluid The major factors affecting the bactericidal activity of an antimicrobial drug in CSF are its relative degree of penetration into the fluid, its concentration there, and its intrinsic activity in infected CSF. The penetration of an antimicrobial drug into CSF is primarily influenced by the characteristics of the drug and the integrity of the BBB (Table 3-1). When the barrier is intact, penetration is limited because vesicular transport across cells is minimal, and

Table 3-1 Empiric Selection of Antibiotics for the Treatment of Suspected Bacterial Meningitis Group of Patients

Likely Pathogen

Choice of Antibiotic

Neonate < 1 month

S. agalactiae, E. coli, Group D Other enterobacteriae Listeria S. pneumoniae, N. meningitidis + neonatal pathogens or L. monocytogenes N. meningitidis, S. pneumoniae

Ampicillin plus cefotaxime or ceftriaxone Ampicillin plus cefotaxime, ceftriaxone; dexamethasone if H. influenzae Cefotaxime/ceftriaxone ± dexamethasone + vancomycin ± rifampin if DRSP suspected Cefotaxime/ceftriaxone + Dexamethasone Vancomycin + rifampin if pneumococci Ampicillin plus cefotaxime or ceftriaxone plus dexamethasone plus rifampin if pneumococci Ampicillin plus ceftazidime or cefepime or meropenem

Infant 1–3 months

Age, 3 mo to <7 years

Age, 7 to 50 years

S. pneumonia or N. meningitidis H. influenzae

Age, >50 years

S. pneumoniae, L. monocytogenes, or gram-negative bacilli (rare) L. monocytogenes or gram-negative bacilli including P. aeruginosa

With impaired cellular immunity (alcoholics, other, primary or secondary) With head trauma, neurosurgery, or cerebrospinal fluid shunt With recurrent episodes of meningitis

Staphylococci, gram-negative bacilli, P. aeruginosa, or S. pneumoniae

Vancomycin plus ceftazidime or meropenem

S. pneumoniae (most common)

Broad-spectrum cephalosporins Cefotaxime/ceftriaxone Vancomycin plus dexamethasone plus rifampin

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the junctions between the endothelial cells of the cerebral microvasculature are tight. However, during meningitis there is an increase in vesicular transport across cells in meningeal arterioles and complete separation of the tight junctions between endothelial cells in meningeal venules. These changes result in increased permeability of the BBB, increasing the penetration of many microbial drugs (such as beta-lactam drugs) into the CSF to 5% to 10% of their serum concentrations. For other antibiotics more highly soluble in lipids (such as chloramphenicol, rifampin, and trimethoprim), penetration into CSF is high (reaching 30% to 40% of their serum concentration) even when the meninges are not inflamed (1). The CSF concentration of an antimicrobial agent needed for maximal bactericidal activity is unknown. In experimental meningitis, maximal bactericidal activity occurs when the concentration of drug is 10 to 30 times the minimal bactericidal concentration against the organism in vitro (48). One explanation for this difference is that infected CSF decreases the activity of an antimicrobial drug (19). Because the activity of a beta-lactam drug such as penicillin G on bacterial cell-wall synthesis depends on bacterial cell division, fever can impair its bactericidal effect in vivo (49).

Hazards of Antimicrobial Therapy Bactericidal therapy often results in bacteriolysis of the pathogen. As a result, treatment can promote the release of biologically active cell-wall products (e.g., the lipopolysaccharide of gram-negative bacteria and the teichoic acid and peptidoglycan of streptococci) into the CSF. This release of cell-wall fragments can increase the production of cytokines (IL-1, IL-6, and tumor necrosis factor-α [TNFα]) in CSF, exacerbating inflammation and further damaging the BBB. Achieving a rapid bactericidal effect in CSF remains a primary goal of therapy for meningitis (19,30).

When Should Treatment Be Started? It is important to promptly institute antibiotic therapy for bacterial meningitis, and the accusation of failure to promptly treat the disease is a common reason for malpractice litigation (19). The intuitive assumption is that a delay in therapy of even a few hours affects the prognosis adversely, although the clinical data on this are inconclusive (19). One of the most important factors contributing to delayed diagnosis and treatment of bacterial meningitis is the decision to perform cranial CT imaging before lumbar puncture is done. If imaging is indicated, investigators have suggested obtaining blood cultures, instituting empirical antimicrobial therapy, and performing lumbar puncture immediately after imaging if it

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discloses no intracranial mass lesion (5,12,19). Instituting antimicrobial therapy 1 to 2 hours before lumbar puncture will not decrease the diagnostic sensitivity if the culture of CSF is done in conjunction with testing of CSF for bacterial antigens and with blood cultures (19,45,50,51).

Empiric Antimicrobial Therapy When lumbar puncture is delayed or a Gram stain of CSF is nondiagnostic, empirical therapy is essential and should be directed at the most likely pathogens on the basis of the patient’s age and underlying health status (see Table 3-1 and Figure 3-3). For most patients, the IDSA treatment guidelines and most authors recommend therapy with vancomycin and a broadspectrum cephalosporin (cefotaxime or ceftriaxone), supplemented with ampicillin in neonates (younger than 1 month of age) and in young infants (1 to 3 months of age), because in these groups infections with S. agalactiae and L. monocytogenes are more prevalent. These recommendations require modification under special circumstances (2,8,13,19,30,45,50). For immunocompromised patients, treatment should include ampicillin (for possible Listeria) and vancomycin plus a broad-spectrum cephalosporin (such as ceftazidime or cefepime) that has more inclusive activity against gramnegative organisms, and specifically P. aeruginosa. Patients with recent head trauma or neurosurgery, and those with CSF shunts, should be given broadspectrum antibiotics effective against both gram-positive and gram-negative organisms, such as a combination of vancomycin and ceftazidime. For patients with identifiable bacteria on a Gram stain of CSF, microbial therapy should be directed toward the presumptive pathogen (Table 3-2). For all patients, therapy should be modified when the results of CSF culture and antibiotic susceptibility testing become available (12,19).

Empiric Glucocorticoid Therapy The IDSA guidelines state that consideration should be given to administration of adjunctive dexamethasone in certain patients with suspected or proven bacterial meningitis. The rationale for use is derived from experimental animal models of infection, which have shown that the subarachnoid space inflammatory response during bacterial meningitis is a major factor contributing to morbidity and mortality (45,52-55). The IDSA guidelines state that, at present, there are insufficient data to make a recommendation on the use of adjunctive dexamethasone in neonates with bacterial meningitis. For infants and children the recommendation is derived from a retrospective study involving children with pneumococcal meningitis that showed that in the dexamethasone group, there was a

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Bacterial Meningitis

Modification for Age Empiric Therapy

Neonate < 1 mo S. agalactiae E. coli L monocytogenes

Ages 1 mo–7 years H. influenzae N. meningiditis S. pneumoniae

Ages 7–50 N. meningitidis S. pneumoniae

Ages > 50 S. pneumoniae N. meningitidis Listeria

Cefotaxmine or ceftriaxone plus Ampicillin

Cefotaxime or Ceftriaxone*

Cefotaxime or Ceftriaxone*

Cefotaxime or Ceftriaxone*

*If suspect DRSP consider adding vancomycin and or rifampin

Look at Results of Cultures/Serologies Studies of bacterial antigens Evaluate Clinically

Clinical Evaluation

No improvement or Deterioration

Improvement

Consider Repeat Continue Therapy CSF Exam and Follow up

Figure 3-3 Algorithm for the empirical therapy and follow-up guidelines for bacterial meningitis based on the age of the patient.

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Table 3-2 Recommendations for Antibiotic Therapy in Patients with Bacterial Meningitis Who Have a Positive Gram Strain or Culture of Cerebrospinal Fluid* Type of Bacteria

Choice of Antibiotic

By Gram stain

Cocci Gram-positive Gram-negative

Vancomycin plus cefotaxime or ceftriaxone, plus dexamethasone plus rifampin Penicillin high dose (300,000 U/kg up to 24 million U)

Bacilli

Gram-positive

Gram-negative

Ampicillin 100 mg/kg every 18 hours in children and 12 g/day in adults (or penicillin G) plus gentamicin 1.5 mg/kg every 1.8 hours Cefotaxime/ceftriaxone/ceftazidime or meropenem if P. aeruginosa likely

By culture

S. pneumoniae H. influenzae N. meningitidis L. monocytogenes S. agalactiae Enterobacteriaceae Pseudomonas aeruginosa, Acinetobacter

Vancomycin plus cefotaxime or ceftriaxone plus dexamethasone plus rifampin Ceftriaxone or cefotaxime Penicillin G high dose Ampicillin plus gentamicin—see gram-negative bacilli Penicillin G (some add gentamicin in neonates) Broad-spectrum cephalosporin or meropenem plus aminoglycoside (intravenous gentamicin; may need intrathecal) Ceftazidime or meropenem with or without aminoglycoside susceptibility studies

* Modified from Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708–16.

higher incidence of moderate or severe hearing loss (46% vs. 23%; P = .016) or any neurologic deficits (55% vs. 33%; P = .02) (56). In a recently published randomized, placebo-controlled, double-blind trial of adjunctive dexamethasone in children in Malawi (57), the overall number of deaths (31% vs. 31%; P = .93) and presence of sequelae at final outcome (28% vs. 28%; P = .97) were not significantly different in the children who received adjunctive dexamethasone. The guidelines state that adjunctive dexamethasone does not reverse the CNS damage that develops as a result of existent cerebral edema, increased intracranial pressure, or neuronal injury that is present at diagnosis. Despite some variability in result of published trials, the IDSA guideline authors believe the available evidence supports the use of adjunctive dexamethasone in infants and children with H. influenzae type b meningitis. Dexamethasone should be initiated 10 to 20 minutes prior to, or at least concomitant with, the first antimicrobial dose, at 0.15 mg/kg every 6 hours for 2 to 4 days. Adjunctive dexamethasone should not be given to infants and children who have already received antimicrobial therapy, because administration of dexamethasone in this cir-

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cumstance is unlikely to improve patient outcome. In infants and children with pneumococcal meningitis, there is controversy concerning the use of adjunctive dexamethasone therapy. The guidelines state that “For infants and children 6 weeks of age and older, adjunctive therapy with dexamethasone can be considered after weighing the potential benefits and possible risks. Experts vary in recommending the use of corticosteroids in pneumococcal meningitis; data are not sufficient to demonstrate clear benefit in children” (58). For adults the IDSA guideline recommendations (45) are based on a recent published prospective, randomized, placebo-controlled, double-blind multicenter trial that did provide important data on the use of adjunctive dexamethasone in adults with bacterial meningitis (59). At 8 weeks after enrollment, the percentage of patients with an unfavorable outcome (15% vs. 25%; P = .03) and death (7% vs. 15%; P = .04) was significantly lower in the dexamethasone group. The IDSA guidelines (45) establish that on the basis of the available evidence on the use of adjunctive dexamethasone in adults, the use of dexamethasone is recommended (0.15 mg/kg every 6 hours for 2-4 days with the first dose administered 10-20 minutes before, or at least concomitant with, the first dose of antimicrobial therapy) in adults with suspected or proven pneumococcal meningitis. The authors of the guidelines recommend that adjunctive dexamethasone should be initiated in all adult patients with suspected or proven pneumococcal meningitis, because assessment of the score can delay initiation of appropriate therapy. Dexamethasone should only be continued if the CSF Gram stain reveals gram-positive diplococci, or if blood or CSF cultures are positive for S. pneumoniae. Adjunctive dexamethasone should not be given to adult patients who have already received antimicrobial therapy, because administration of dexamethasone in this circumstance is unlikely to improve patient outcome. The IDSA guidelines recommend that adjunctive dexamethasone be administered to all adult patients with pneumococcal meningitis, even if the isolate is subsequently found to be highly resistant to penicillin and cephalosporins; in patients with suspected pneumococcal meningitis who receive adjunctive dexamethasone, the addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin can be reasonable pending culture results and in vitro susceptibility testing.

Treatment of Specific Infections Common Pathogens Streptococcus Pneumoniae In treating meningitis caused by penicillin-susceptible strains of S. pneumoniae, penicillin G and ampicillin are similar in effectiveness and are the drugs of choice. For patients with suspected S. pneumoniae meningitis (for

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which the susceptibilities are unknown) and patients known to have antibiotic-resistant S. pneumoniae, the choices of drug are problematic. This is because the CSF concentrations of penicillin may not be bactericidal and second, because clinical failures have been reported with broadspectrum cephalosporins (cefotaxime or ceftriaxone) even though they can be effective against penicillin-resistant strains. Almost all failures have occurred in children with strains of S. pneumoniae for which the MIC of cefotaxime or ceftriaxone is 2 µg/mL or greater, although some reports suggest that treatment can fail when the MICs of the two drugs are 1.0 µg per milliliter (60). As the MIC of penicillin for S. pneumoniae increases, resistance increases to other antimicrobial agents, including cephalosporins, chloramphenicol, trimethoprim–sulfamethoxazole, and erythromycin, but not vancomycin. Therefore, vancomycin can be the most effective treatment agent for S. pneumoniae meningitis in the era of beta-lactam resistance. However, concern about the penetration of vancomycin into the CSF in adults has promoted studies of combination regimens. In experimental S. pneumoniae meningitis, the combination of vancomycin and ceftriaxone was synergistic even against strains for which the MIC of ceftriaxone was greater than 4 µg/mL (61). However, in animals given dexamethasone concomitantly, the penetration of vancomycin into the CSF was reduced, and sterilization of the CSF was delayed (62). Only the combination of ceftriaxone and rifampin effectively sterilized the CSF with respect to highly resistant strains of S. pneumoniae when dexamethasone was given concomitantly (62). In children, vancomycin has been used in a dose of 15 mg/kg; the data for adults with higher double doses of vancomycin are not strong, but many clinicians recommend this practice, especially when suspected drug resistant S. pneumoniae are found or when the infection is documented. Although these regimens have not yet been studied in humans, and recommendations for the management of bacterial meningitis are evolving, the increasing prevalence of antibiotic-resistant S. pneumoniae warrants the combination of ceftriaxone plus vancomycin in patients with a Gram stain of CSF that suggests the presence of S. pneumoniae (19). This regimen should be continued if the S. pneumoniae isolate is resistant to penicillin (MIC 0.1 µg/mL) and to ceftriaxone and cefotaxime (MIC > 0.5 µg/mL). In adults treated with adjunctive dexamethasone, ceftriaxone plus rifampin is the preferred combination regimen pending studies of susceptibility (19). Because the penetration of vancomycin into CSF is not reduced in children treated with dexamethasone, ceftriaxone plus vancomycin can still be given (63). Unless the isolate of S. pneumoniae is known to be susceptible to penicillin, many authors recommend a second lumbar puncture within 24 to 48 hours to document bacteriologic cure, because adjunctive dexamethasone therapy can prevent adequate clinical assessment of the response to therapy (62).

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Neisseria Meningitidis Penicillin and ampicillin are effective treatment agents for meningitis caused by N. meningitidis, although rare isolates of beta-lactamase–producing strains have high-level resistance (MIC 250 µg/mL). Clinical isolates with altered penicillin-binding proteins and intermediate resistance to penicillin (MIC 0.11.0 µg/mL) have been identified in Europe and South Africa, and recently in North Carolina. The clinical importance of such resistance is unclear, because most patients with meningitis caused by these intermediately resistant strains can be treated effectively with penicillin. At present, penicillin is the drug of choice for meningitis caused by N. meningitidis the bacterial isolates from patients who do not have adequate responses should be formally tested, and the treatment should be changed to ceftriaxone (or cefotaxime) if the isolate is resistant to penicillin (MIC 0.1 µg/mL) (5,12,13,19).

Less Common Pathogens Listeria Ampicillin and penicillin are the treatments of choice for L. monocytogenes meningitis (13,19). However, neither drug is bactericidal against Listeria in vitro, and mortality rates as high as 30% have been reported with the use of these drugs in Listeria. These observations, and the enhanced bactericidal activity in experimental Listeria meningitis when penicillin (or ampicillin) is combined with gentamicin, have prompted many to recommend these latter combinations. Some authors recommend ampicillin (or penicillin) plus gentamicin for patients of all ages who have Listeria meningitis (12,13,19). Trimethoprim–sulfamethoxazole is bactericidal against Listeria in vitro, and has been a successful alternative agent in specific patients. Despite being effective in vitro, chloramphenicol and vancomycin have proved ineffective in patients with systemic Listeria infection. Meropenem is active in vitro and in laboratory animals with Listeria meningitis, but there are inadequate data to recommend its use in humans (19). Streptococcus Agalactiae For neonates with meningitis caused by S. agalactiae (group B streptococcus), the combination of ampicillin and gentamicin is the regimen of choice because of the in-vitro synergy of these drugs and reports of penicillintolerant strains of S. agalactiae. In adults with group B streptococcal meningitis, the benefit of the combination regimen over penicillin (or ampicillin) is unproved, and mortality is influenced primarily by the presence of underlying illness (12,13,19). Gram-Negative Bacterial Meningitis With the advent of the broad-spectrum cephalosporins (cefotaxime, ceftriaxone, ceftazidime, and cefepime), clinical outcomes in bacterial meningitis have improved remarkably (success rate, 85%-90%) because of the high level

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of activity of these antibiotics against gram-negative pathogens, and their high degree of penetration into CSF. Ceftazidime in particular has enhanced activity against P. aeruginosa, and has proved very effective (cure rate 70%-75%, with or without concomitant systemic aminoglycoside therapy). Other promising antimicrobial agents are aztreonam, trimethoprim–sulfamethoxazole, ciprofloxacin, cefepime, and meropenem. Although no results are available from comparative trials, some authors (19) recommend ceftazidime combined with a parenterally administered aminoglycoside as first-line therapy for gramnegative bacillary meningitis. In patients who do not have a response, they recommend a repeat lumbar puncture with CSF culture and antibiotic susceptibility testing. If gram-negative bacilli continue to grow in cultures of CSF and resistance develops to cephalosporin during therapy, intrathecal (or intraventricular) therapy with aminoglycosides or alternative systemic antimicrobial agents can be given on the basis of the results of susceptibility studies. Chloramphenicol has been found ineffective in gram-negative bacteria because its effect against gram-negative bacilli in CSF is only bacteriostatic. Although aminoglycosides are bactericidal in vitro, systemic therapy with gentamicin and amikacin was not highly effective because of inadequate penetration into CSF. Unfortunately, in neonates with gram-negative meningitis, the intrathecal administration of aminoglycosides was ineffective, and the mortality rate for patients given intraventricular aminoglycoside therapy was higher than for patients given intravenous aminoglycoside therapy. Subsequent smaller case series suggested that individualized dosing of aminoglycosides through an intraventricular reservoir can lead to better outcomes.

Staphylococcus Aureus Treatment of S. aureus meningitis involves the use of intravenous nafcillin or oxacillin. For meningitis caused by methicillin-resistant S. aureus, or when such methicillin-resistant organisms are likely, or for patients who are allergic to penicillin, vancomycin is the alternative drug of choice (12,13,19). Some investigators recommend the addition of rifampin to either nafcillin or vancomycin when the therapeutic response to these latter two drugs has been inadequate, or from the beginning when the infection is severe (13,19). Because coagulase-negative staphylococci are the most frequent causes of CSF shunt infections (and complicating meningitis), and because more than one third of such nosocomial strains of staphylococci are methicillin resistant, vancomycin is the initial drug of choice for treating shunt infections, although its penetration is limited in the absence of marked meningeal inflammation. If the response to treatment is unsatisfactory, rifampin (which readily penetrates the CSF) might be added.

Duration of Antibiotic Therapy The optimal duration of antibiotic therapy for patients with bacterial meningitis is undefined (3,4,6-10,12,13,19,30,43,45,63). Most texts recommend a

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Table 3-3 Guidelines for the Duration of Antibiotic Therapy Pathogen

Suggested Duration of Thearpy (Days)

H. influenzae N. meningitidis S. pneumoniae L. monocytogenes Group B streptococci Gram-negative bacilli (other than H. influenzae)

7 7 10–14 14–21 14–21 21

* Modified from Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16.

range of 7 to 10 days for meningococcal meningitis, and longer courses (1021 days) for meningitis caused by other pathogens (Table 3-3). In a randomized trial of therapy with ceftriaxone in children with nonmeningococcal meningitis (primarily H. influenzae disease), 7 days of therapy was as effective as 10 days of therapy (12,19,64). Clinical trials involving patients with meningococcal meningitis showed that 7-day treatment regimens (including penicillin, cefotaxime, ceftriaxone, and chloramphenicol) were very effective, and the vast majority of patients were cured in 4 or 5 days (12,19,65). No comparative studies have been done on the duration of treatment in patients with meningitis caused by S. pneumoniae, L. monocytogenes, S. agalactiae, or enteric gram-negative bacilli. We recommend that the duration of therapy be tailored to the individual patient on the basis of the clinical and microbiologic response.

Prevention Meningococcal Diseases The risk of meningococcal disease for household contacts of an initial case is 500 to 800 times greater than the endemic rate for meningococcal disease in the general population (12). Chemoprophylaxis is indicated for close contacts (e.g., household or day care center personnel, medical personnel in close direct contact with the patient) of patients with meningococcal disease. Rifampin is 80% to 90% effective in eliminating asymptomatic nasopharyngeal carriage of N. meningitidis and is the recommended drug for chemoprophylaxis of meningococcal meningitis. The dose is 600 mg given orally every 12 hours for 2 days for adults, 10 mg/kg every 12 hours for children older than 1 month of age, and 5 mg/kg every 12 hours for children younger than 1 month of age. Because the carrier state can recur shortly after discontinuation of treatment with high doses of penicillin, rifampin should also be administered to patients with meningococcal disease before their discharge from the hospital. Minocycline has been almost as effective as rifampin in eliminating N. meningitidis from nasopharyngeal carriers, but is not commonly used

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because of reports of vestibular side effects. Oral ciprofloxacin reaches concentrations in nasal secretions that are greater than the MIC for N. meningitidis. Single-dose oral ciprofloxacin, 500 or 750 mg for adult patients, is approximately 90% effective in eradicating pharyngeal carriage of N. meningitidis. Ceftriaxone (250 mg intramuscularly in adults and 125 mg in children) was reported to eliminate the carriage of serogroup A meningococci in more than 90% of patients for up to 2 weeks. Immunoprophylaxis of meningococcal disease currently involves use of a quadrivalent (A/C/Y/W-135) polysaccharide vaccine. It is used in the military, in travelers to countries with hyperendemic or epidemic disease, in aborting outbreaks caused by meningococcal serogroups covered by the vaccine, and for persons at high risk, such as asplenic patients or those who have terminal complement-component deficiencies. Meningococcal vaccines are important in quelling epidemics in developing countries where they are used as a component to prophylactic chemotherapy in neighborhood or school outbreaks.

Haemophilus Influenzae Infection The risk of secondary spread of invasive Hib infection from infected persons to nonimmunized household contacts younger than 4 years of age is 2% to 6% during the 30-day period after exposure (12). The highest rate occurs in contacts younger than 1 year of age. The majority of secondary cases occur within a week of onset of disease in the index case. Rifampin is effective in eliminating nasopharyngeal carriage of Hib. If another child (whether previously given Hib vaccine or not) younger than 4 years of age resides in the household, rifampin prophylaxis is recommended for all household contacts, including adults (except pregnant women) of any index case. The dose is 20 mg/kg given orally once daily for 4 days (maximal daily dose is 600 mg). Because nasopharyngeal carriage can reappear after discontinuation of antimicrobial therapy for systemic Hib infection, the index patient should receive rifampin before hospital discharge. Current recommendations of the American Academy of Pediatrics Committee on Infectious Diseases call for vaccination of all infants beginning at 2 months of age with one of three licensed Hib PRP (or PRP oligomer) protein-conjugate vaccines: 1. HbOC (HibTITER) is a diphtheria CRM 197 protein conjugate. 2. PRP-OPM (PedvaxHIB) is a N. meningitidis serogroup B outer membrane protein complex conjugate. 3. PRP-T (ActHIB, OmniHIB) is a tetanus toxoid protein complex. A primary series of HbOC or PjRP-T consists of three doses given at 2, 4, and 6 months of age, whereas for PjR-OMP, only two doses, given at 2

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and 4 months, are recommended. An additional booster dose of a conjugate vaccine should be given at 12 to 15 months of age. A fourth vaccine, PRP-D (ProHIBIT), a diphtheria toxoid-protein conjugate vaccine, is recommended only for use in children 12 months of age and older, and can be substituted at that time for one of the other vaccines as the booster dose.

REFERENCES 1. Unhanand M, Mustafa MM, McCracken GH Jr., Nelson JD. Gram-negative enteric bacillary meningitis: a twenty-one-year experience. J Pediatr. 1993;122:15-21. 2. Durand ML, Calderwood SB,Weber DJ, Miller SI, Southwick FS, Caviness VS Jr., et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8. 3. Hosoglu S, Ozen A, Kokogly OF, et al. Acute bacterial meningitis in adults: Analysis of 218 episodes. Indian J Med Sci. 1997;166:231-4. 4. Schuchat A, Robinson K,Wenger JD, Harrison LH, Farley M, Reingold AL, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med. 1997;337:970-6. 5. Andersen J Wandall JH, Skinhoj P, et al. Acute meningococcal meningitis: Analysis of features of the disease according to the age of 255 patients. J Infect Dis. 1997;34:227-35. 6. Segreti J, Harris AA. Acute bacterial meningitis. Infect Dis Clin North Am. 1996;10:797-809. 7. Sigurdardóttir B, Björnsson OM, Jónsdóttir KE, Erlendsdóttir H, Gudmundsson S. Acute bacterial meningitis in adults. A 20-year overview. Arch Intern Med. 1997;157:425-30. 8. Tunkel AR, Scheld WM. Acute bacterial meningitis in adults. Curr Clin Top Infect Dis. 1996;16:215-39. 9. Andersen J,Wandall JH,Voldsgaard P, et al. Acute meningitis of unknown etiology: Analysis of 219 cases admitted to the hospital between 1977 and 1990. J Infect Dis. 1995;31:115-22. 10. Townsend GC, Scheld WM. Infections of the central nervous system. Adv Intern Med. 1998;43:403-47. 11. Pruitt AA. Infections of the nervous system. Neurol Clin. 1998;16:419-47. 12. Swartz M. Acute bacterial meningitis. In: Gourbach SL, Barlett JG, Blacklow NR, eds. Infectious Diseases. 2nd ed. Philadelphia, PA: WB Saunders; 1998:1377-81. 13. Roos KL,Tunkel AR, Scheld WM. Acute bacterial meningitis in children and adults. In: Scheld WM, Whittey RJ, Durack DT, eds. Infections of the Central Nervous System. 2nd ed. Philadelphia, PA: Lippincott-Raven; 1997:297-312. 14. Griffin DE. Approach to the patient with infections of the central nervous system. In: Gourback SI, Bartlett JG, Blacklow NR, eds. Infectious Diseases. 2nd ed. Philadelphia, PA: WB Saunders; 1998:1377-1381. 15. Adams WG, Deaver KA, Cochi SL, Plikaytis BD, Zell ER, Broome CV, et al. Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era. JAMA. 1993;269:221-6. 16. Naraqi S, Kirkpatrick GP, Kabins S. Relapsing pneumococcal meningitis: isolation of an organism with decreased susceptibility to penicillin G. J Pediatr. 1974;85:671-3. 17. Fenoll A, Martín Bourgon C, Muñóz R,Vicioso D, Casal J. Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 19791989. Rev Infect Dis. 1991;13:56-60. 18. Wenger JD, Hightower AW, Facklam RR, Gaventa S, Broome CV. Bacterial meningitis in the United States, 1986: report of a multistate surveillance study. The Bacterial Meningitis Study Group. J Infect Dis. 1990;162:1316-23. 19. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med. 1997;336:708-16. 20. Cherubin CE, Marr JS, Sierra MF, Becker S. Listeria and gram-negative bacillary meningitis in New York City, 1972-1979. Frequent causes of meningitis in adults. Am J Med. 1981;71: 199-209. 21. Durand ML, Calderwood SB,Weber DJ, Miller SI, Southwick FS, Caviness VS Jr., et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21-8. 22. Schlesinger LS, Ross SC, Schaberg DR. Staphylococcus aureus meningitis: A broad-based epidemiologic study. Medicine (Baltimore). 1987;66:148. 23. Swartz MN. Central nervous system infection. In: Finegold SM, George WL, eds. Anaerobic Infections in Humans. San Diego, CA: Academic Press; 1989:155-212.

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24. Tunkel AR, Scheld WM. Pathogenesis and pathology of bacterial infections of the central nervous system. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System. Philadelphia, PA: Lippincott-Raven; 1997:297-312. 25. Carpenter RR, Petersdorf RG. The clinical spectrum of bacterial meningitis. Am J Med. 1962;33:262-75. 26. Salwén KM,Vikerfors T, Olcén P. Increased incidence of childhood bacterial meningitis. A 25year study in a defined population in Sweden. Scand J Infect Dis. 1987;19:1-11. 27. Pfister HW, Borasio GD, Dirnagl U, Bauer M, Einhäupl KM. Cerebrovascular complications of bacterial meningitis in adults. Neurology. 1992;42:1497-504. 28. Eavey RD, Gao YZ, Schuknecht HF, Gonzalez-Pineda M. Otologic features of bacterial meningitis of childhood. J Pediatr. 1985;106:402-7. 29. Bohr VA, Rasmussen N. Neurological sequelae and fatality as prognostic measures in 875 cases of bacterial meningitis. Dan Med Bull. 1988;35:92-5. 30. Tunkel AR, Scheld WM. Issues in the management of bacterial meningitis. Am Fam Physician. 1997;56:1355-62. 31. Hoen B, Canton P, Gerard A, et al. Multivariate approach to differential diagnosis of acute meningitis. Eur J Clin Microbiol Infect Dis. 1996;15:252-4. 32. Ferraro MJ. Rapid immunologic diagnosis of meningitis—Is there a future? In: Balows A, Tilton RC, Turano A, eds. Rapid Methods and Automation in Microbiology and Immunology. Italy: Brixia Academic Press; 1988:481-7. 33. Martin WJ. Rapid and reliable techniques for the laboratory detection of bacterial meningitis. Am J Med. 1983;75:119-23. 34. Bohr V, Rasmussen N, Hansen B, Kjersem H, Jessen O, Johnsen N, et al. 875 cases of bacterial meningitis: diagnostic procedures and the impact of preadmission antibiotic therapy. Part III of a three-part series. J Infect. 1983;7:193-202. 35. Wilson CB, Smith AL. Rapid tests for the diagnosis of bacterial meningitis. Curr Clin Top Infect Dis. 1986;7:134. 36. Koskiniemi M, Vaheri A, Taskinen E. Cerebrospinal fluid alterations in herpes simplex virus encephalitis. Rev Infect Dis. 1984;6:608-18. 37. Bryan CS, Reynolds KL, Crout L. Promptness of antibiotic therapy in acute bacterial meningitis. Ann Emerg Med. 1986;15:544-7. 38. Packer RJ, Bilaniuk LT, Zimmerman RA. CT parenchymal abnormalities in bacterial meningitis: clinical significance. J Comput Assist Tomogr. 1982;6:1064-8. 39. Bodino J, Lylyk P, Del Valle M,Wasserman JP, Leiguarda R, Monges J, et al. Computed tomography in purulent meningitis. Am J Dis Child. 1982;136:495-501. 40. Crossley GH, Dismukes WE. Central nervous system epidermoid cyst: a probable etiology of Mollaret’s meningitis. Am J Med. 1990;89:805-6. 41. Prasad K, Haines T. Dexamethasone treatment for acute bacterial meningitis: how strong is the evidence for routine use? J Neurol Neurosurg Psychiatry. 1995;59:31-7. 42. Wubbel L, McCracken GH Jr. Management of bacterial meningitis: 1998. Pediatr Rev. 1998;19:78-84. 43. Rockowitz J, Tunkel AR. Bacterial meningitis. Practical guidelines for management. Drugs. 1995;50:838-53. 44. Simberkoff MS, Moldover NH, Rahal J Jr. Absence of detectable bactericidal and opsonic activities in normal and infected human cerebrospinal fluids. A regional host defense deficiency. J Lab Clin Med. 1980;95:362-72. 45. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39:1267-84. 46. Zwahlen A, Nydegger UE,Vaudaux P, Lambert PH,Waldvogel FA. Complement-mediated opsonic activity in normal and infected human cerebrospinal fluid: early response during bacterial meningitis. J Infect Dis. 1982;145:635-46. 47. Crane LR, Lerner AM. Nontraumatic gram-negative bacillary meningitis in the Detroit Medical Center, 1964-1974. Medicine (Baltimore). 1978;57:197. 48. Strausbaugh LJ, Sande MA. Factors influencing the therapy of experimental pneumococcal meningitis in rabbits. Infect Dis. 1978;137:251-60. 49. Small PM, Täuber MG, Hackbarth CJ, Sande MA. Influence of body temperature on bacterial growth rates in experimental pneumococcal meningitis in rabbits. Infect Immun. 1986;52: 484-7. 50. Coant PN, Kornberg AE, Duffy LC, Dryja DM, Hassan SM. Blood culture results as determinants in the organism identification of bacterial meningitis. Pediatr Emerg Care. 1992;8:200-5.

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51. Kanra GY, Ozen H, Seçmeer G, Ceyhan M, Ecevit Z, Belgin E. Beneficial effects of dexamethasone in children with pneumococcal meningitis. Pediatr Infect Dis J. 1995;14:490-4. 52. Tunkel AR. Bacterial meningitis. Philadelphia, PA: Lippincott Williams &Wilkins; 2001. 53. Tunkel AR, Scheld WM. Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev. 1993;6:118-36. 54. Scheld WM, Koedel U, Nathan B, Pfister HW. Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury. J Infect Dis. 2002;186 Suppl 2:S225-33. 55. van der Flier M, Geelen SP, Kimpen JL, Hoepelman IM,Tuomanen EI. Reprogramming the host response in bacterial meningitis: how best to improve outcome? Clin Microbiol Rev. 2003;16:415-29. 56. Arditi M, Mason EO Jr., Bradley JS,Tan TQ, Barson WJ, Schutze GE, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics, and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics. 1998;102:1087-97. 57. Molyneux EM, Walsh AL, Forsyth H,Tembo M, Mwenechanya J, Kayira K, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet. 2002;360:211-8. 58. American Academy of Pediatrics. Pneumococcal infections. In: Pickering LK, ed. Red book: 2003 report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:490-500. 59. European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002;347:1549-56. 60. Friedland IR, Shelton S, Paris M, Rinderknecht S, Ehrett S, Krisher K, et al. Dilemmas in diagnosis and management of cephalosporin-resistant Streptococcus pneumoniae meningitis. Pediatr Infect Dis J. 1993;12:196-200. 61. Friedland IR, Paris M, Ehrett S, Hickey S, Olsen K, McCracken GH Jr. Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother. 1993;37:1630-6. 62. París MM, Hickey SM, Uscher MI, Shelton S, Olsen KD, McCracken GH Jr. Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother. 1994;38:1320-4. 63. Klugman KP, Friedland IR, Bradley JS. Bactericidal activity against cephalosporin-resistant Streptococcus pneumoniae in cerebrospinal fluid of children with acute bacterial meningitis. Antimicrob Agents Chemother. 1995;39:1988-92. 64. Knockaert DC. Bacterial meningitis: diagnostic and therapeutic considerations. Eur J Emerg Med. 1994;1:92-103. 65. Lin TY, Chrane DF, Nelson JD, McCracken GH Jr. Seven days of ceftriaxone therapy is as effective as ten days’ treatment for bacterial meningitis. JAMA. 1985;253:3559-63.

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Chapter 4

Viral Meningitis and Viral Encephalitis K.V. GOPALAKRISHNA, MD MANMEET S. AHLUWALIA, MD

Key Learning Points: 1. Enteroviruses are the most common cause of aseptic meningitis syndrome. 2. It is important to recognize herpes simplex virus (HSV) encephalitis early, as the mortality of untreated disease is high. 3. West Nile virus has caused wide spread outbreaks of encephalitis (WNE) in United States since 1999. 4. Diagnosis of viral encephalitis is aided by CSF analysis, detection of viral antigen by polymerase chain reaction (PCR) and radiologic imaging techniques. 5. The only form of viral encephalitis for which effective treatment exists is that caused by HSV.

Aseptic Meningitis Aseptic meningitis syndrome is a self-limiting disease characterized by meningeal symptoms of acute onset, cerebrospinal fluid (CSF) pleocytosis (usually with a mononuclear cell predominance), and the inability to isolate a bacterial agent. At least 300,000 cases of this syndrome occur each year in the United States (1). Aseptic meningitis is commonly caused by an infectious agent but may be of noninfectious origin (2). Viruses are the most common identifiable agents of this syndrome, and enteroviruses are responsible for more than 80% of cases (3). Outbreaks of enteroviral meningitis are seasonal. Table 4-1 shows the common and uncommon causes of acute aseptic meningitis syndrome. The most commonly affected 80

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New Developments in Viral Meningitis and Encephalitis • Japanese encephalitis and West Nile virus have spread into new habitats and

environments. • This illustrates the need for continued international surveillance to meet

emerging disease threats.

Table 4-1 Causes of Acute Aseptic Meningitis Syndrome More Common Infectious Causes Viral Enteroviruses (nonpolio) HIV Mumps virus Herpes simplex virus type 2 Vector-borne viruses (e.g., mosquitoand tick-borne) Lymphocytic choriomeningitis virus (arenavirus) Spirochetes Leptospira species Borrelia burgdorferi Mycobacteria Mycobacterium tuberculosis Less Common and Rare Infectious Causes Viral Adenovirus Herpes simplex virus type I Varicella-zoster virus Cytomegalovirus Epstein-Barr virus Influenza virus types A and B Parainfluenza virus Measles virus Rubella virus Poliovirus Rotavirus Encephalomyocarditis virus Attenuated vaccine strains of poliovirus, mumps, measles, and vaccinia Spirochetes Treponema pallidum Borrelia recurrentis Bartonella henselae

Chlamydia Chlamydia psittaci Chlamydia trachomatis Rickettsia Rickettsia rickettsii Coxiella burnetii R. prowazekii R. typhi R. tsutsugamushi Ehrlichia species Mycoplasma Mycoplasma pneumoniae M. hominis Ureaplasma urealyticum Other Bacteria Brucella species Listeria monocytogenes Nocardia species Actinomycetes Fungi Cryptococcus neoformans Coccidioides immitis Histoplasma capsulatum Blastomyces dermatidis Sporothrix schenkii Zygomycetes Pseudoallescheria boydii Cladosporium species Parasites Angiostrongylus cantonensis Strongyloides stercoralis Taenia solium Schistosoma species Trichenella spiralis Paragonimus species Echinococcus granulosus Continued

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Table 4-1 Continued Multiceps multiceps Gnathostoma spinigerum Toxoplasma gondii Naegleria/Acanthomoeba species Trypanosoma species Other Infections Partially treated bacterial meningitis Parameningeal focus of infection Endocarditis or bacteremia Bacterial toxins Viral postinfectious syndromes Postvaccination for mumps, measles/mumps, poliovirus, pertussis, rabies, or vaccinia Noninfectious Causes Medications NSAIDs (e.g., ibuprofen, naproxen, tolmetin, diclofenac, ketoprofen) Antimicrobial agents (e.g., sulfisoxazole, isoniazid, ciprofloxacin, beta-lactam agents, metronidazole, pyrazinamide) Muromonab-CD3 (OKT-3) Azathioprine Carbamazepine Phenazopyridine Ranitidine Immunoglobulin Intracranial Tumor and Cysts Craniopharyngioma Dermoid/epidermoid cyst Pituitary adenoma Astrocytoma Glioblastoma multiforme

Medulloblastoma Pinealoma Ependymoma Teratoma Lymphomatous Meningitis, Carcinomatous Meningitis, Leukemia Neurosurgery-Related Illness Intrathecal injections (e.g., air, isotopes, antimicrobial agents, antineoplastic agents, steroids, radiographic contrast media) Chymopapain injection Systemic Illness Systemic lupus erythematosis Sarcoidosis Behçet disease Sjo˙gren’s syndrome Mixed connective-tissue disease Rheumatoid arthritis Polymyositis Wegener granulomatosis Lymphomatoid granulomatosis Polyarteritis nodosa Granulomatous angiitis Cerebral vasculitis Familial Mediterranean fever Kawasaki disease Multiple sclerosis Vogt–Koyanagi–Harada syndrome Serum sickness Heavy-metal poisoning (e.g., lead, mercury) Procedure-related complications (e.g., spiral anesthesia)

NSAIDs = nonsteroidal anti-inflammatory drugs; TMP-SMX = trimethoprim–sulfamethoxazole. Modified from Hasbun R. The acute aseptic meningitis syndrome. Curr Infect Dis Rep. 2000;3:345–51; and Connolly KJ. Hammer SM. The acute septic meningitis syndrome. Infect Dis Clin North Am. 1990;4:599–622.

age groups are infants and children (4). The discussion in this chapter includes the clinical manifestations of aseptic meningitis syndrome in older children and adults. The clinical manifestations of acute bacterial meningitis and those of aseptic meningitis are difficult to distinguish from one another. In older children and adults, both conditions present with fever of acute onset (usually with a temperature of 38˚C–40˚C), severe headache, and meningismus. Neck

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Table 4-2 Cerebrospinal Fluid Findings in Patients Who Present with Meningeal Signs

Diagnosis

Glucose Pressure Leukocytes PMNLs (CSF:blood (cm H2O) (105/L) (per mm3) ratio)

Normal <20 Acute bacterial >20 meningitis Chronic meningitis Variable Aseptic (viral) <20

Protein Lactate (g/L) (mmol/L)

1–2 >1000

<1 >50

>0.5 <0.4

<0.45 >1.00

<2 >4

>1000 <1000

Variable <50

<0.4 >0.4

>0.45 Variable

>2 <2

CSF = cerebrospinal fluid; PMNLs = polymorphonuclear leukocytes. Republished with permission from Leib SL, Tauber MG. Acute and chronic meningitis. In Armstrong D, Cohen J, eds. Infectious Diseases. London: Mosby; 1997.

stiffness is of variable severity. Photophobia is a common accompanying sign of enteroviral meningitis. Nonspecific findings include vomiting, anorexia, rash, diarrhea, cough, and pharyngeal irritation. The course of aseptic meningitis is generally benign and self-limited. However, viral persistence, rheumatologic manifestations, and even death may occur in patients with immunoglobulin deficiency (5). Because of the difficulty in differentiating acute bacterial meningitis from nonbacterial, examining the CSF is usually helpful but not conclusive. Table 4-2 shows the differential findings in the CSF. The CSF in a patient with acute bacterial meningitis usually contains more than 1000 cells/mm3 with a predominance of neutrophils, whereas in viral meningitis the CSF has fewer than 1000 cells/mm3 with a predominance of mononuclear cells. In the early stage of the disease, neutrophils may predominate for a few hours. A mild increase in the CSF protein concentration and a mild decrease in the CSF glucose concentration are typical. After lumbar puncture, CSF specimens should be tested for bacterial agents and subjected to rapid viral diagnostic techniques. Use of the polymerase chain reaction (PCR) test for enteroviruses has been shown to reduce the duration of hospitalization of patients with enterovirus meningitis (3). From findings in a large enterovirus meningitis outbreak in Rhode Island in the summer of 1991, Rice and coworkers (6) recommended that lumbar puncture be performed routinely to differentiate bacterial from viral meningitis. They recommended that if the CSF is suggestive of viral meningitis during an outbreak, patient observation alone is sufficient. Empirical antibacterial therapy and hospitalization are indicated only for patients who present with atypical clinical and laboratory features. The clinical features of viral meningitides not caused by enterovirus infection are listed in Table 4-3. Currently, there is no antiviral agent effective for treating viral meningitis. Use of antienteroviral agents (e.g., pleconaril) is being investigated for treating enteroviral meningitis but has not been approved (2). Most patients with aseptic meningitis do not need hospitalization; treatment is largely supportive once bacterial meningitis has been ruled out.

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Table 4-3 Clinical Features of the Common Viral Causes of Meningitis Viral Agent

Season

Age

Enteroviruses

Summer, early fall

Children, young adults

HSV-2

No seasonal Young pattern adults

HIV

No seasonal Any age pattern (peak in young adults)

Mumps virus

Late winter to spring

Classically peaks in children aged 5–9 years*

LCMV

Late fall to early winter

Young adults

Exposure History

CSF Profile

Diagnostic Tests

Known outbreak of enteroviral disease in community

Early (first Culture of 48 hours) CSF, blood, neutrophilic stool, throat; pleocytosis PCR with a shift to mononuclear cells Sexually <500 cells HSV-2 active, new with culture from partner lymphocyte CSF and predomigenital nance lesions; seroconversion Sexual history, <200 cells HIV testing IV drug use, with transfusion, lymphocyte specific predomiexposure nance (needle stick) Known Low CSF CSF culture community glucose in and outbreaks 25% of serology patients; CSF pleocytosis <500 cells Contact with Low CSF Culture of pet rodents glucose in CSF, blood, (e.g., ham25% of urine; sters, mice) patients; serology or their pleocytosis excreta usually <750 cells†

CSF = cerebrospinal fluid; HSV-2 = herpes simplex virus type 2; IV = intravenous; LCMV = lymphocytic choriomeningitis virus; PCR = polymerase chain reaction test. * In the vaccine era, adolescents now comprise a more significant proportion of those infected. † Counts to more than several thousands have been found. Hammer SM, Connolly KJ. Viral aseptic meningitis in the United States: Clinical features, viral etiologies, and differential diagnosis. In Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Disease. Vol 12. Boston: Blackwell Scientific; 1992.

Viral Encephalitis The term encephalitis means inflammation of the substance of the brain. Because inflammation of the brain and the meninges often accompany each other, terms such as meningoencephalitis are also used to describe such conditions. Acute encephalitis associated with a viral infection has two

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distinct types. In the first type, the virus invades neuronal tissues directly and causes perivascular inflammation and tissue necrosis. In the second type, called postinfectious encephalomyelitis, demyelination is localized to the white matter, without infection of the neuronal cells themselves. The incidence of viral encephalitis varies greatly with the specific causative virus, geographical location, and season. The reported incidence of acute encephalitis is between 3.5 and 7.4 cases per 100,000 patient-years (7).

Etiology Many viruses have been associated with encephalitis; however, even with the help of sophisticated techniques, a definitive cause is identified in only approximately half of all cases (8). Although enteroviruses are the most common causes of acute viral meningitis, these viruses account for less than 3% of the cases of acute viral encephalitis (9). Enterovirus infections occur primarily in late summer and fall. Arbovirus infections vary widely in occurrence throughout the world. Because arboviruses are arthropod-borne, the incidence of arbovirus encephalitis increases when the viruses’ insect vectors are active. Mosquito-borne encephalitis peaks in late summer in regions of temperate climate. Tick-borne diseases occur most often in spring and early summer (10). In the United States, viruses of the California serogroup (LaCrosse strain) and St. Louis encephalitis, western equine encephalitis, and eastern equine encephalitis viruses are the most common arboviruses (Table 4-4). A first-known outbreak of West Nile virus encephalitis was reported in the New York City metropolitan area in 1999 when an infectious disease clinician at Flushing Hospital noticed that some of her patients with aseptic meningitis during the summer months had developed muscle weakness (11). Since its first isolation in 1937 from the blood of a febrile woman in the West Nile district of Uganda, West Nile virus is now known to have an extensive distribution throughout Africa, the Middle East, parts of Europe and the former Soviet Union, south and central Asia, and Australia (where it is known as Kunjin virus) (12). HSV type 1 (HSV-1) is the most common cause of the localized, sporadic form of encephalitis seen in the United States. This disease has no seasonal preference. Approximately 1000 cases are reported annually. In addition to arboviruses and HSV, many other viruses can cause encephalitis. These encephalitides usually present with milder disease and have fewer sequelae and a lower mortality than does arbovirus or HSV encephalitis (13). The ease of world travel, urbanization, and encroachment on natural environments have led to the spread of viruses and disease vectors from the developing world to the developed world. An example of this scenario is the importation of the Asian tiger mosquito (Aedes albopictus, the vector for both dengue and yellow fever) to the southern United States in a shipment of used tires from Japan (14).

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Table 4-4 Characteristics of Viral Encephalitis Virus

Transmission

Diagnostic Studies

Enteroviruses Person to person Arboviruses*

Mosquitoes

HSV

Person to person

EBV CMV

Person to person Person to person, bloodborne Person to person, bloodborne

HIV

Mumps virus

Person to person

Rabies virus

Animal to person

Comments

Culture of throat, stool, Rare fatal encephalitis and CSF; PCR test of CSF in neonates CSF viral specific IgM; Japanese encephalitis acute and convalescent is the most sera widespread around the world; West Nile encephalitis emerged in New York City area in 1999 PCR test of CSF; MRI Only viral and EEG encephalitis with effective antiviral therapy PCR test of CSF Lymphadenopathy Culture and PCR test Immunosuppressed of CSF host Serum ELISA Western blot Encephalitis found at the time of primary infection is rare Culture of CSF and saliva; Associated parotitis or serology orchitis Culture of CSF and saliva; Disease can be fatal PCR test of CSF and skin

CMV = cytomegalovirus; CSF = cerebrospinal fluid; EBV = Epstein–Barr virus; EEG = electroencephalography; ELISA = enzyme-linked immunosorbent assay; HSV = herpes simplex virus; IgM = immunoglobulin M; MRI = magnetic resonance imaging; PCR = polymerase chain reaction test. * Including Japanese encephalitis, St. Louis encephalitis, California serogroup (LaCrosse) encephalitis, Eastern and Western equine encephalitis, and West Nile encephalitis.

Pathogenesis and Pathology Infectious agents can invade the central nervous system by means of the blood (e.g., arbovirus, mumps virus, measles virus) or the peripheral nerves (e.g., HSV, herpesvirus B from monkeys, and rabies virus). HSV encephalitis is thought to result either from reinfection or from reactivation of the latent virus in the trigeminal and other cranial ganglia. More than 90% of adults have antibody to HSV-1, and approximately 25% of patients with encephalitis have a history of cold sores.

Clinical Findings Patients with viral encephalitis often present with headache, fever, nuchal rigidity, and alteration of consciousness. The degree of this latter alteration may vary from mild lethargy to stupor and coma. Various focal features

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(e.g., motor weakness, accentuated deep tendon reflexes, abnormal movements, tremors, and seizures) have been described. Increased intracranial pressure can lead to papilledema, and cranial nerve palsies may develop. From the initial experience in New York in 1999, the hallmark of West Nile encephalitis (WNE) in the United States is asymmetric and nonascending muscle weakness and paralysis that is often described as polio-like syndrome (15). Rash and lymphadenopathy have rarely been seen. WNE has a predilection for the brain stem and the anterior horn cells of the spinal cord. Tremors, myoclonus, and Parkinson disease are not uncommon. In contrast to flaccid paralysis, which is usually irreversible and permanent, the patients with movement disorders do well and usually resolve over time with few, if any, sequelae. Various ophthalmological findings including optic neuritis, chorioretinitis, multifocal choroiditis, or combinations of optic neuritis/chorioretinitis have been reported in WNE patients (15). Encephalitis caused by HSV may have an insidious or abrupt onset. Affected patients often present with bizarre behaviors or hallucinations. These findings suggest temporal lobe localization of the disease (16).

Laboratory Findings Examining the CSF is essential for the diagnosis of viral encephalitis. Pleocytosis is variable (10–1000 cells/mm3), with a predominance of mononuclear cells; however, considerable numbers of polymorphonuclear cells may be present at an early stage of infection. Erythrocytes are frequently present in HSV encephalitis. The CSF protein is usually increased, and the CSF glucose is typically normal or slightly below normal. Although CSF can be cultured for arboviruses and enteroviruses, attempts to culture CSF for HSV have been unsuccessful. Rapid diagnosis of arbovirus encephalitis is possible with an enzyme-linked immunosorbent assay for virus-specific immunoglobulin M antibodies in the CSF. Serum antibody measurements made in the acute and convalescent phases sometimes help establish the diagnosis of arbovirus encephalitis. Because identifying the cause in arbovirus encephalitis outbreaks is so important, certain state agencies offer laboratory assistance in making the laboratory diagnosis. In HSV encephalitis, cerebral tissue biopsy with virus isolation has been the gold standard of diagnosis. However this has been replaced by the detection of specific nucleic acid from CSF or brain. For nucleic acid detection, PCR technology provides the most convenient test. In laboratories experienced in doing this test, the specificity of PCR approaches 100%, and the sensitivity is between 75% and 98% (7). Assays for HSV-1, HSV-2, varicella-zoster virus, human herpesvirus 6 and 7, CMV, EBV, enteroviruses, and respiratory viruses as well as for HIV have been developed. In addition to single PCR tests, the multiplex or microassay PCR has increasingly

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been used. Culture of vesicular skin lesion is important if herpes encephalitis is suspected. Throat and stool culture should be a part of the workup if encephalitis is caused by enterovirus or measles. In viral encephalitis, electroencephalography often reveals a diffuse slowing of brain waves. Slow-wave complexes, at regular intervals of two to three per second in the temporal lobe, are characteristic of HSV encephalitis. The EEG in patients with WNE reveals a fairly specific pattern with prominent slowing over the anterior regions of the brain (not seen in other enteroviral CNS infections). The degree of slowing seems to be related to the severity of the encephalitis. Computed tomography (CT) of the brain in HSV encephalitis reveals low-density lesions in 1 or both temporal lobes; however, this finding tends to appear late in the disease. Magnetic resonance imaging (MRI) of the brain may show the abnormality at an early stage of disease and is superior to computed tomography in sensitivity and in localizing lesions in the temporoparietal region. An MRI not only allows earlier detection and treatment of inflammatory processes but also provides valuable information for patient follow-up. In WNE, MRI abnormalities may be found in the gray/white matter but may also be present in the basal ganglia and thalamus. These findings resemble those found in Japanese encephalitis. However, because Japanese encephalitis is rare in the United States (unless seen in travelers), the finding of abnormalities in the region of the basal ganglia/thalamus in a patient with encephalitis should suggest the possibility of WNE. Magnetic resonance spectroscopy (MRS) identifies and quantitates concentration of various brain metabolites. Although the gold standard in acquiring functional imaging data, the positron emission tomography (PET) scan technique remains complex, costly, and generally unavailable. In summary, CT scan and MRI provide structural information whereas MRS and PET can provide functional and metabolic data.

Treatment The only form of viral encephalitis for which effective treatment exists is that caused by HSV. Treatment with acyclovir therapy has proven superior to that with vidarabine in reducing illness and death in HSV encephalitis (17). Untreated HSV encephalitis carries a 70% death rate. Acyclovir reduces the mortality to less than 19% (18). Usually, intravenous acyclovir 10 mg/kg is given every 8 hours for 14 days in immunocompetent adult patients and 21 days for immunosuppressed patients. Use of vidarabine for HSE is generally limited to rare patients who cannot receive acyclovir because of side effects. The patient’s age and level of consciousness at the beginning of therapy are important prognostic factors. Younger age and a Glasgow coma scale score of greater than 6 favor recovery.

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The management of other viral encephalitides is usually supportive and is intended to avoid nosocomial complications. Antiretroviral therapy must be added or continued in HIV-infected patients. Cerebral edema may be treated with mannitol or corticosteroids. Seizures should be controlled with anticonvulsants.

Summary Acute viral infections of the CNS produce illnesses that range from mild to serious. Acute viral meningitis is usually mild and self-limiting. Acute viral encephalitis may result in serious brain injury and even death. Treatment is available for HSV encephalitis, and its prognosis depends on early recognition and treatment with acyclovir.

REFERENCES 1. Parasuraman TV, Deverka PA,Toscani MR. Estimating the economic impact of viral meningitis in the United States. Infect Med. 2000;17:417–27. 2. Hasbun R. The acute aseptic meningitis syndrome. Curr Infect Dis Rep. 2000;3:345–51. 3. Ramers C, Billman G, Hartin M, Ho S, Sawyer MH. Impact of a diagnostic cerebrospinal fluid enterovirus polymerase chain reaction test on patient management. JAMA. 2000;283:2680–5. 4. Rotbart HA, Brennan PJ, Fife KH, Romero JR, Griffin JA, McKinlay MA. Enterovirus meningitis in adults. Clin Infect Dis. 1998;27:896–8. 5. Rotbart HA. Viral meningitis and the aseptic meningitis syndrome. In Scheld WM, Whitley RJ, Durak DT (eds). Infections of the Central Nervous System. New York: Raven Press; 1991:19–40. 6. Rice SK, Heinl RE,Thornton LL, Opal SM. Clinical characteristics, management strategies, and cost implications of a statewide outbreak of enterovirus meningitis. Clin Infect Dis. 1995;20:931–7. 7. Johnson RT. Acute encephalitis. Clin Infect Dis. 1996;23:219–26. 8. Bergstrom SM, Hagberg L. Acute viral encephalitis in adults: a prospective study. Scand J Infect Dis. 1998;30:215–20. 9. Meyer HM Jr., Johnson RT, Crawford IP, Dascomb HE, Rogers NG. Central nervous system syndromes of “viral” etiology: A study of 713 cases. Am J Med. 1960;29:334–7. 10. Montalbano MA, Knowles CM,Adams DA, et al. Summary of notifiable diseases—United States, 1996. MMWR Morbid Mortal Wkly Rep. 1997;45:1–87. 11. Anonymous. Update: West Nile virus encephalitis—New York 1999. MMWR Morbid Mortal Wkly Rep. 1999;48:944–6. 12. Mackenzie JS, Gubler DJ, Petersen LR. Emerging flaviviruses: The spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med. Dec 2004;10(12 suppl):S98–109. Review. 13. Griffin DE. Encephalitis, myelitis, and neuritis. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingstone; 1995:874–81. 14. Rogers DJ, Parker MJ. Vector-borne diseases, models, and global change. Lancet. 1993;342:1282– 4. 15. Cunha BA. Differential diagnosis of West Nile encephalitis. Curr Opin Infect Dis. 2004 Oct;17(5):413–20. Review. 16. Whitley RJ, Soong S-J, Linneman C Jr., Liu C, Pazin G, Alford CA. Herpes simplex encephalitis: Clinical assessment. JAMA. 1982;247:317–20. 17. Whitley RJ, Lakeman F. Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations. Clin Infect Dis. 1995;20:414-20. 18. Whitley RJ. Viral encephalitis. N Engl J Med. 1990;323:242-50.

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Chapter 5

Brain Abscess SCOTT A. FULTON, MD ROBERT A. SALATA, MD

Key Learning Points 1. Seeding of the brain with pathogenic microorganisms may occur hematogenously, by direct implantation or by contiguous spread. 2. Brain abscesses occurs primarily in men 20-50 years of age. 3. A high index of suspicion is critical for early recognition and diagnosis of brain abscess. 4. Less than 50% of patients with brain abscess present with the classic triad of fever, headache and neurologic deficit. However, fever and headache are usually present in the majority of patients with brain abscess. 5. Mental status of the patient at the time of presentation is the best predictor of morbidity and mortality which are highest when patients are obtunded or comatosed. 6. The presentation of abscess is similar in patients with solitary or multiple abscesses. 7. Brain abscesses are most frequently localized to the frontal lobe.

B

rain abscess is a relatively rare diagnosis, with 1500 to 2500 cases occurring annually in the United States (1, 2). Its prevalence has not increased significantly, despite increases in patients who are chronically immunosuppressed by medical therapy (e.g., corticosteroids, cytotoxic chemotherapy), systemic inflammatory diseases (e.g., sarcoidosis, systemic lupus erythematosus), and HIV infection. Brain abscess occurs with a striking male predominance (from 2–3:1) and generally occurs in patients 20 to 50 years of age (3-5). However, children with congenital heart disease represent most brain abscess patients younger than 20 years 90

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New Developments in the Management of Brain Abscess • Fluoroquinolone antibiotics and meropenem are emerging as effective agents for

the treatment of brain abscess. • Judicious use of antibiotics will help prevent the emergence of resistant

pathogens causing both community-acquired and nosocomial brain abscesses.

of age (6). Not all patients with a space-occupying lesion of the central nervous system have a pyogenic brain abscess. The differential diagnosis is relatively limited to infectious and neoplastic causes. Knowledge of a patient’s medical, surgical, travel, and HIV-exposure histories is important during the initial evaluation and treatment of brain abscess. This chapter provides a concise review of the pathogenesis and approaches to the diagnosis and management of cerebral brain abscesses and focuses primarily on bacterial abscesses in immunocompetent patients. More extensive discussions of brain abscesses in immunocompromised patients can be found in other sources (2,7).

Definition and Differential Diagnosis A brain abscess is a focal collection of purulent material within the brain parenchyma. Involvement of the overlying pia and arachnoid meninges usually occurs only in the setting of concomitant meningitis or after an intraventricular rupture. By definition, cerebral brain abscess does not comprise subdural, epidural, or spinal abscesses, which vary in pathogenesis and etiology. Brain abscess is a term reserved for an encapsulated (matured), nonneoplastic, space-occupying mass seen with contrastenhanced computed tomography (CT) or magnetic resonance imaging (MRI) either as a finely nodular or ring-enhancing lesion (8,9). The ring enhancement represents the vascularized capsule that surrounds a central area of necrosis. Abscess formation begins as a focal inflammatory reaction or cerebritis. The cerebritis stage of abscess formation can present a diagnostic difficulty, because there is no collection of material for diagnostic aspiration. In addition, early inflammatory changes seen in cases of brain abscess are not specific to this condition and also can arise from encephalitis, vasculitis, and in some cases from a tumor or the early stage of an infarct (8,9). The differential diagnosis of a brain abscess takes into consideration the cause of ring-enhancing lesions. The typical pathogens involved in brain abscesses include a broad range of microorganisms, including aerobic, microaerophilic, and anaerobic bacteria. Fungi, mycobacteria, and parasites also can cause brain abscesses. However, opportunistic pathogens such as Nocardia asteroides, Aspergillus, and Toxoplasma gondii are identified

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almost exclusively in patients who have an underlying immunodeficiency that results from corticosteroid treatment, cancer chemotherapy, transplantation, or HIV infection (2,10,11). The differential diagnosis can be prioritized on the basis of comorbid conditions and the patient’s immunocompetence. Additionally, travel history or point of origin can identify patients who are at risk for brain abscesses caused by mycobacteria, Brucella, or Coccidioides (2,7,12).

Pathogenesis Anatomical Considerations The brain parenchyma is covered by the pia mater, arachnoid, and dura mater, which are penetrated by emissary and diploic (valveless) veins that drain into the cerebral venous sinuses. Additionally, venous drainage of the soft tissues of the head converges within cerebral venous sinuses (13). Because these valveless conduits allow retrograde blood flow directly to the brain, brain abscesses can result from infections in the periorbital and facial soft tissues, paranasal sinuses, ears, and dentition. Brain abscesses that arise hematogenously from distant infectious foci also have been described in cases of endocarditis, lung abscess, hepatic abscess, and inflammatory bowel disease; however, many cryptic abscesses arise without an obvious distant or contiguous focus (3,7,14). Brain abscesses that arise from direct extension from adjacent bony structures (e.g., the frontal, sphenoid, and mastoid sinuses, but not usually the maxillary sinuses) and from direct inoculation during surgery or after a penetrating trauma also are well described. Thus, the seeding of the brain with pathogenic microorganisms can occur hematogenously, by direct implantation, or by contiguous inoculation.

Brain Abscess Formation and Radiographic Correlates The classic studies of Britt and Enzmann correlated neuropathologic and CT findings in experimental streptococcal brain abscesses induced in dogs (9). In subsequent studies, pathologic and radiographic analysis of human brain abscess paralleled findings reported in the animal model (4,8). In brief, a focal area of inflammation (cerebritis) that is caused by small-vessel thrombosis and perivascular inflammation, marks early abscess formation. Since neovascularization is minimal, variable central diffusion of contrast medium is seen on CT and ring enhancement is scant or absent. The late cerebritis stage is characterized by more prominent diffusion of contrast and by the development of ring enhancement associated with central necrosis and increased edema. Although the time course for abscess formation is variable, the cerebritis stage evolves over a period of 3 to 10 days.

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Capsule formation around an abscess results from organization of collagen by fibroblasts and from neovascularization that is accompanied by reduced inflammation. At this stage of abscess development CT shows less central contrast diffusion and a well-defined ring enhancement because of maximal neovascularization and capsular blood flow. The time to encapsulation generally occurs within 10 to 14 days. Matured abscesses tend to have well-defined capsules; however, because neovascularization is more rapid at the cortical aspect of an abscess, abscess walls adjacent to the ventricles tend to be thinner and more prone to rupture. Depending on anatomical location and the degree of edema, abscesses can remain undetected for days or even weeks. However, most patients present within 10 to 14 days of their initial symptom (3,4,13).

Location of Brain Abscesses Abscesses can involve the cerebrum, basal ganglia, cerebellum, and rarely, the brain stem. However, most abscesses are located in the cerebrum, where the frontal and temporal lobes represent the major sites of involvement (50%) that are reported in most series (3,4,11,15). In early studies (16), a large percentage of reported abscesses involved the temporal lobes and was attributed to the greater incidence of chronic otitis media in children and adults (17). More recent studies suggest a significant decline in temporal lobe abscesses, presumably from the expedient antibiotic treatment of otitis media. Frontal lobe abscesses remain the most common and occur in approximately 30% of reported cases. Temporal and parietal lobes occur in 20% to 25% of cases. Nonetheless, although patients with a brain abscess are heterogeneous with respect to age, sex, and comorbid conditions, the distribution of abscesses among the frontal, parietal, and temporal lobes has been remarkably similar among the individual studies reported in the United States and abroad. In the subset of pediatric and adolescent patients with cyanotic congenital heart disease (CCHD), the distribution of abscesses in the cerebrum does not differ significantly although the mechanism of inoculation is considered to be strictly hematogenous (18). However, hematogenous inoculation of the brain can slightly increase the incidence of cerebellar and occipital brain abscesses and can correlate with the occurrence of multiple abscesses as suggested in bone marrow–transplant patients who are at increased risk for recurrent occult bacteremia or fungemia (11). However, no cerebral or cerebellar lobe shows a unique proclivity for abscess formation except when inoculated by direct extension (e.g., chronic otitis media that affects the temporal lobe or mastoiditis that affects the cerebellum).

Epidemiology The risk of brain abscess formation through direct extension from rhinogenic, otogenic, or odontogenic foci has been recognized for many years, and these attributable causes are associated with nearly half of the reported cases in the

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literature (5,6,19-21). Patients with CCHD and pulmonary infections also are at risk, but as many as 30% of brain abscesses are not associated with an identifiable risk factor and are considered cryptogenic. Surprisingly, the overall prevalence of brain abscess caused by rhinogenic and otogenic infections and the general distribution of attributable causes of brain abscess has remained remarkably similar over the last 20 to 30 years (4,7,13,19). It is well known that many patients with brain abscess do not have an identifiable comorbid infection. Many case reports implicate several clinical conditions in brain abscess formation (see Table 5-1). In this regard, CCHD represents a prototypical risk factor for hematogenous brain abscess formation and accounts for 75% of cases of brain abscess in patients younger than 20 years of age. Right-to-left shunts within the cardiopulmonary vasculature increase the opportunity for microorganisms to bypass pulmonary host defenses and gain access to the brain. Arteriovenous shunting also occurs in patients with advanced cirrhosis and portal hypertension, hereditary hemorrhagic telangiectasia, and congenital pulmonary arteriovenous fistula, which also have been described as conditions predisposing to brain abscess formation (3-5). Interestingly, bacteremia associated with intravenous narcotic abuse has not been associated with a disproportionately large number of brain abscesses, a finding that underscores the complexity of brain abscess formation via hematogenous mechanisms. Other medical conditions associated with brain abscesses (Table 5-1) have included diabetes, infective endocarditis, hemolytic uremic syndrome, cystic fibrosis, premature birth, and pelvic inflammatory disease (6,14). It is important to note that most patients (70%) present with solitary abscesses (4,13,19). There are fewer data on patients with multiple brain abscesses, which presumably arise hematogenously. However, multiple abscesses have been reported for 26% of patients with otogenic infections, which are thought to inoculate the brain by contiguous spread (21). Thus, otogenic infections also can inoculate the brain hematogenously to yield multiple abscesses. In contrast, hematogenous seeding of the brain in CCHD patients infrequently results in multiple abscesses (18). Thus, hematogenous

Table 5-1 Medical Conditions Associated with Brain Abscess Diabetes mellitus Portal hypertension Cirrhosis Infective endocarditis Postdental care Transplantation Pneumonia Periodontal disease HIV disease Liver abscess Sarcoidosis

Inflammatory bowel disease Pelvic inflammatory disease Systemic lupus erythematosus Intravenous drug use Cyanotic congenital heart disease Hemolytic uremic syndrome Chronic mastoiditis, otitis, or sinusitis Premature birth Trauma and neurosurgery Congenital pulmonary arteriovenous fistula Cystic fibrosis

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inoculation of the brain does not necessarily result in multiple abscesses. In addition, some patients with two or more abscesses can have no identifiable comorbid infection (1). Thus, no clear association can be drawn between a comorbid infection and the multiplicity of brain abscess. The principal pathophysiologic mechanisms for brain abscess formation in normal and immunosuppressed patients are not well understood. For example, in patients with inflammatory bowel disease, brain abscess formation can result from an impaired mucosal barrier or as a consequence of corticosteroid treatment. When opportunistic pathogens such as N. asteroides are identified within a brain abscess, an underlying immunologic defect must be considered. However, even in conditions with relatively normal immune function (e.g., pregnancy), opportunistic pathogens have been identified in brain abscesses. Nevertheless, brain abscess formation has typically been associated with an array of clinical conditions (Table 5-1) (2,4-7,10), which should help physicians maintain a high clinical suspicion of its existence when accompanied by the appropriate epidemiologic, clinical, and radiographic findings.

Clinical Manifestations Signs and symptoms of brain abscess are extremely variable and often are masked by comorbidities. The classic triad of fever, headache, and neurologic deficit occurs in less than 50% of patients (4,5,11,18). However, fever and headache occur in 40% to 75% of patients reported in most series for which data are available (22). Table 5-2 summarizes the signs and

Table 5-2 Percentage of Patients with Signs and Symptoms Associated with Brain Abscesses at Presentation Signs and Symptoms

Headache Fever or chills Seizure Nausea or vomiting Confusion Motor weakness Visual disturbances Hemiparesis Speech disturbances Dizziness Syncope Stiff neck Cranial nerve abnormality

USA (3)

India (31)*

Japan (8)†

USA (18)‡

72 42 35 35 26 21 21 9 9 7 7 5 –

76 65 39 – 7.9 – 13 26 – – – 26 34

60 65 47 42 – – 7 52 3 – – – –

7 83 22 2 50 – – 26 – – – – 31

* All patients had two or more abscesses. † All patients had congenital cyanotic heart disease. ‡ All patients were bone marrow transplant recipients only. Data from references 3, 8, 18, and 31.

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symptoms associated with brain abscess from studies representing four distinct groups of patients. In a comprehensive description reported by Chun and colleagues (4), fever and headache were present in 40% to 72% of patients and associated with increased intracranial pressure (e.g., nausea, vomiting, confusion) in 20% to 35% of patients. When only patients with two or more abscesses were studied (21), the presence of headache, fever, and seizures was similar to those in other reports. In addition, patients at risk for recurrent septicemia (CCHD and bone marrow transplant) and multiple brain abscesses often presented with hemiparesis and cranial nerve deficits (11, 18). However, whereas 52% of patients with CCHD often present with hemiparesis, only 10% to 20% of patients had two or more abscesses. Thus, abscess multiplicity does not consistently predict or correlate with the presenting signs and symptoms of brain abscess. Patients with brain abscess come to clinical attention at different times. Most often, signs and symptoms of the abscess evolve insidiously. Patients with minimal symptoms can not seek attention for weeks, by which time the abscess has matured. However, delayed presentation (1-2 weeks) is not generally associated with an increased mortality. In other cases, abscess location and associated edema cause severe symptoms, usually headache or seizure (30%), forcing the patient to seek medical attention at an early stage (2-5 days). Symptom duration is highly variable, with patients tending to present within 10 to 14 days of the their initial symptoms even in patients with multiple abscesses (2,4,5). Early presentation with abrupt neurologic changes (e.g., seizure, blindness, hemiparesis) or coma portends a poor prognosis and is observed more often at the extremes of age. Despite the variable presentation of brain abscesses, only the grading of mental status at evaluation is predictive of mortality (23). Essentially, the more obtunded the patient is at the time of presentation, the higher the mortality. Although the diagnosis and treatment are more rapid today than in the past, patients with a neurologic status of grade C (i.e., responding to painful stimuli only) or grade D (coma) have the highest predicted mortality rates. Overall, mortality rates have decreased from 17% to 83% in the pre-CT era to less than 20% with the aid of modern CT and MR imaging techniques (1,7,16). Although the variability in mortality among reported series is extensive, overall mortality has averaged 30% for patients who presented in the pre- and post-CT eras. Mortality rates exceeding 80% are usually associated with brain abscess complicated by meningitis or ruptured intraventricular brain abscesses (24). Generally, most patients (>80%) present with grade A or B neurological status, which accounts for the relatively low mortality from brain abscess (4,13,25). Interestingly, patients with multiple abscesses do not seem to present more often with neurological status of grades C and D (1,14,21). Thus, abscess multiplicity also does not correlate well with mental status at the time of diagnosis.

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Diagnosis The data in Table 5-2 illustrate clinical findings associated with brain abscess. However, because less than 50% of patients present with hard neurological findings (e.g., cranial nerve deficit, focal weakness, seizure), a high index of suspicion is necessary for initiating a diagnostic evaluation. Altered mental status, particularly headache, often prompts CT or MRI imaging of the brain. These revolutionary imaging modalities have largely replaced cerebral angiography and radionuclide scanning in the diagnosis of brain abscess. Britt and Enzmann have provided crucial histopathologic and radiographic data about the evolution of brain abscess (8, 9). Although imaging characteristics consistent with brain abscess are variable, patients typically have lesions that demonstrate ring enhancement when injected with iodinated contrast medium or gadolinium. Figure 5-1 shows a T1-weighted MRI

Figure 5-1 Magnetic resonance imaging scan of a brain abscess. This T1-weighted image shows a mature (encapsulated) abscess that involves the left temporal lobe.

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scan of a typical mature abscess with gadolinium enhancement of the peripheral capsule. T2-weighting generally produces a hyperintense signal within the abscess and the surrounding edematous tissue. Because the etiology of ring-enhancing lesions tends to be infectious or neoplastic, a major concern in the diagnosis of brain abscess is ruling out malignancy. Rare instances have been cited in which both an abscess and a tumor coexisted (26). If there is high suspicion for malignancy, biopsy is essential and a search for a primary malignancy (especially in the lung) is necessary. Radionuclide scanning with either technium-99m (99mTc)- or indium-111 (111In)-labeled leukocytes can help differentiate tumor from infection (26). Although biopsy remains the gold standard and is often feasible with modern stereotactic techniques, lesions that are small, immature, or located within the brainstem can not be amenable to stereotactic aspiration or biopsy. Therefore, close consultation with both a neurosurgeon and a neuroradiologist is essential. Although identification and localization of the lesion are key elements of imaging in brain abscess cases, diagnostic aspiration and/or biopsy are critical in establishing a microbiological diagnosis. Because 20% to 40% of abscesses are cryptogenic, an effort should be made to obtain abscess material for cultivation in the microbiology laboratory. Results of abscess cultures reveal organisms (e.g., aerobic, anaerobic, fungal) in 60% to 80% of cases (4,15,27), unless patients have been given antibiotics previously (23,28). Obtaining cultures of abscess fluid allows more directed antibiotic therapy and can suggest an anatomical source of infection. Clinicians should be prompted to evaluate patients for extraneural sources of infection that can reveal the offending pathogens, especially when diagnostic aspiration is not possible or when cultures are negative. However, there are no consensus guidelines for this, and results are often negative. Using CT or MRI can help identify rhinogenic or otogenic disease and cultures of sputum, pleural fluid, and blood can be helpful in cases of pneumonia, pleural empyema, and endocarditis. Positive blood cultures have been noted in 60% to 70% of brain abscess patients with active endocarditis and are of help in directing the appropriate antibiotic therapy. In contrast, other studies have reported positive blood cultures in only 10% to 12% patients (4,23). Nonetheless, obtaining blood cultures during the initial evaluation can have some use, especially if diagnostic aspiration is delayed or not performed. On the basis of associated risk factors, empirical therapy for brain abscess can be governed by a knowledge of the microbiological flora that are typical for this condition. Table 5-3 summarizes some expected pathogens associated with brain abscess and their treatment. With regard to the usual risk factors (see Table 5-1), aerobic and anaerobic streptococci predominate (40%-80% of cases) when the source is considered to be rhinogenic, otogenic, odontogenic, pulmonary, or cardiac. Enteric bacilli also can arise from chronic otogenic infection. Staphylococci, including methicillin-resistant Staphylococcus aureus, and Enterobacteriaceae pre-

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Table 5-3 Brain Abscess in Adults: Microbiology and Empiric Antimicrobial Therapy* Primary Source of Abscess

Site of Abscess

Paranasal sinus

Frontal lobe

Microbial Flora

Empiric Therapy†

Aerobic streptococci Metronidazole Anaerobic and ceftriaxone# streptococci Haemophilus species Bacteroides species Fusobacterium Inner ear Temporal Aerobic and Metronidazole (otitis lobe and anaerobic and ceftriaxone media) and cereStreptococci species mastoid bellum Haemophilus species sinus Enterobacteriaceae Bacteroides Metastatic Any lobe Depends on source: from a Endocarditis: distant MSSA (MRSA), and Nafcillin (or focus Streptococci vancomycin) (viridans group) and gentamicin Pulmonary Lesion: Aerobic and anaerobic Streptococci Enterobacteriaceae Actinomycetes species Nocardia species

Penetrating trauma

Postoperative

Metronidazole and ceftriaxone

MRSA Enterobacteriaceae Pseudomonas

500 mg IV q 6 h 2 g IV q 4 h

500 mg IV q 6 h 2 g IV q 12 h

2 g IV q 4 h 15 mg/kg q 12 h 3-5 mg/kg IV q 8-12 h 500 mg IV q 6 h 2 g IV q 12 h

Add penicillin G

2-4 million units IV q 4 h Add high-dose 2-5 mg/kg TMP-SMX DS (or PO q 6 h sulfisoxazole) 2 g PO q 6 h Metronidazole 500 mg IV q 6 h and ceftriaxone* 2 g IV q 12 h Add ampicillin (or 2 g IV q 4 h vancomycin) 15 mg/kg q 12 h

Intra-abdominal Infection: Enterobacteriaceae Streptococci Anaerobes (B. fragilis) Enterococci species¶ Depends MSSA (MRSA) Nafcillin (or on Staph. Epidermidis vancomycin) location Anaerobes Add metronidazole Enterobacteriaceae Add ceftriaxone Bacillus species Add vancomycin (or clindamycin) Depends on site

Dosing of Antimicrobial Agents‡

Vancomycin Add ceftriaxone Add ceftazidime

2 g IV q 4 h 15 mg/kg q 12 h 500 mg IV q 6 h 2 g IV q 12 h 15 mg/kg q 12 h 400-600 mg IV q 6h 15 mg/kg q 12 h 2 g IV q 12 h 1-2 g IV q 4-8 h

Abbreviations: IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillinsusceptible Staphylococcus aureus; PO, orally; q, every. * Antimicrobial therapy is best determined in consultation with an infectious diseases specialist and must be tailored to definitive culture results and the patient’s clinical condition.

Continued

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Table 5-3 Continued †

Treatment of mycobacterial, fungal, and nocardial abscesses is discussed elsewhere (2, 7) and requires input from an infectious diseases specialist. ‡ Dosages need adjustment in patients with underlying renal or liver diseases. # Ceftriaxone can be substituted for cefotaxime 1 to 2 g IV every 4 to 8 hours (with a 12 g /day maximum) or cefepime 2 g IV every 12 hours. ¶ Treatment of Enterococci can require coadministration of an aminoglycoside.

dominate in neurosurgical and trauma patients (19). Additionally, penetrating trauma to the head should alert the physician to such organisms as Bacillus (12). Even in immunocompromised patients, typical streptococci (aerobic and microaerophilic), including resistant Streptococcus pneumoniae, must be considered in cases of brain abscess, along with opportunistic pathogens. In most cases for which aspirates are available for cultivation in the laboratory, positive results are obtained in well over 80% of the samples evaluated in many series (3,4,20,29). Importantly, 10% to 40% of brain abscess cultures also are polymicrobial (10); therefore, antibiotic therapy must be tailored appropriately. Ancillary laboratory evaluation is generally of little value in the diagnosis of brain abscess. Many patients have a modestly increased leukocyte count (>10,000 cells/mm3). Although an increased erythrocyte sedimentation rate is likely in brain abscess, few data have evaluated this indicator. Similarly, C-reactive protein (CRP) probably has little diagnostic use beyond being a helpful correlate or in monitoring the response to treatment. Presently, the treatment of brain abscess is monitored clinically through physical examination and repeated CT or MR imaging. The use of cerebrospinal fluid analysis in the diagnosis of brain abscess dates back to studies done in the pre-CT era. Cerebrospinal fluid analysis can reveal pleocytosis and increased protein levels. However, cultures are usually negative. The high mortality rates associated with lumbar puncture in patients with brain abscess were determined before the availability of modern imaging (16). However, lumbar puncture is best avoided until a space-occupying lesion or severe edema has been ruled out. If necessary, cerebrospinal fluid sampling is performed optimally in consultation with a neuroradiologist and a neurologist or neurosurgeon.

Management The treatment of patients with brain abscess is complicated and necessitates the close interaction of the primary physician, a neurosurgeon, and an infectious disease specialist. Two key elements are critical in the initial evaluation and treatment of the patient with a brain abscess. First, as discussed previously, a regimen of antibiotics must be chosen on the basis of an assessment of attributable risk factors and comorbid conditions (see Table 5-1). If no obvi-

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ous focus of infection is present, a search for other infection sites is necessary, even though as many as 30% to 40% of patients have no identifiable source of brain abscess. In these patients, a thorough medical history can help identify other clues. For example, a history of drug abuse indicates a need for either a semisynthetic penicillin (e.g., nafcillin) or vancomycin, depending on corroborative cultures, allergy history, and the prevalence of methicillin-resistant staphylococci. Additionally, risk factors for HIV should be discussed. If HIV infection is a possibility, consent should be obtained and testing should be performed. This is especially important because the therapy for a common cause of brain abscess in these patients (T. gondii) is different (e.g., sulfadiazine, pyrimethamine) and best managed in consultation with an infectious diseases specialist. The second crucial element in the initial management of patients with brain abscess is the decision to evacuate or aspirate the lesion surgically or stereotactically. Abscess location, size and multiplicity dictate the treatment plan. Perhaps most critical is the patient’s mental status at the time of diagnosis, because mortality is highest for patients who present acutely or with grade C or D neurological status. This following section briefly considers these issues, with treatment guidelines that must be individualized to each patient.

Antibiotic Penetration of Brain Abscess Cavities Ideally, antibiotic choice in the therapy of brain abscess would be guided by data that demonstrates penetration of antibiotics into the abscess cavities. Unfortunately, these data are limited. Penicillin G has considerable efficacy and has been measured in abscesses at concentrations exceeding minimal inhibitory concentrations for typical offending streptococci (30). Although chloramphenicol and nafcillin penetration into abscess cavities was more erratic, these agents have been used successfully in treating brain abscesses (2,7). Other important antibiotics that reach measurable levels within abscess cavities include metronidazole, vancomycin, cefotetan, ceftriaxone, cefotaxime, ceftazidime, and fluoroquinolones (30-32). Of these, metronidazole has been a pivotal agent against anaerobic streptococci, which are frequently present (40%-50%) and often tolerant or resistant to penicillin. It should be emphasized that first- and second-generation cephalosporins and aminoglycosides are not recommended for treating brain abscesses. In cases of ventricular rupture that involve Enterobacteriaceae, intraventricular instillation of an aminoglycoside can have benefit. The clinical evaluation of antibiotic combinations in treating brain abscess has not been systematic or well controlled. Although the efficacies of newer antimicrobial agents have not been well studied, carbapenems (e.g., meropenem) have been used successfully despite concerns regarding the risk of seizures. In addition, the efficacy of new fluoroquinolones (e.g., moxifloxacin) has been demonstrated experimentally and can offer an alternative treatment choice in individualized cases.

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Treatment Strategies Antibiotic Treatment: General Guidelines All patients with cerebral brain abscesses require antibiotic treatment (see Table 5-3). The antibiotics used must have activity against suspected pathogens or those related to an identified source of infection. For example, if there is a history of intravenous drug abuse, coverage must include an antistaphylococcal antibiotic such as nafcillin. If there is reason to suspect methicillin-resistant staphylococci as the source of infection, vancomycin should be used. Antibiotic selection is even more critical when attributable risk factors are absent. Because brain abscesses arising from rhinogenic, otogenic, odontogenic, pulmonary, and cryptogenic sources are often also infected with anaerobic bacteria, combination therapy must ensure adequate coverage of anaerobes. This has been accomplished classically with combinations of penicillin G and chloramphenicol. Chloramphenicol has been replaced successfully by metronidazole in the past 20 years. For empiric therapy, a third- generation cephalosporin has replaced penicillin G which remains primary therapy for Actinomycetes and Fusobacterium species (2,7). When an otogenic source is implicated or suspected, a third-generation cephalosporin (e.g., ceftriaxone, ceftazidime, ceftizoxime, cefotaxime) should be included in the treatment regimen, because Enterobacteriaceae and Pseudomonas can be present. When comorbid immunosuppressive conditions are known to exist (e.g., chronic renal failure, corticosteroid therapy, or diabetes), the physicians treating the case must, in consultation with an infectious diseases physician, either rule out or empirically direct antimicrobial therapy against Listeria, Nocardia, Aspergillus, and Candida. This is especially true in the setting of functional or absolute neutropenia. Abscesses that arise from trauma or neurosurgery are empirically treated with nafcillin or vancomycin in combination with a third-generation cephalosporin; however, ceftazidime, which has better antipseudomonal activity, is often reserved for treating postoperative abscesses. Despite extensive, successful experience with empirical treatment of brain abscesses, the identification of organisms within the abscess cavity should be sought. Empirical treatment guidelines for brain abscesses have been adapted from multiple primary sources and are shown in Table 5-3. Definitive or empirical treatment of nocardial, listerial, fungal, and mycobacterial brain abscesses is discussed in detail in other sources (2,7). Surgical Treatment and Aspiration Although antibiotics are critical in the treatment of brain abscesses, surgical intervention is usually necessary. For this reason, prompt neurosurgical consultation and evaluation are essential. Before modern imaging techniques were available, open craniotomy and the excision of an abscess provided contents for definitive culture. This approach was successful for most patients, especially when the abscess was solitary and located peripherally (16). Today,

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most authors suggest an open procedure for patients with either grade C (obtunded) or grade D (comatose) neurological status, both of which have been associated with the highest mortality rates in children and adults (4,6,23,24). Additionally, old age or a pulmonary source for a brain abscess seems to increase mortality (4). Certainly, the decision to perform open craniotomy must take into consideration any comorbid conditions that can increase operative mortality (33). Less invasive, CT-guided aspiration of single peripheral abscesses has been successful (25,29,34). Precise stereotactic aspiration has been used with success for peripheral lesions but is reserved more often for deep lesions of the brain stem or cerebellum in stable patients with either grade A (normal) or grade B (lethargic) neurological status (1,7,29). It should be stressed that regardless of the surgical technique chosen, abscess contents or tissue must be obtained and sent promptly to the laboratory for Gram and fungal stains and for aerobic, anaerobic, and fungal cultures. Additional cultures for mycobacteria also should be considered in consultation with an infectious diseases specialist. The availability of modern CT and MRI techniques has revolutionized the surgical treatment of brain abscesses and has been associated with a reduction in mortality from 41% in the pre-CT era (before 1970-1974) to 4% in the post-CT era. Through prospective studies on multiple abscesses, stereotactic aspiration has emerged as an excellent treatment option for patients unless lesions are located in the posterior fossa or are superficial, well matured, and excisable (1). However, this is not the case for the treatment of nocardial brain abscesses, which often require evacuation through a craniotomy for cure (35). Other studies have advocated placement of catheters for repeated aspiration and instillation of antibiotics (25); however, this approach has not been used widely. Stereotactic aspiration and treatment of brain abscesses is effective and is not associated with a significant increase in neurological disability after the procedure (29). This outcome is similar to that for patients undergoing craniotomy and emphasizes the failure of any study to demonstrate a surgical procedure of choice for brain abscess. When resources for advanced neuroradiographic intervention have been unavailable, open procedures (e.g., craniotomy, the classic free-hand burr-hole approach) have been used with excellent success (16).

Antibiotics Alone Although abscesses are traditionally thought to require drainage for cure, some clinicians have noted successful treatment of these lesions with antibiotics alone. Antibiotics alone can be considered for the treatment of an abscess if the patient is of grade A or B neurological status at the time of clinical suspicion or diagnosis. The efficacy of antibiotic treatment alone can rely on improved antibiotic penetration during the early cerebritis stage of an abscess, emphasizing the importance of early diagnosis. Additionally, most studies show that the success of antibiotic therapy is dictated by

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abscess size: Small abscesses (<2.0-2.5 cm), even when numerous, have been treated successfully with antibiotics alone (14,27,33,36). The success of this approach, however, depends on careful antibiotic selection and close clinical monitoring. Duration of therapy must be individualized and can vary widely from the longest periods required for a patient with Nocardia and other opportunistic pathogens. Although antibiotics alone can be curative in nonsurgical patients (33) failures of antibiotic therapy have been reported (23). The success of antibiotic therapy alone as the primary modality for treating a brain abscess rests on close clinical monitoring of the patient and repeat CT or MRI scans at weekly or biweekly intervals until a definitive response is seen (28,29). Because abscesses tend to shrink in size by the second or third week of treatment, patients with lesions that do not improve should be considered for prompt neurosurgical evaluation. Patients who develop new lesions or show declining mental status with antibiotic therapy alone also should be treated surgically. A change in these patients’ antibiotic regimens should be considered in close consultation with an infectious diseases specialist. The duration of antibiotic therapy is dictated primarily by clinical improvement, but most studies support at least 6 weeks of parenteral therapy, followed by oral therapy for an additional 2 to 4 weeks (2,7,13). Some authors suggest that antibiotic treatment alone requires a prolonged course of at least 12 weeks, but such choices must be individualized to each patient on the basis of clinical responses and radiographic findings. Despite extensive experience with empirical treatment, identifying organisms within the abscess cavity or from distant sites should be pursued diligently, and therapy should be directed toward the most likely pathogens (see Table 5-3), especially in immunocompromised patients. Definitive or empirical treatment of nocardial, listerial, fungal, and mycobacterial brain abscesses is discussed in detail in other more comprehensive sources (2,7).

Supportive Therapy and Outcome Corticosteroids have been used to reduce cerebral edema associated with brain abscess. However, there is some controversy about whether corticosteroids impair immune defenses and antibiotic efficacy. Although the role of corticosteroids has not been studied systematically, most authors recommend weaning the patient from steroids when cerebral edema has resolved. As prophylaxis against seizure in patients with brain abscesses, most clinicians administer anticonvulsants during the treatment phase and wean the patient from the drugs when the abscess has resolved completely (7). These decisions are best made in consultation with a neurologist or neurosurgeon. A variety of neurological deficits have been reported in cases of brain abscess, encompassing a spectrum of disabilities including hemiparesis, aphasia, blindness, and weakness. In most series that we have studied,

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the incidence of neurological deficits has been highly variable, has borne no relationship to abscess multiplicity, and has ranged from 0% to 20% among the patients reported.

Summary Although pyogenic brain abscesses are relatively infrequent, the clinician should maintain a high index of suspicion for their existence when confronted with suggestive clinical signs and symptoms. With advances in stereotactic aspiration and surgery, craniotomy can be avoided without increasing mortality, even in cases of multiple abscesses. However, craniotomy remains a time-honored surgical modality that should be considered particularly for large, single, peripheral abscesses such as cortical lesions. In all cases, efforts to identify pathogens should be diligent even in the face of culture-negative aspirates (15%-20%), and antibiotic therapy should be tailored appropriately to the findings. Duration of therapy is highly variable and is dictated by the patient’s clinical status, the etiologic organism’s antibiotic sensitivity, adverse antibiotic effects, and resolution of lesions on radiographic images. Therapy generally requires at least 8 to 12 weeks for best outcomes. The treatment of patients with pyogenic brain abscess is highly individualized and critically dependent on dialogue among the primary care physician, neurosurgeon, radiologist, and infectious disease specialist. REFERENCES 1. Mamelak AN, Mampalam TJ, Obana WG, Rosenblum ML. Improved management of multiple brain abscesses: a combined surgical and medical approach. Neurosurgery. 1995;36:76-85; discussion 85-6. 2. Tunkel AR. Brain abscess 6th ed. In: Mandell G, Bennett J, Dolin R, eds. Principles and Practice of Infectious Diseases Vol. 1. New York: Churchill Livingstone; 2005:1150-63. 3. Brewer NS, MacCarty CS,Wellman WE. Brain abscess: a review of recent experience. Ann Intern Med. 1975;82:571-6. 4. Chun CH, Johnson JD, Hofstetter M, et al. Brain abscess. A study of 45 consecutive cases. Medicine (Baltimore). 1986;65:415-31. 5. Kao PT,Tseng HK, Liu CP, Su SC, Lee CM. Brain abscess: clinical analysis of 53 cases. J Microbiol Immunol Infect. 2003;36:129-36. 6. Sáez-Llorens X. Brain abscess in children. Semin Pediatr Infect Dis. 2003;14:108-14. 7. Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis. 1997;25:763-79; quiz 780-1. 8. Britt RH, Enzmann DR. Clinical stages of human brain abscesses on serial CT scans after contrast infusion. Computerized tomographic, neuropathological, and clinical correlations. J Neurosurg. 1983;59:972-89. 9. Britt RH, Enzmann DR,Yeager AS. Neuropathological and computerized tomographic findings in experimental brain abscess. J Neurosurg. 1981;55:590-603. 10. Maniglia RJ, Roth T, Blumberg EA. Polymicrobial brain abscess in a patient infected with human immunodeficiency virus. Clin Infect Dis. 1997;24:449-51. 11. Hagensee ME, Bauwens JE, Kjos B, Bowden RA. Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center, 1984-1992. Clin Infect Dis. 1994;19:402-8. 12. Bert F, Ouahes O, Lambert-Zechovsky N. Brain abscess due to Bacillus macerans following a penetrating periorbital injury. J Clin Microbiol. 1995;33:1950-3.

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13. Heilpern KL, Lorber B. Focal intracranial infections. Infect Dis Clin North Am. 1996;10:879-98. 14. Boom WH,Tuazon CU. Successful treatment of multiple brain abscesses with antibiotics alone. Rev Infect Dis. 1985;7:189-99. 15. Lu CH, Chang WN, Lin YC,Tsai NW, Liliang PC, Su TM, et al. Bacterial brain abscess: microbiological features, epidemiological trends and therapeutic outcomes. QJM. 2002;95: 501-9. 16. Garfield J. Management of supratentorial intracranial abscess: a review of 200 cases. Br Med J. 1969;2:7-11. 17. Yang SY, Zhao CS. Review of 140 patients with brain abscess. Surg Neurol. 1993;39: 290-6. 18. Takeshita M, Kagawa M,Yato S, Izawa M, Onda H,Takakura K, et al. Current treatment of brain abscess in patients with congenital cyanotic heart disease. Neurosurgery. 1997;41:1270-8; discussion 1278-9. 19. Rau CS, Chang WN, Lin YC, Lu CH, Liliang PC, Su TM, et al. Brain abscess caused by aerobic Gram-negative bacilli: clinical features and therapeutic outcomes. Clin Neurol Neurosurg. 2002;105:60-5. 20. Xiao F,Tseng MY,Teng LJ,Tseng HM,Tsai JC. Brain abscess: clinical experience and analysis of prognostic factors. Surg Neurol. 2005;63:442-9; discussion 449-50. 21. Sharma BS, Khosla VK, et al. Multiple pyogenic brain abscesses. Acta Neurochir (Wien). 1995;133:36-43. 22. Powers JH, Scheld WM. Fever in neurologic diseases. Infect Dis Clin North Am. 1996;10:45-66. 23. Seydoux C, Francioli P. Bacterial brain abscesses: factors influencing mortality and sequelae. Clin Infect Dis. 1992;15:394-401. 24. Zeidman SM, Geisler FH, Olivi A. Intraventricular rupture of a purulent brain abscess: case report. Neurosurgery. 1995;36:189-93; discussion 193. 25. Hasdemir MG, Ebeling U. CT-guided stereotactic aspiration and treatment of brain abscesses. An experience with 24 cases. Acta Neurochir (Wien). 1993;125:58-63. 26. Nassar SI, Haddad FS, Hanbali FS, Kanaan NV. Abscess superimposed on brain tumor: two case reports and review of the literature. Surg Neurol. 1997;47:484-8. 27. de Louvois J. The bacteriology and chemotherapy of brain abscess. J Antimicrob Chemother. 1978;4:395-413. 28. Dyste GN, Hitchon PW, Menezes AH,VanGilder JC, Greene GM. Stereotaxic surgery in the treatment of multiple brain abscesses. J Neurosurg. 1988;69:188-94. 29. Mampalam TJ, Rosenblum ML. Trends in the management of bacterial brain abscesses: a review of 102 cases over 17 years. Neurosurgery. 1988;23:451-8. 30. Black P, Graybill JR, Charache P. Penetration of brain abscess by systemically administered antibiotics. J Neurosurg. 1973;38:705-9. 31. Sjölin J, Lilja A, Eriksson N,Arneborn P, Cars O. Treatment of brain abscess with cefotaxime and metronidazole: prospective study on 15 consecutive patients. Clin Infect Dis. 1993;17:857-63. 32. Yamamoto M, Jimbo M, Ide M, Tanaka N, Umebara Y, Hagiwara S. Penetration of intravenous antibiotics into brain abscesses. Neurosurgery. 1993;33:44-9. 33. Rosenblum ML, Hoff JT, Norman D, Edwards MS, Berg BO. Nonoperative treatment of brain abscesses in selected high-risk patients. J Neurosurg. 1980;52:217-25. 34. Chacko AG, Chandy MJ. Diagnostic and staged stereotactic aspiration of multiple bihemispheric pyogenic brain abscesses. Surg Neurol. 1997;48:278-82; discussion 282-3. 35. Mamelak AN, Obana WG, Flaherty JF, Rosenblum ML. Nocardial brain abscess: treatment strategies and factors influencing outcome. Neurosurgery. 1994;35:622-31. 36. de Louvois J, Gortvai P, Hurley R. Antibiotic treatment of abscesses of the central nervous system. Br Med J. 1977;2:985-7.

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Part III

Heart and Vascular Infections

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Chapter 6

Infective Endocarditis JACK EBRIGHT, MD DONALD P. LEVINE, MD

Key Learning Points 1. Endocarditis primarily affects the elderly and those with chronic medical conditions, although among the young injection drug use remains an important risk factor. 2. Staphylococcus aureus is increasingly important among noninjection drug users. 3. Perform blood cultures prior to initiation of therapy. They are the most important diagnostic procedure. 4. Duke criteria are widely accepted to assist in diagnosis, but are not a substitute for sound clinical judgment. 5. Prolonged treatment with bactericidal drugs is required.

O

sler described malignant endocarditis at the dawn of the microbiology age. Later authors began to use the term bacterial endocarditis because of the frequent observation that bacteria were the causative agents. However, in view of the broad spectrum of potential pathogens, the term infective endocarditis (IE) is now preferred. IE refers to an infection of the endocardial surface of the heart, usually on the atrial surface of the valve cusps along the line of closure. However, the valve-supporting structures, septal defects, or, in certain circumstances, the mural endocardium may also be involved. The hallmark of endocarditis is continuous shedding of organisms into the bloodstream. All organs may be affected; and depending on the virulence of the pathogen, disease may vary clinically from an indolent chronic illness to an acute, rapidly fatal, catastrophic event. Too often, organs other than the heart manifest signs of disease, misleading clinicians to an incorrect analysis. Hence, a high degree of clinical suspicion is required for 109

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New Developments in Infective Endocarditis • Because of the transient nature of bacteremia related to dental procedures as well as lack of data to support previous recommendations, recent guidelines from the American Heart Association for the prevention of endocarditis have been modified; prophylaxis is now recommended for only high risk patients such as those with prosthetic valves, congenital heart disease with residual defects or repaired with prosthetic material and those undergoing valvulopathy after heart transplantation. • There is continued evolution of antimicrobial resistance among pathogens

associated with endocarditis that impact therapeutic decisions. • Despite advances in diagnosis, surgical techniques, antimicrobial therapy and

management of complications, there is still high morbidity and mortality associated with infective endocarditis.

diagnosis (1). Most patients will initially present to their primary care physicians with vague complaints that fail to point directly to the diagnosis. Yet, it is incumbent on those clinicians to recognize and to initiate a proper workup and management if patients are to avoid the many complications of disease.

Epidemiology In the United States and Western Europe, the incidence of communityacquired native-valve endocarditis ranges from 1.7 to 7.0 cases per 100,000 person-years and may be increasing (1-4). However, a recent report from Olmstead County, Minnesota, that covered the period 1970 to 2000, demonstrated the incidence was stable at 5.0 to 7.0 cases/100,000, suggesting that in areas with stable populations the incidence is unchanged (3). Although IE can occur at any age, the incidence in older persons is increasing. In the preantibiotic era, the median age was 30 to 40 years and reflected structural heart disease and valves previously damaged by rheumatic fever. Among young patients with IE, injection drug use is most often the underlying risk factor (5). Currently, most patients are older than age 50 years (4,6). In a recent comprehensive multinational survey, the mean age was 58 years (7). Most likely, several factors are responsible for the increasing age among IE patients. Rheumatic fever has largely disappeared among the young; the susceptible population with rheumatic heart disease is now an older population. In addition, most structural cardiac lesions are corrected in childhood, thus further decreasing the pool of susceptible patients in the younger age group. Older patients are also more likely to have prosthetic heart valves, another risk factor for IE. These factors, combined with the normal changes in cardiac valves that accompany aging, help explain this increasing trend toward older patients. Endocarditis is also increasingly a disease of medical progress, occurring

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in patients with prosthetic heart valves or indwelling intravascular catheters during hospitalization and in those who have received parenteral nutrition or have undergone invasive cardiac procedures. Hemodialysis is another recently recognized risk factor (8).

Pathogenesis Trauma to the endocardial endothelium is probably the most common pathogenic mechanism for infective endocarditis. Three hemodynamic characteristics seem to predispose to endothelial trauma: turbulent, especially regurgitant blood flow; the presence of high-pressure gradients; and a narrow orifice (9). Cardiac abnormalities marked by these characteristics, such as mitral and aortic regurgitation, aortic stenosis, or ventricular septal defect, are associated with a high incidence of infective endocarditis. In contrast, structural abnormalities lacking these characteristics, such as an ostium secundum atrial septal defect, do not predispose to endocarditis. Except among the population of intravenous drug abusers, the prevalence of endocarditis of the right side of the heart (where there is low pressure) is very low. Trauma to the endothelium triggers the local deposition of platelets and fibrin, forming a sterile thrombotic endocardial lesion or vegetation, also known as nonbacterial thrombotic endocarditis (NBTE). If bacteremia or fungemia occurs even transiently, the involved microorganisms may adhere to the surface of the vegetation. The absence of local host-defense mechanisms at the vegetation site allow microorganisms to multiply, and more platelets and fibrin deposit onto the vegetation. In the absence of therapeutic intervention, this cycle continues, resulting in ever-larger vegetations consisting of platelets, fibrin, and colonies of microorganisms (10). Certain microorganisms, most notably viridans streptococci, Streptococcus mutans, Streptococcus mitior, and Streptococcus sanguis, are more likely to be involved because of their ability to adhere to the altered valve surface by means of synthesized extracellular polysaccharides or glycocalyx (11). There is also experimental evidence that Staphylococcus aureus and viridans streptococci can bind to the host matrix proteins, fibronectin, fibrinogen, and collagen, found within the NBTE lesion (10). Some host-defense mechanisms, such as the bactericidal activity of serum complement, protect against endocardial infection. This may explain why some gram-negative enteric bacilli such as Escherichia coli, which are usually serum sensitive, seldom cause infective endocarditis. In 1 instance of E. coli endocarditis, the causative organism was serum resistant (12). The mechanism by which organisms such as S. aureus infect apparently normal heart valves remains unknown. The initial event may be the binding of staphylococci directly to endothelial cells. There is also evidence that endothelial cells ingest staphylococci as part of the initial pathologic process (13). Reasons for the high prevalence of tricuspid valve endocarditis among

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injection drug abusers, few of whom have any evidence of previous valve damage, remain speculative. Trauma to the endothelium by repeated insult with impure injected substances is 1 potential explanation (5).

Pathophysiology Infective endocarditis affects the entire body. Many pathologic processes, including local destruction of valvular and other cardiac tissue, systemic embolization with possible ischemic injury or secondary infected sites, continuous bacteremia, as well as immunopathologic factors contribute to the systemic nature of the disease. Emboli from the infected vegetation circulate widely. Patients with rightside infection routinely develop septic emboli to the lungs; those with infection of the mitral or aortic valve have systemic emboli, most notably to the brain. Septic infarctions or abscesses may result. Large arterial emboli are especially common in IE because of Candida, Aspergillus, Haemophilus, and group B streptococci (14). The persistent bacteremia of endocarditis elicits a substantial immunologic response, manifested by hypergammaglobulinemia, production of rheumatoid factor (immunoglobulin M [IgM] antibody directed to IgG) and immune complex formation that occur in patients with prolonged illness and probably result from antibody formation to bacterial antigens. Clinically relevant consequences may include diffuse glomerulonephritis and Osler nodes (10).

Etiology Staphylococci, streptococci, and enterococci cause most cases of IE; however, many other microorganisms are responsible under the appropriate circumstances (Table 6-1). The virulence of the infecting pathogen tends to predict the nature of the disease. Endocarditis is often characterized as acute or subacute, the distinction based on whether the disease follows an aggressive (acute) or an indolent (subacute) course. Viridans streptococci (α-hemolytic streptococci) are the most common cause of subacute bacterial endocarditis (SBE). Streptococcus bovis, although less common, is an important cause of endocarditis and is frequently associated with colonic pathology, such as carcinoma or villous adenoma (15). Enterococcus, especially Enterococcus faecalis, is a well-known cause of endocarditis in elderly men and also is associated with hospital-acquired endocarditis (6,16). The HACEK microorganisms (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Ki, a group of fastidious gram-negative bacilli that are part of the normal flora of the oral cavity) are also capable of causing

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Table 6-1 Microorganisms that Cause Endocarditis in Different Clinical Settings Subacute Endocarditis (Indolent Course)

Prosthetic Valve Endocarditis

Viridans streptococci* (S. mitis, S. salivarius, S. sanguis, S. mutans) Group D streptococcus (Streptococcus bovis)* Enterococcus species* Staphylococcus epidermidis HACEK Group

Staphylococcus epidermidis*

Staphylococcus aureus Candida species Gram-negative bacilli Viridans streptococci Enterococcus species Aspergillus species

Some Unusual Causes of Native Valve Endocarditis

Bartonella species (B.quintana, B. henselae) Brucella species Coxiella burnetii

Chlamydia species Legionella pneumophila Mycobacterium species Opportunistic fungi

Acute Endocarditis (Aggressive Course)

Staphylococcus aureus* Groups A, B, C, G streptococci Streptococcus pneumoniae Staphylococcus lugdunensis Enterococcus species Neisseria gonorrhea Endocarditis in Intravenous Drug Abusers

Staphylococcus aureus* Streptococcus groups A, B, G Pseudomonas aeruginosa Enterococcus species Candida species Polymicrobial * Most common microorganisms HACEK = Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Ki.

endocarditis (10,17). Prolonged incubation may be required to grow these microorganisms in blood culture. Staphylococcus epidermidis rarely causes SBE of a native valve (18). Occasionally, endocarditis caused by Staphylococcus aureus also has an indolent course. S. Aureus is the most important cause of acute endocarditis, and in a recent series has surpassed viridans streptococci as the most common cause of IE in patients who have conditions necessitating frequent exposure to the health care system or infected intravascular access devices (7,16,19). βHemolytic streptococci, groups A, B, C, and G have also been increasingly reported as causes of acute endocarditis (10,20). Staphylococcus lugdunensis, a coagulase-negative species, also causes IE with an acute, destructive

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course (21). Bartonella species are the cause of some cases of culturenegative endocarditis, with Bartonella henselae found in individuals who own kittens and B. quintana found in homeless people (22). Streptococcus pneumoniae and Neisseria species are rare causes of endocarditis. Enterococcal endocarditis occasionally presents with an acute clinical course. Staphylococcus aureus is the most common cause of endocarditis in injection drug users, in whom it often infects the tricuspid valve. Group A streptococcus, Pseudomonas aeruginosa, Candida species (especially nonalbicans species), and other microorganisms infrequently seen in others also can cause endocarditis in this population (23). Clinicians traditionally characterize prosthetic valve endocarditis (PVE) as early or late based on its occurrence before or after 60 postoperative days, respectively. Coagulase-negative staphylococci are the most frequent infecting organisms closely followed by S. aureus during the year after valve replacement. After the first year, S. aureus and coagulase-negative staphylococci remain important causes of PVE, but viridans streptococci exceed them in frequency (24). Candida species, often nonalbicans, and various gram-negative bacilli also are important causes of PVE.

Clinical Manifestations Infective endocarditis is a systemic disease, and affected individuals may present with diverse clinical manifestations. In acute endocarditis, the duration from onset of illness to presentation is brief; patients usually come to medical attention within 1 week. High fever is a common feature; however, confusion with or without fever may be the presenting symptom. Patients with left-side infection may present with symptoms of stroke caused by a septic embolus to the brain. Patients with tricuspid infection usually present with chest pain and signs of septic pulmonary embolism. The organisms causing acute endocarditis are usually the more virulent pathogens, such as S. aureus (see Table 6-1). Patients with subacute endocarditis have a more indolent course and have typically been ill for a longer period. Stroke is a frequent presenting complaint and the finding of stroke plus fever should alert the clinician to the possibility of endocarditis. Patients with subacute disease often seem chronically ill and may not recall the exact onset of their illness. Malaise, weight loss, low-grade fever, and night sweats may continue for weeks to months before the patient seeks medical attention (25). The infecting organism in such cases is usually less virulent than in acute endocarditis (see Table 6-1). Fever is an important symptom of infective endocarditis, but a lowgrade fever may go unnoticed. In some cases, and especially in patients with PVE, fever may be the only symptom of infective endocarditis. There may be a chilly sensation and perspiration, often most noticed at night.

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Table 6-2 Common Clinical Symptoms or Signs in Patients with Infective Endocarditis Finding

Causes

Headache/stiff neck

● ●

Acute stroke

● ●

Ischemic extremity Numbness

● ● ●

Hematuria

● ●

Acute chest pain

●

●

Congestive heart failure Fever, pleuritic pain, cough, dyspnea

● ●

Metastatic infection to the brain or meninges Mycotic aneurysm Septic embolus Ruptured mycotic aneurysm Major arterial embolus Nerve compression by adjacent mycotic aneurysm Embolus to vasonervorum Emboli to kidneys Immune complex disease Myocardial infarction caused by embolus to coronary artery Septic pulmonary embolus (tricuspid valve infection) Damaged heart valve with substantial valve dysfunction Infarction or secondary pneumonia caused by septic embolus

Polyarthralgia occurs and may suggest acute rheumatic fever. Pyarthrosis may be another presenting finding in acute endocarditis. Additional presenting complaints include musculoskeletal symptoms, such as joint or back pain from diffuse or localized myalgia. At times, these symptoms may be severe. Some patients may recall transient pain at the tip of a finger or toe, representing the expression of an Osler node (i.e., a transient, painful erythematous nodule on the tip of a finger or toe) (25). Various diverse clinical signs and symptoms also occur in IE (Table 6-2).

Physical Findings Because of the systemic nature of IE, patients may have various nonspecific findings, consistent with involvement of many organs. In subacute infection, pallor is common. Petechiae, especially on the palpebral conjunctiva, buccal mucosa, or on the skin of the trunk, may be a useful clue to the disease. Rarely, purpura occurs in IE, caused by disseminated intravascular coagulation. Osler nodes are red, painful, indurated lesions several millimeters to greater than a centimeter in diameter, which usually occur on the distal plantar or palmar surfaces of the phalanges. Janeway lesions, nontender erythematous macules, occur on the palms and soles. Roth spots, oval retinal lesions that seem red or hemorrhagic with pale centers, may be seen, usually in subacute cases. Although Osler nodes, Janeway lesions, and Roth spots are classically described in patients with IE, they are found in less than 25% of patients with this disease (10). Clubbed fingers is now rare in endocarditis; and splinter hemorrhages of the nails, especially if limited to the distal nail beds, are a nonspecific finding.

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Signs of CHF may occur in patients with severe valvular regurgitation caused by a vegetation or by the rupture of valve cusps, valve leaflets, chordae tendineae, or papillary muscles. In such cases, murmurs of valvular regurgitation are common. Other types of cardiac murmur also may be present, depending on the nature of abnormal blood flow initiated by the infection. However, it is important to note that some patients who have acute endocarditis, especially those with mural endocarditis or cases affecting a previously normal valve or those with right-sided endocarditis, may not have a murmur. The murmur of tricuspid valve endocarditis is a systolic ejection murmur that occurs early in the course of disease. Later, the typical holosystolic murmur of tricuspid regurgitation that increases with inspiration appears, but it may be very difficult to distinguish from a mitral insufficiency murmur. In older patients with arteriosclerotic heart disease, there is often no change in an existing systolic ejection murmur when a valve first becomes infected. Cardiac arrhythmia may occur in patients with myocardial infarction resulting from coronary embolization, an abscess involving the conduction system, or severe CHF. A pericardial friction rub is uncommon in infective endocarditis; it indicates purulent pericarditis caused by rupture of a myocardial abscess or valve-ring abscess into the epicardium (1,10,25). A palpable spleen occurs in up to 60% of patients with IE, particularly in those with subacute disease. In such patients, the spleen is usually firm and nontender and seldom extends more than 2 fingerbreadths below the costal margin. Patients with acute or subacute endocarditis also may present with acute left upper quadrant pain and tenderness resulting from a splenic infarction or abscess (10).

Diagnosis The diagnosis of endocarditis requires prompt recognition that the constellation of symptoms and signs all relate to infection within the heart and the initiation of the proper workup to determine the site and to identify the infecting pathogen. Blood cultures must be obtained and the location of the infected valve must be determined.

Laboratory Findings The leukocyte count is normal in subacute endocarditis, whereas acute endocarditis usually causes a polymorphonuclear leukocytosis. A moderate normocytic anemia (hemoglobin usually not less than 9 g/dL) consistent with the anemia of chronic disease is common in subacute endocarditis. If severe anemia is present, an alternate diagnosis should be considered. Anemia is rare in acute endocarditis except in patients who are intravenous drug users. These patients routinely lose blood in the process of their frequent injections. The erythrocyte sedimentation rate (ESR) is almost always increased and may

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remain so for several weeks after successful therapy for endocarditis. Of note, a normal ESR has been associated with increased death (26). Urinalysis may reveal erythrocytes in patients with endocarditis, and occasionally there is gross hematuria. Mild proteinuria is a common finding. Rheumatoid factor may be present in subacute endocarditis, especially in patients who have had symptoms for more than 6 weeks. Transthoracic echocardiography (TTE) is rapid, noninvasive, and 98% specific for cardiac vegetations. Its sensitivity, however, is lower than that of transesophageal echocardiography (TEE; 60%-70% versus 75%-95%, respectively). A negative TEE has a negative predictive value for IE of 92% (1). TTE is the preferred initial study if the likelihood of IE is relatively low. For patients whose risk of IE is intermediate (unexplained bacteremia with gram-positive cocci, S. aureus bacteremia caused by an infected intravenous catheter, fever, or bacteremia in an injection drug user) or in patients who may have an infected prosthetic heart valve, initial use of TEE is preferred (27). Blood culture is the most important laboratory procedure for the diagnosis of infective endocarditis. The hallmark of bacterial endocarditis is the constant shedding of bacteria from an infected vegetation into the systemic circulation, resulting in persistent, low-grade (80% of cases have less than 100 CFU/mL of blood) bacteremia (28). At least 3 sets of blood cultures should be taken in the first 24 hours to document persistent bacteremia (10). In patients with clinically indolent disease, blood cultures can be obtained over a period of 2 to 3 days. In acutely ill patients, blood cultures should be measured over a period of 2 to 3 hours before empirical antibiotic therapy is instituted. Because of the persistent shedding of bacteria from the infected valve in endocarditis, the infecting organism should grow in all or most blood cultures. An exception is fungal endocarditis, in which case cultures may be negative, or may require special culture techniques to grow the causative organism. Occasionally, a patient has a clinical picture that is compatible with bacterial endocarditis but has negative blood cultures. The true incidence of such culture-negative endocarditis is unknown; however, a recent European study found 14% (88 of 620) of cases of IE were culture-negative (29). The usual reason for negative blood cultures is administration of antibiotics before specimens for blood cultures are obtained. In most cases, blood cultures will become positive after antibiotics are discontinued (30). Fastidious organisms or organisms that require special growth factors, such as Brucella species, may result in negative blood cultures if inadequate methods are used. Prolonged incubation may be required for fastidious organisms such as the HACEK group. In the rare instances of endocarditis caused by Coxiella burnetii, Bartonella species, and Chlamydia species, none of which grows in blood cultures, serologic methods are used to confirm the causative pathogen. PCR-based testing of cardiac tissue is being studied as a potential method to identify the causative agent in patients whose blood cultures remain negative. However, such technology is not readily available in most centers at this time, nor is the methodology standardized. Accordingly, PCR is not a standard diagnostic criterion (31).

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Diagnostic Criteria In 1994, Durack and colleagues proposed the Duke criteria for the diagnosis of IE to facilitate epidemiological and clinical research. Since then, the schema has been extended to clinical settings and has become, with recent modification, the primary diagnostic schema for patients suspected of having IE (32) (Table 6-3). Accordingly, the diagnosis of IE can be considered Table 6-3 Definition of Terms Used in the Modified Duke Criteria for the Diagnosis of Infective Endocarditis Major Clinical Criteria ●

●

Blood culture positive for infective endocarditis ❍ Typical microorganisms consistent with IE from 2 separate blood cultures: ■ Viridans streptococci, Streptococcus bovis, HACEK group, and Staphylococcus aureus ■ Community-acquired enterococci in the absence of a primary focus; or ❍ Microorganisms consistent with IE from persistently positive blood cultures defined as follows: ■ At least 2 positive cultures of blood samples drawn >12 h apart; or all of 3 or most ≥ 4 separate cultures of blood (with first and last sample drawn at least 1h apart); or ■ Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG antibody titer >1:800 Evidence of endocardial involvement ❍ Echocardiogram positive for IE (TEE recommended for patients with prosthetic valves, rated at least possible IE by clinical criteria, or complicated IE [paravalvular abscess]; TTE as first test in other patients) defined as follows: ■ Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; abscess; new partial dehiscence of prosthetic valve; or new valvular regurgitation (worsening or changing or preexisting murmur insufficient)

Minor Criteria ● ● ●

●

●

Predisposition, predisposing heart condition, or IDU Fever, temperature >38˚C Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions Immunologic phenomena: glomerulonephritis, Osler notes, Roth spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted previously* or serological evidence of active infection with organism consistent with IE

Echocardiographic minor criteria eliminated Reprinted with permission from: Clinical Infectious Diseases. Copyright 2000, University of Chicago Press (32). Modifications shown in boldface. * Excludes single positive cultures for coagulase-negative staphylococci and organisms that do not cause endocarditis. Abbreviations: h = hour; HACEK = Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Ki; IDU = intravenous drug user; IE = infective endocarditis; TEE = transesophageal echocardiography; TTE = transthoracic echocardiography.

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definite if the patient with suspected IE fulfills 2 major criteria, or 1 major and 3 minor criteria, or 5 minor criteria. The diagnosis remains possible if 1 major and minor criterion or 3 minor criteria are present. The Duke criteria are a clinical guide for diagnosing IE and must not replace clinical judgment (31).

Treatment Most cases of infective endocarditis are curable. It is important to diagnose IE early and correctly identify the causative pathogen so the proper antibiotic regimen can be prescribed. In general, treatment involves giving high doses of bactericidal antibiotics over a prolonged period; and it is imperative that the antimicrobial susceptibility of clinical isolates is determined. An antibiotic is used that inhibits bacterial cell wall synthesis, and an aminoglycoside is added for synergistic effect in certain situations. Table 6-4 lists recommended antibiotic regimens for infective endocarditis based on the infecting organisms (31). Antibiotic choice for patients with culture-negative IE is problematic and we recommend consultation with an expert in infectious diseases. Most patients with culture-negative IE have received antibiotics before having blood cultures. In such a circumstance, it may be helpful to consider the tempo of the patient’s illness. Patients with acute IE should have coverage for S. aureus (and for enterococcus as well, if hospital acquired). Because viridans streptococci, enterococci, and HACEK microorganisms are the likeliest presumed cause of culture-negative subacute IE, patients with subacute illness should treated for those pathogens (31).

Anticoagulant Therapy Although animal data suggest there are potential benefits of anticoagulants in treatment of IE, patients treated with aspirin had increased complications from bleeding, increased embolic events with no effect on vegetation resolution, or valvular dysfunction (33). Hence, the use of anticoagulation is discouraged. The question of continuing anticoagulation in patients with infected prosthetic mechanical valves is especially difficult. Such patients may have their anticoagulation cautiously continued during antibiotic treatment; however, it should be suspended for approximately 2 weeks in patients with S. aureus prosthetic valve endocarditis in the event of a new central nervous system embolic event (31).

Monitoring Antibiotic Treatment In most cases, when appropriate antibiotics are given at recommended dosages to patients with bacterial endocarditis, fever and bacteremia cease

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Table 6-4 Treatment Regimens for Infective Endocarditis Duration (wk)

Infecting Organisms

Regimen†

Viridans streptococci, Streptococcus bovis (MIC* of penicillin ≤0.12 µg/mL)

Penicillin, 12-18 million 4 U/24 h, IV or Ceftriaxone, 2 g, once 4 daily, IV or Vancomycin, 30 mg/kg/ 4 24 h in 2 divided doses, IV‡

Viridans streptococci, S. bovis (MIC* of penicillin ≥0.12≤0.5 µg/mL)

Streptococci with MIC* of penicillin >0.5 µg/mL, and Enterococcus species

Staphylococcus aureus, methicillin susceptible,in absence of prosthetic material

Penicillin, 24 million U/24 h, IV or Ceftriaxone, 2 g, once daily, IV plus Gentamicin, 3 mg/kg once daily IV/IM§ or Vancomycin, 30 mg/kg/ 24 h in 2 divided doses, IV Ampicillin, 12 g/24 h, IV or Penicillin, 18-30 million U/24 h, IV plus Gentamicin, 3 mg/kg/ 24 h in 3 divided doses, IV/IM or Vancomycin, 30 mg/kg/ 24 h in 2 divided doses, IV plus Gentamicin, 3 µg/kg/ 24 h in 3 divided doses, IV/IM Nafcillin or oxacillin, 12 g/24 h, IV with optional use of Gentamicin, 3 mg/kg/ 24 hin 3 divided doses, IV/IM or cefazolin, 6 g/24 h in 3 divided doses, IV with optional use of gentamicin, 3 mg/kg/ 24 h in 3 divided doses, IV/IM

Comments

Only for patients intolerant of penicillin/ cephalosporins

4

4 2

4

4-6 4-6

Only for patients intolerant of penicillin/ cephalosporins 6 wk for patients with symptoms for ≥3 mo

4-6

6

6

6 3-5 d

6 3-5 d

6 wks recommended because of reduced activity against enterococci

For complicated rightsided IE and for left-sided IE; for uncomplicated right-sided, treat IE with nafcillin with or without gentamicin for 2 wk** For penicillin-allergic (nonanaphylactic) patients Continued

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Table 6-4 Continued Infecting Organisms

Regimen†

S. aureus, Vancomycin, 30 mg/kg/ methicillin24 h in 2 divided resistant, in doses, IV absence of prosthetic material Prosthetic Valve IE Nafcillin or oxacillin, caused by 12 g/24 h, IV methicillinplus rifampin 900 mg/ susceptible 24 h in 3 divided staphylococci doses, PO/IV plus gentamicin 3 mg/kg/ 24 h in 3 divided doses, IV/IM Prosthetic valve IE Vancomycin, 30 mg/kg/ caused by 24 h in 2 divided methicillin-doses, IV resistant staphylo plus rifampin 900 mg/ cocci 24 h in 3 divided doses, PO/IV plus gentamicin, 3 mg/ kg/24 h in 3 divided doses, IV/IM HACEK microCeftriaxone, 2 g, once organisms daily, IV or Ampicillin-sulbactam, 12 g/24 h in 4 divided doses, IV or Ciprofloxacin, 1000 mg/ 24 h, PO, or 800 mg/ 24 h, IV in 2 divided doses

Duration (wk)

Comments

6

≥6 ≥6

2 ≥6 ≥6

2

4

4

4

Fluoroquinolone therapy recommended only if penicillin or cephalosporin are not an option

Adapted from Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis diagnosis, antimicrobial therapy, and management of complications: Statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association. Circulation. 2005;111:e394-433. † Dosages recommended for adults with normal renal function. ‡ Vancomycin peak of 30-45 µg/mL and trough 10-15 µg/mL. § Gentamicin peak of 3-4 µg/mL and trough < 1 µg/mL. Note: In treating prosthetic valve endocarditis caused by streptococci/enterococci, duration is at least 6 wks; penicillin dosage is at least 24 million units/24 h; Gentamicin is given for 6 wks for streptococci with MIC* of penicillin > 0.12 µg/mL and for enterococci. For streptococci with MIC* of penicillin <0/12 µg/mL, gentamicin is given only for 2 wk. * Uncomplicated right-sided IE excludes patients with renal failure, extrapulmonary metastatic infections, aortic or mitral valve involvement, meningitis, or methicillin-resistant S. aureus. Note: Patients with prosthetic valve endocarditis caused by HACEK microorganisms should be treated for at least 6 weeks. Abbreviations: d = day; h = hour; HACEK = Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Ki; IE = infective endocarditis; IM = intramuscular; IV = intravenous; MIC = minimum inhibitory concentration; PO = by mouth; wk = week.

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within a few days. Bacteremia that persists for longer than 1 week of antibiotic therapy requires careful patient reevaluation and often consultation with an infectious disease specialist. In such cases, verify the correct antibiotic choice and dosage and the possible need for valve resection, which might be required when IE is caused by organisms that respond poorly to antibiotics, such as Pseudomonas species or other gram-negative bacilli. One should also consider the possibility of an abscess in cardiac or extracardiac sites (1). Fever that persists for longer than 1 to 2 weeks also raises concern for complications such as myocardial or extracardiac abscess (brain, spleen, liver, and kidney), drug fever, or intercurrent nosocomial infection (34).

Surgical Intervention Cardiac surgery is an important adjunct in the management of infective endocarditis. When there is an indication, the infected valve should be replaced regardless of how long the patient has received antibiotic therapy. The risk of infection of a newly implanted prosthetic valve is very low, even if there is active valvular infection at the time of surgery, if antibiotic therapy continues postoperatively. Table 6-5 lists the indications for evaluation for possible urgent or emergency surgical therapy (1,31,35). The correct duration of antimicrobial therapy after valve replacement is unknown. In general, if valve culture is negative, the total duration of preand postsurgical therapy should equal the duration for individual microorganisms included in Table 6-4. If the resected valve or perivalvular tissue is culture-positive, or there is a positive tissue Gram’s stain, it seems prudent to give a full course of antimicrobial therapy after surgery (1,36).

Follow-Up The relapse rate for patients appropriately treated for native-valve endocarditis caused by viridans streptococci is less than 2%. It increases to 8% to 20% if the infecting organism is Enterococcus species. The relapse rate Table 6-5 Patients with Infective Endocarditis Needing Evaluation for Possible Urgent or Emergency Surgical Therapy ● ●

●

● ● ● ●

Heart failure that is not easily managed medically One or more systemic (nonpulmonary) embolic episodes during the first 2 wks of therapy* Large vegetation (>10 mm) on anterior leaflet of mitral valve during first 1-2 wks of therapy Valve dehiscence, perforation, rupture, fistula, or large perivalvular abscess Prosthetic valve endocarditis Fungal endocarditis IE caused by aggressive, antibiotic-resistant bacteria

* Remaining vegetation possibly increasing concern. Abbreviations: IE = infective endocarditis; wk = week.

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for prosthetic valve endocarditis is approximately 10% to 15%. Other microorganisms such as S. aureus, Enterobacteriaceae, and fungi are more likely to be associated with treatment failure during the primary course of therapy (1). After cessation of antibiotic therapy, the patient should be seen every 2 weeks for the first month and monthly for 2 more months. Blood cultures should be taken if the patient’s temperature increases to more than 38ºC more than once and there is no obvious reason for fever. Relapse is unlikely after 3 months.

Antimicrobial Prophylaxis Although there is no proof that the prophylactic use of antibiotics in humans can prevent bacterial endocarditis, it is justified on theoretical and experimental grounds. The aim is to provide high serum concentrations of effective antibiotics during procedures associated with a high incidence of transient bacteremia in patients predisposed to infection and with cardiac and intravascular defects. Only 1 dose of appropriate antibiotics is necessary, given shortly before the performance of a high-risk procedure.

Conclusion Endocarditis is a challenging disease with protean manifestations. Few patients present with findings suggestive of intracardiac infection, yet it is the responsibility of the primary care physician to recognize the significance of their complaints and to arrive at the proper diagnosis. Careful attention to details of history, physical examination, and properly selected laboratory tests ultimately lead to a successful approach. The recently modified Duke criteria help make the diagnosis, and the updated antibiotics provide the latest information to assist with making the correct therapeutic decision.

REFERENCES 1. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-30. 2. Berlin JA, Abrutyn E, Strom BL, Kinman JL, Levison ME, Korzeniowski OM, et al. Incidence of infective endocarditis in the Delaware Valley, 1988-1990. Am J Cardiol. 1995;76:933-6. 3. Tleyjeh IM, Steckelberg JM, Murad HS,Anavekar NS, Ghomrawi HM, Mirzoyev Z, et al. Temporal trends in infective endocarditis: a population-based study in Olmsted County, Minnesota. JAMA. 2005;293:3022-8. 4. Hogerik H, Olaison L, Andersson R, Lindberg J, Alestig K. Epidemiologic aspects of infective endocarditis in an urban population: A 5-year prospective study. Medicine (Baltimore). 1995;74:324-39. 5. Frontera JA, Gradon JD. Right-side endocarditis in injection drug users: review of proposed mechanisms of pathogenesis. Clin Infect Dis. 2000;30:374-9. 6. Watanakunakorn C, Burkert T. Infective endocarditis at a large community teaching hospital, 1980–1990: A review of 210 episodes. Medicine (Baltimore). 1993;72:90-102. 7. Cabell CH,Abrutyn E. Progress toward a global understanding of infective endocarditis. Early lessons from the International Collaboration on Endocarditis investigation. Infect Dis Clin North Am. 2002;16:255-72, vii.

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8. ICE Investigators. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005;293:3012-21. 9. Weinstein L, Schlesinger JJ. Pathoanatomic, pathophysiologic and clinical correlations in endocarditis (first of two parts). N Engl J Med. 1974;291:832-7. 10. Fowler VG, Scheld MW, Bayer AS. Endocarditis and intravascular infections. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Churchill Livingstone, 2005; 975-1022. 11. Gould K, Ramirez-Ronda CH, Holmes RK, Sanford JP. Adherence of bacteria to heart valves in vitro. J Clin Invest. 1975;56:1364-70. 12. Watanakunakorn C, Kim J. Mitral valve endocarditis caused by a serum-resistant strain of Escherichia coli. Clin Infect Dis. 1992;14:501-5. 13. Yao L, Bengualid V, Lowy FD, Gibbons JJ, Hatcher VB, Berman JW. Internalization of Staphylococcus aureus by endothelial cells induces cytokine gene expression. Infect Immun. 1995;63:1835-9. 14. Gallagher PG, Watanakunakorn C. Group B streptococcal endocarditis: report of seven cases and review of the literature, 1962-1985. Rev Infect Dis. 1986;8:175-88. 15. Klein RS, Recco RA, Catalano MT, Edberg SC, Casey JI, Steigbigel NH. Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med. 1977;297:800-2. 16. Fernández-Guerrero ML, Verdejo C, Azofra J, de Górgolas M. Hospital-acquired infectious endocarditis not associated with cardiac surgery: an emerging problem. Clin Infect Dis. 1995;20:16-23. 17. Ellner JJ, Rosenthal MS, Lerner PI, McHenry MC. Infective endocarditis caused by slow-growing, fastidious, Gram-negative bacteria. Medicine (Baltimore). 1979;58:145-58. 18. Caputo GM, Archer GL, Calderwood SB, DiNubile MJ, Karchmer AW. Native valve endocarditis due to coagulase-negative staphylococci. Clinical and microbiologic features. Am J Med. 1987;83:619-25. 19. Fowler VG Jr., Li J, Corey GR, Boley J, Marr KA, Gopal AK, et al. Role of echocardiography in evaluation of patients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardiol. 1997;30:1072-8. 20. Smyth EG, Pallett AP, Davidson RN. Group G streptococcal endocarditis: two case reports, a review of the literature and recommendations for treatment. J Infect. 1988;16:169-76. 21. Teong HH, Leo YS,Wong SY, Sng LH, Ding ZP. Case report of Staphylococcus lugdunensis native valve endocarditis and review of the literature. Ann Acad Med Singapore. 2000;29:673-7. 22. Drancourt M, Mainardi JL, Brouqui P, Vandenesch F, Carta A, Lehnert F, et al. Bartonella (Rochalimaea) quintana endocarditis in three homeless men. N Engl J Med. 1995;332:419-23. 23. Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical Center. II. Infectious endocarditis: a prospective comparative study. Rev Infect Dis. 1986;8:374-96. 24. Baddour LM, Wilson WR. Infections of prosthetic valves and other cardiovascular devices. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, PA: Elsevier Churchill Livingston; 2005, 1022-44. 25. Crawford MH, Durack DT. Clinical presentation of infective endocarditis. Cardiol Clin. 2003;21:159-66, v. 26. Wallace SM,Walton BI, Kharbanda RK, Hardy R,Wilson AP, Swanton RH. Mortality from infective endocarditis: clinical predictors of outcome. Heart. 2002;88:53-60. 27. Heidenreich PA, Masoudi FA, Maini B, Chou TM, Foster E, Schiller NB, et al. Echocardiography in patients with suspected endocarditis: a cost-effectiveness analysis. Am J Med. 1999;107:198-208. 28. Beeson PB, Brannon ES, Warren JV. Observations on the sites of removal of bacteria from the blood of patients with bacterial endocarditis. J Exp Med. 1945;81:9-23. 29. Hoen B, Selton-Suty C, Lacassin F, Etienne J, Briançon S, Leport C, et al. Infective endocarditis in patients with negative blood cultures: analysis of 88 cases from a one-year nationwide survey in France. Clin Infect Dis. 1995;20:501-6. 30. Pazin GJ, Saul S,Thompson ME. Blood culture positivity: suppression by outpatient antibiotic therapy in patients with bacterial endocarditis. Arch Intern Med. 1982;142:263-8. 31. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:e394-434. 32. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr., Ryan T, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633-8.

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33. Investigators of the Multicenter Aspirin Study in Infective Endocarditis. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol. 2003;42:775-80. 34. Blumberg EA, Robbins N, Adimora A, Lowy FD. Persistent fever in association with infective endocarditis. Clin Infect Dis. 1992;15:983-90. 35. Olaison L, Pettersson G. Current best practices and guidelines indications for surgical intervention in infective endocarditis. Infect Dis Clin North Am. 2002;16:453-75, xi. 36. Morris AJ, Drinkovifá D, Pottumarthy S, MacCulloch D, Kerr AR,West T. Bacteriological outcome after valve surgery for active infective endocarditis: implications for duration of treatment after surgery. Clin Infect Dis. 2005;41:187-94.

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Chapter 7

Vascular Infections LOUIS D. SARAVOLATZ, MD

Key Learning Points 1. Vascular infections are usually associated with bactereremia and significant morbidity and mortality. 2. The microbial etiology may be similar to endocarditis and rarely includes a variety of less common organisms. 3. Magnetic resonanance angiography for arterial studies and high resolution computed tomography for venous studies are most helpful. 4. Antimicrobial therapy needs to be prolonged, parenteral and guided by susceptibility and local resistance patterns. 5. A combined surgical and medical approach is needed for the management of endovascular infections.

V

ascular infections are uncommon infections that can arise from the deposition of bacteria circulating in the bloodstream onto the vascular endothelial surface, or from contiguous spread of bacteria to a vessel wall. These infections are associated with significant illness and death. This chapter will address mycotic aneurysms, infected pseudoaneurysms, and septic thrombophlebitis.

Mycotic Aneurysms Mycotic aneurysms were described in 1885 by Sir William Osler in association with bacterial endocarditis arising in a patient with multiple aneurysms of the aorta (1). Osler described a case of endocarditis and its association 126

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New Developments in Vascular Infections • Advances in diagnostic imaging including use of magnetic resonance angiography and contrast-enhanced computerized tomography of the veins have improved diagnostic accuracy • The increase in community-associated methicillin-resistant Staphylococcus aureus

(MRSA) reinforces the need for anti-MRSA therapy in these infections. • The role of anticoagulation in these infections remains controversial.

with an aneurysm as a consequence of hematogenous seeding of bacteria through the vascular supply to the large blood vessels. However, mycotic aneurysms had in fact originally been noted as many as 30 years earlier by Edward Koch, who described a superior mesenteric artery aneurysm associated with rheumatism (2). Although the term mycotic was used to describe the appearance of the vegetation, most of these aneurysms are caused by bacteria not fungi. Mycotic aneurysms can involve a normal vessel or infect a preexisting aneurysm. These aneurysms were traditionally described as primary and secondary. Primary aneurysms were those that were considered cryptogenic. These develop from a primary intravascular focus of infection, without any evidence of an inflammatory process in the surrounding tissue. A primary mycotic aneurysm is suspected when the patient presents clinically with evidence of infection as the result of bacteremia from an obscure focus of infection. The clinician’s suspicion of this diagnosis would be increased if the bacteremia were antedated by an illness caused by the same bacterial agent. Primary infections arise from bacterial embolic seeding to the vasa vasorum of the media of arterial walls. Secondary mycotic aneurysms are associated with another focus of infection and sometimes with an inflammatory process in the adjacent tissue. These latter forms of aneurysm are often referred to as pseudoaneurysms, and will be addressed separately.

Clinical Manifestations The clinical manifestations of mycotic aneurysms can vary substantially according to the virulence of the organism. Often characterized by a long, febrile course that eludes the diagnostic acumen of the clinician, a mycotic aneurysm becomes clinically apparent when the affected blood vessel ruptures. In 75% of cases, rupture is the initial presentation. If the site is intracranial, the presentation is headache and rapid neurologic deterioration. If the site is intrathoracic, a catastrophic aortic rupture is the presentation with fever and back and abdominal pain as presenting symptoms. In the case of an intra-abdominal site, retroperitoneal hemorrhage is commonly found. Leukocytosis occurs in most patients, and blood cultures are positive in 50% to 85% of patients (3,4). Primary mycotic aneurysms are associated with

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atherosclerosis, cystic medial necrosis, or syphilitic aortitis. The underlying disease process generally involves the intima of the vessel wall. The microbial cause of mycotic aneurysms includes Streptococcus viridans and Staphylococcus aureus, and to a lesser extent Salmonella species, enterococci, and Streptococcus pneumoniae. There are also reports of Mycobacterium tuberculosis causing mycotic aneurysm as well as many other organisms that rarely cause this disease (5). In a series of 330 patients, bacterial endocarditis was the disease most commonly associated with infectious aneurysms and occurred in 294 cases (2). Coarctation of the aorta occurred in approximately 15% of cases. Pneumonia, osteomyelitis, lung abscess, primary bacteremia, otitis media, urinary sepsis, and meningitis each occurred in less than 5% of cases. The average age at presentation was 33 years. Blood vessels involved were most commonly the aorta, followed by superior mesenteric, cerebral, femoral, hepatic, pulmonary, splenic and even coronary arteries.

Diagnosis The diagnosis of a mycotic aneurysm requires a high index of suspicion in unexplained bacteremias associated with systemic signs of sepsis, or in the case of systemic sepsis in the bacteremic patient. The existence of infective endocarditis in the year before presentation, or of other recent serious bacterial infections, should heighten suspicion of the possibility of a mycotic aneurysm. Laboratory findings are generally nonspecific and are those associated with sepsis. Radiographic evaluations can help. A palpable aneurysm is rarely seen, and unfortunately a diagnosis is established before rupture in only slightly more than half of cases. Ultrasonography can be useful, but computed tomography with enhancement is preferred (4). Angiography of the site of suspected involvement is the definitive test before surgical exploration. For intracranial mycotic aneurysms, magnetic resonance angiography and intravenous digital subtraction angiography are promising techniques (6,7).

Treatment Optimal treatment of mycotic aneurysms requires surgical excision and concomitant antimicrobial therapy (8). In the case of rupture of aneurysms of large vessels such as the abdominal aorta, survival is infrequent even for patients who undergo emergency surgery. Even in the case of elective surgery, excision of an aneurysm and revascularization can be associated with severe perioperative illness and death. During the operative procedure, affected tissue should be collected for both histology and culture. Adequate excision of all infected material and establishment of adequate drainage is essential. Unfortunately, this is extremely difficult to do when a large vessel is involved, and particularly if there is preexisting prosthetic material that cannot be removed. Several investigators have shown that placing arterial

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homografts or plastic prosthesis through contaminated tissues, even in the face of systemic antibiotic coverage, can result in persistent infection and frequent disruption of the graft anastomoses. In contrast, arterial bypass reconstruction through clean tissue planes has produced healing with favorable results. In the surgical approach to the peripheral vessels, a bypass is created with an uninvolved vessel. In such cases, a vein graft can also be used. In these cases, there has been greater success in eradicating infection even in the face of persistent infection in the adjacent tissue (9,10). Optimal antimicrobial therapy for infectious aneurysms requires selection of bactericidal antimicrobial agents that can be given in high doses for prolonged periods. These requirements are general, and there are no controlled studies that provide objective evidence for an optimal duration of therapy. The dose, selection, and duration of antimicrobial therapy are similar to those for infective endocarditis. Some clinicians use an even longer duration because of the potential contamination of prosthetic material that can be implanted into an infected surgical site. In such cases it would be prudent to administer antimicrobial therapy for a minimum of 6 weeks by means of a parenteral route, and combination therapy should be considered for more resistant organisms, as is the case in the treatment of infective endocarditis (11). Moreover, even though the infection can seem to be brought under control, the patient’s clinical course can deteriorate rapidly and terminate in early disruption of the arterial suture line with associated hemorrhage. In such cases, the patient can develop hemorrhagic shock, and death is to be expected. Such complications can occur at any time from 1 to 2 months after surgery, thus necessitating careful long-term follow-up to permit intervention on an emergent basis. Even though embolic complications can occur, anticoagulation should not be used in these patients. The role of anticoagulation in general in patients with associated endocarditis remains controversial (12).

Prognosis and Prevention Today, the overall prognosis in the case of a mycotic aneurysm is generally poor. Medical management alone is almost always fatal (96%) versus a much more favorable survival rate (38%) when a combined medical and surgical approach is used (3). There is often an abrupt onset making a rapid diagnosis difficult at best. The use of magnetic resonance angiography should be considered in place of traditional angiography. Once the diagnosis is made, the challenge is to excise the infected tissue and eradicate any organisms in the vascular suture line or that are clinically inapparent on areas of the blood vessel wall. Some organisms are more virulent than others, making it even more difficult to eliminate them and necessitating prolonged antibiotic therapy. In addition, penetration of antimicrobial agents into atherosclerotic plaques and thrombi is poor. These areas tend to be avascular resulting in subtherapeutic levels of antimicrobial agents.

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Thus, antimicrobial therapy for indefinite periods can be given consideration in some infections because of the fear of relapse and its devastating consequences. Prevention of such infections is best achieved by eradicating the primary focus of infection, which will be either infective endocarditis or bacterial infection at another site. With available therapy and the high cure rate in infective endocarditis, most cases of infectious aneurysm can be prevented. The clinician should monitor patients for evidence of relapse of these infections and promptly treat them. There is no evidence for primary prophylaxis for infectious aneurysms. If a prosthetic graft is present some clinicians can treat these patients in a similar way as those with a cardiac valve graft in place, and give antimicrobial prophylaxis for high-risk procedures such as dental and genitourinary procedures.

Infected False Aneurysms (Pseudoaneurysms) Various terms have been associated with infected mycotic aneurysms involving the major or peripheral vessels and resulting in destruction of the vessel wall, aneurysm formation, and aneurysm rupture (13). False aneurysms, in contrast to true mycotic aneurysms, almost always involve a blood vessel that was normal before the infection. Thus, there is no intimal involvement, and the lesion does not result in embolomycotic events. These false or pseudoaneurysms are usually triggered by an unsuccessful attempt at femoral vein access, often for use of illicit injectable drugs. Failure to use aseptic technique establishes a perivascular infection. There is inadvertent trauma to the arterial wall resulting in a vascular or perivascular hematoma, which in turn leads to the formation of a false aneurysm. As the infection continues to spread, there is a destructive process involving the blood vessel wall, and eventual rupture leading to rapid clinical deterioration and demise within a relatively short ensuing period.

Etiology Infected false aneurysms are most often associated with parenteral drug abuse as a risk factor, although other techniques, such as intravascular catheter placement and angiography, can be associated with mycotic aneurysms. However, because aseptic technique is generally used during these procedures, the risk for such complications is extremely low. Nonetheless, there are reports of hematoma with local infection resulting in contiguous spread and infected aneurysm formation in association with cardiac catheterization. Thus, the evolution of a false aneurysm involves trauma to the outer layer of the arterial wall, or externa, resulting in perivascular hematoma and infection leading to aneurysm formation with intimal sparing.

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Clinical Manifestations The history and physical findings made by McIlroy and colleagues in a series of 60 patients with infected false aneurysms of the femoral artery included groin swelling and/or a mass in the femoral artery area in more than 90% with pain and tenderness in 80% (13). Fever and chills were found in 62%; other symptoms were nonspecific and included nausea, vomiting, paresthesias, and purulent drainage in less than 15% of patients. A pulsatile mass in the groin or femoral artery area was found in only 63% of the patients in this series, but its presence should alert the clinician to the high probability of an infected aneurysm. Fever and/or groin tenderness were present in only slightly more than half of the patients on admission. Other findings, such as an audible bruit over the palpable mass, were made in only 27% of the cases. Associated cellulitis, erythema, and purulent drainage were found in less than 25% of the patients. Absence of a pulse distal from the involved artery was present in less than 10% of the patients, and distal emboli were found in only 1 of the 60 patients. The history of groin swelling, pain, and tenderness with the finding on physical examination of a mass in cases of mycotic aneurysm of the femoral artery make the clinical presentation indistinguishable from that of a groin abscess or phlegmon evolving into an abscess. The findings that one would like to make, such as bruit, diminished pulses, distal emboli, and even a pulsatile mass, are often absent, thus making the diagnosis extremely difficult to establish.

Diagnosis As in the case of mycotic aneurysms, laboratory findings in cases of infected false aneurysm are nonspecific. Leukocytosis is present in many cases, but is not always found. Blood cultures should be done, but were positive in only 60% of the 60 patients in the McIlroy and colleagues series. Nonetheless, the organisms were discovered in the blood vessels at the time of surgery in more than 90% of these patients. The most common isolated pathogen was S. aureus, in 80% of the latter patients; other organisms that were noted, which included Streptococcus pyogenes, other streptococci, and anaerobes, were each found in 20% of the patients. The anaerobes included Bacteroides, Fusobacterium, and Peptococcus. Gram-negative aerobic bacilli occurred in 15% of the patients, with no single predominant organism, but included Pseudomonas aeruginosa, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Citrobacter freundii. The procedures used to diagnose false aneurysms include digital subtraction angiography (DSA), conventional arteriography, ultrasonography (US), and computed tomography (CT). Figure 7-1 demonstrates by intravenous digital subtraction angiogram a bilobed false aneurysm in the medial aspect of the distal left common femeral artery. In addition, small

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Figure 7-1 Digital subtraction angiogram of a bilobed false aneurysm in the medial aspect of the distal left common femoral artery.

numbers of patients have false aneurysms diagnosed at the time of surgical intervention for drainage of an abscess when surgeons discover that they are inadvertently dissecting into the blood vessel wall. In the case of DSA and arteriography, the sensitivity is 90% to 96% (14). US is considerably less effective, with a diagnostic sensitivity of only 24%. The value of US is that it can quite accurately reveal the presence of a perivascular abscess, which, if detected, might arouse suspicion of contiguous spread of infection leading to a mycotic aneurysm.

Treatment Treatment of infected false aneurysms requires a combined medical and surgical approach (3,13,15). The empiric treatment used before organisms are identified should include vancomycin, gentamicin, and metronidazole for beta-lactam–resistant S. aureus, gram-negative bacilli, and anaerobes. Once the organisms are identified and appropriate susceptibility testing has been done, a specific antimicrobial regimen can be prescribed. In a large published series, the mean duration of effective antibiotic therapy for infected false aneurysms was 24 days for patients who were successfully cured (13). Bacteriologic treatment failure was accompanied by a recur-

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rence rate of 10% (6 of 60 patients) for cellulitis and/or wound infection at the site of the aneurysm. However, these six patients had initially received short-term (less than 15 days) parenteral antibiotic therapy, versus the other patients who were cured with more than 16 days of therapy ( p = 0.002, Fisher exact test). In this series, in contrast to findings with mycotic aneurysms, all treatment failures occurred within the first month after discharge from the hospital. There was no one predominant organism among the cases of treatment failures, with S. aureus being most common both in cases of treatment failure and treatment success. Interestingly, none of the patients who experienced bacteriologic treatment failure required amputation, and all were subsequently cured with the second course of antimicrobial treatment. We can therefore conclude that prolonged antimicrobial therapy for at least 3 weeks and even as long as 6 weeks will provide a reasonable margin of safety. For false aneurysms that manifest as swelling in the groin and with evidence of overlying infection, management requires a combined medical-surgical approach. Initial antimicrobial therapy should be broad spectrum, to treat beta-lactam–resistant S. aureus, anaerobes, and gram-negative bacilli. Thus, combination therapy with vancomycin, gentamicin, and metronidazole should be considered. In cases in which the groin is not involved, anaerobes are less relevant and metronidazole can be avoided. Perivascular abscesses and infected hematomas should be appropriately excised. Interestingly, in the large published series mentioned earlier (13), various surgical approaches were taken, including grafting and/or reanastomotic procedures involving saphenous vein grafts and prosthetic grafts (Dacron). Graft failures did occur, and in the case of femoral mycotic aneurysms, 10% of the patients required above-knee amputation. Interestingly there were no deaths in this series of 60 aneurysms with the current availability of optimal antimicrobial therapy and vascular surgical techniques. Infected false aneurysms need to be ligated and removed, with the wound left open, and adequate surgical debridement of the infected perivascular tissue. Surgical management is an area for future investigation in terms of defining the extent of debridement, optimal graft material, and revascularization procedures (3,15). State-of-the-art vascular surgery and advances in this discipline with prosthetic or homologous graft procedures will determine the surgical management.

Prevention Among the 169 cases of infected false aneurysm reported in the United States literature between 1966 and 1988, the overwhelming majority occurred in intravenous drug users, and the main mechanism for preventing these lesions is therefore dealing with socioeconomic considerations of illicit drug use, which is not within the scope of this chapter (13). To prevent infected false

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aneurysms associated with cardiac catheterizations, optimal aseptic technique should be used during the catheterization procedures. Antimicrobial therapy for infected hematomas and consideration of pressure decompression for noninfected pseudoaneurysms should be given before surgical intervention is needed.

Suppurative Septic Thrombophlebitis Suppurative septic thrombophlebitis evolves from an infected venous thrombosis that becomes associated with venous obstruction, high-grade bacteremia and metastatic seeding. This is a serious condition resulting in significant illness and death.

Etiology Suppurative septic thrombophlebitis has changed with time from chiefly involving intracranial veins and the dural sinus, both of which are now rarely involved, to mainly consisting of suppurative phlebitis of cannulated and great veins as a complication of intravenous therapy (16-18). Other sites at which the condition can occur, but again relatively rarely, include pylephlebitis and pelvic septic thrombophlebitis. Local infection is the major factor predisposing to septic thrombophlebitis. Major risk factors for suppurative thrombophlebitis are intravenous catheters, steroids, burns, and intravenous drug use (19,20). Suppurative septic thrombophlebitis arises from thrombus suppuration within the vein wall that develops because of stasis, hypercoagulability, and endothelial injury. These risk factors are all increased when there is adjacent inflammation. If the inflammatory process is associated with microorganisms, the latter migrate by means of lymphatics or the vascular supply to the wall of the vein resulting in suppuration within the vein wall. The associated infection can be anywhere in the body, including intracranial veins, neck veins, great veins of the thorax, abdominal veins, pelvic veins, and peripheral veins. In addition to the periphlebitic method of acquisition, a more common current route for the development of septic thrombophlebitis is the endovascular route, by means of an intravenous cannula, especially if the latter is left in place for more than 48 hours. However, cannula-associated infections usually have both perivascular and endovascular components, and it is often unclear which route initiated the infection in such cases. A third possible route is hematogenous seeding from a distant site. Certain pathogens, such as streptococci, Bacteroides fragilis, and Campylobacter fetus have a higher rate of occurrence in septic phlebitis than do other pathogens that are isolated more frequently from the primary source of infection. There is evidence that these organisms can release substances that inhibit the coagulation cascade.

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Clinical Manifestations The clinical manifestations of septic thrombophlebitis are local inflammation and infection, sepsis, and embolic manifestations. The latter include fever, rigors, diaphoresis, confusion, tachycardia, tachypnea, hypotension, abdominal pain, and ecchymoses. The local process varies with the site of involvement. Patients with suppurative thrombophlebitis generally present with fever (70%-90%). The signs and symptoms are described in Table 7-1 on the basis of the site of involvement. Understanding the anatomy of the site of involvement in the case of intracranial veins and dural sinuses can assist the clinician in understanding what to expect in terms of clinical manifestations (Fig. 7.2).

Table 7-1 Clinical Manifestations of Intracranial Septic Thrombophlebitis Vein

Predisposing Illness

Cavernous sinus

Chronic sinusitis, diabetes mellitus, facial cellulitis

Symptoms/Signs

Headache (ophthalmic and maxillary branch CN V), periorbital edema, unilateral progressing to bilateral eye findings, diplopia, photophobia, tearing, ptosis, and mental status changes. Hemiparesis, and seizures are less common. Sinus tenderness to palpation, exophthalmus, chemosis, ophthalmoplegia CN III, IV, and VI), papilledema, V1 and V2 deficit. Lateral sinus Usually absent other than Subacute onset with headache chronic otitis media (fronto-occipital and temporal occipital) nausea, vomiting, vertigo, signs of ear infection, ruptured tympanic membranes (40%), posterior auricular swelling (Cresinger sign 50%), papilledema (15%), CN VI palsy (33%), nuchal rigidity (33%). Superior sagittal sinus Bacterial meningitis, Similar to bacterial meningitis: extension from cavernous headache, nausea, vomiting, or lateral sinus septic seizure, coma, hemiparesis, phlebitis, sinusitis brain stem compression, and (ethmoid and maxillary), papilledema scalp infection. Less common: pulmonary or odontogenic infections. Cortical Bacterial meningitis and Seizures, focal deficits and signs sinusitis and symptoms of meningitis

Abbreviations: CN, cranial nerve; V1, fifth cranial nerve (ophthalmic division); V2, fifth cranial nerve (maxillary division).

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Cortical veins

Inferior sagittal sinus

Superior sagittal sinus

Great vein of Galen

Falx cerebri

Straight sinus Cavernous sinus

Sphenoid sinus Transversa sinus

Superior petrosal sinus Tentorium cerebelli

Inferior petrosal sinus

Figure 7-2 Intracranial veins and ducal sinuses.

Diagnosis The laboratory findings in cases of suppurative septic thrombophlebitis are those of sepsis. An increased leukocyte count with a left shift and laboratory evidence of disseminated intravascular infection are common. Blood cultures are usually positive and essential in the diagnosis of septic thrombophlebitis. Two sets of cultures should be obtained initially, and two additional sets after 24 to 48 hours. If bacteremia persists despite appropriate empiric antimicrobial therapy, this can suggest the need for surgical intervention. Aspiration of the vein or direct culture of the excised vein can be useful in identifying the etiologic organism. Careful examination of initial and subsequent chest radiographs can disclose evidence of septic pulmonary emboli. Irregularly defined pulmonary infiltrates progressing to cavitation suggest this complication. High-resolution CT can be more sensitive than plain radiography, and can be done if the diagnosis is strongly considered in the face of a negative chest radiograph. The diagnosis of suppurative septic phlebitis is definitively established by venotomy with histologic and microbiologic examination of the thrombus. When this is done, the laboratory must be asked for aerobic, anaerobic, and fungal cultures. In seeking a specific site of infection as the source of suppurative septic thrombophlebitis, the clinician should order cultures appropriate for probable sites. If, for example, an intracranial focus is suspected, cerebrospinal fluid should be obtained, culture of which will reflect either meningitis or a parameningeal inflammatory process (increased leukocyte count with both

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polymorphonuclear leukocytes and mononuclear cells, a normal glucose, a slightly elevated protein concentration and culture negativity). Radiographic assessment with high-resolution CT or magnetic resonance imaging (MRI) can be helpful. If used, contrast-enhanced CT or MRI with gadolinium can be very sensitive modalities in demonstrating filling defects consistent with thrombus caused by septic phlebitis (21,22).

Treatment Antimicrobial therapy with high-dose intravenous antibiotics should be initiated empirically for septic thrombophlebitis on the basis of the site of the lesion and most likely pathogens (Table 7-2). The optimal duration of

Table 7-2 Microbial Etiology and Treatment Considerations for Suppurative Septic Phlebitis Site

Microbial Agents

Empiric Treatment Options*

Cavernous sinus

Staphylococcus aureus (70%), group A streptococci, Streptococcus pneumoniae, gram-negative bacilli, anaerobes Group A streptococcus, S. aureus, Bacteroides, gram-negative (Proteus mirabilis and Escherichia coli) S. aureus, Group A streptococci S. pneumoniae, Haemophilus influenzae, Neisseria meningitis

Vancomycin, ceftriaxone (or cefotaxime) plus metronidazole

Lateral sinus

Sagittal sinus Cortical

Internal jugular vein

Great vein

S. aureus, gram-negative bacilli, candida If candida is suspected S. aureus, gram-negative bacilli

Pelvic veins

Anaerobes (Bacteriodes fragilis), microaerophilic, steptococci, gram-negative bacilli

Pylephlebitis

Anaerobes (Clostridium), gramnegative bacilli S. aureus, Group A streptococci

Peripheral

Ceftriaxone (or cefotaxime), vancomycin, plus metronidazole Vancomycin Vancomycin plus ceftriaxone if brain abscess or sinus source add metronidazole Vancomycin and ceftriaxone or aminoglycosides Add amphotericin B As in internal jugular sources Metronidazole plus an aminoglycoside or carbapenems or betalactam/beta-lactamase inhibitors plus an aminoglycoside As in pelvic veins Vancomycin. Add an aminoglycoside if patient had prolonged hospitalization or prior antimicrobial agents.

* Dosing with normal renal and hepatic function: Ceftriaxone 2 g IV every 12 h; cefotaxime 2 g IV every 4 to 6 h; aminoglyosides: gentamicin/tobramycin 1.5 mg/kg IV every 8 h; amphotericin 0.6-1.0 mg/kg every 24 h; beta-lactam/beta-lactamase inhibitors; ticarcillin/clavulunate 3.1 g every 4 h; ampicillin-sulbactam 3.0 g every 6 h; piperacillin-tazobactam 3.375 g every 6 h.

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therapy has not been established, but 2 weeks of therapy would be a minimum, with at least 4 weeks if S. aureus is the pathogen (23). If the vein is accessible and the patient demonstrates persistent bacteremia or perivascular infection, surgical excision of the infected clot should be considered (24). Other ancillary measures include drainage of any primary focus of infection such as a contiguous abscess. The involved area should be elevated to a 45-degree angle to enhance venous drainage. The use of anticoagulation remains controversial. There is some anecdotal evidence for a benefit of anticoagulation in the case of internal jugular vein involvement and pelvic septic phlebitis. In cases involving other sites, the risk of hemorrhage and complications of therapy must be carefully weighed before anticoagulation is instituted, in the view of the lack of convincing evidence to support such therapy. Some experts have considered anticoagulation if there is evidence of the extension of the thrombosis while on therapy (25).

Prevention and Future Developments Prompt and appropriate treatment of bacterial infections of the skin, ear, dentition, sinuses, and pelvis is the main measure that can be effective in preventing septic thrombophlebitis. In case a venous cannula is in place, its removal should occur within 48 to 72 hours whenever possible, and more promptly when there is development of local infection or sepsis of unknown source. A detailed discussion of strategies for preventing infected emboli from vascular catheters has been published by the Centers for Disease Control and Prevention (26). As for further research, the role of anticoagulants should be critically evaluated in a randomly assigned, placebo-controlled trial, which has not been done to date. Unfortunately, the difficulty in agreeing on diagnostic criteria, and the low rate of septic thrombophlebitis at most sites can make such a trial difficult if not impossible to do.

REFERENCES 1. Osler W. The Gustonian lecture on malignant endocarditis. Br Med J. 1885;1:4672-70. 2. Goadby HK, McSwiney RR, Rob CG. Mycotic aneurysm. St. Thomas Hospital Report. 1949;5: 44-52. 3. Johnson JR, Ledgerwood AM, Lucas CE. Mycotic aneurysm. New concepts in therapy. Arch Surg. 1983;118:577-82. 4. Suravia-Dunand VA, Lou VG, Salit IE. Aortitis due to salmonella; report of 10 cases and comprehensive review of the literature. Clin Infect Dis. 1999;29;862. 5. Long R, Guzman R, Greenberg H. Tuberculous mycotic aneurysms of the aorta: Review of published medical and surgical experience. Chest. 1999;115:52. 6. Tunkel AR, Kaye D. Neurologic complications of infective endocarditis. Neurol Clin. 1993;11:419-40. 7. Kimura I, Okumura R,Yamashita K, Shibata T, Hayashi N, Hayakawa K, et al. Mycotic aneurysm. Radiat Med. 1989;7:121-3.

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8. Mundth ED, Darling RC,Alvarado RH, Buckley MJ, Linton RR,Austen WG. Surgical management of mycotic aneurysms and the complications of infection in vascular reconstructive surgery. Am J Surg. 1969;117:460-70. 9. Johansen K, Devin J. Mycotic aortic aneurysms. A reappraisal. Arch Surg. 1983;118:583-8. 10. Bitseff EL, Edwards WH, Mulherin JL Jr., Kaiser AB. Infected abdominal aortic aneurysms. South Med J. 1987;80:309-12. 11. Cina CS,Arena, CO, Fiture SO. Ruptured mycotic thoracoabdominal aortic aneurysms: A report of 3 cases and a systematic review. J Vasc Surg. 2001;33:361. 12. Kamalakannan D, Beeai M, Gardin J, Saravolatz L. Anticoagulation in infective endocarditis: A survey of infectious disease specialists and cardiologists. Infect Dis Clin Pract. 2005;13: 122-26. 13. McIlroy MA, Reddy D, Markowitz N, Saravolatz LD. Infected false aneurysms of the femoral artery in intravenous drug addicts. Rev Infect Dis. 1989;11:578-85. 14. Shetty PC,Krasicky GA,Sharma RP, Vemuri BR,Burke MM. Mycotic aneurysms in intravenous drug abusers: the utility of intravenous digital subtraction angiography. Radiology. 1985;155:319-21. 15. Reddy DJ, Smith RF, Elliott JP Jr., Haddad GK,Wanek EA. Infected femoral artery false aneurysms in drug addicts: evolution of selective vascular reconstruction. J Vasc Surg. 1986;3:718-24. 16. Maki DG. Septic thrombophlebitis. Hosp Med. 1976:36-49. 17. Southwick FS. Septic thrombophlebitis of major dural venous sinuses. Curr Clin Top Infect Dis. 1995;15:179-203. 18. Rupp ME. Infections of intravascular catheters and vascular devices. In: Crossley KB, Archer GL, eds. The staphylococci in human disease. New York: Churchill Livingstone; 1997:379-99. 19. Andes DR, Urban AW,Acher CW, Make DG. Septic thrombosis of the basilie, axillary, and subclavian veins caused by a peripherally inserted central venous catheter. Am J Med. 1998;105:446. 20. Arnow PM, Quimosing, EM, Beach M. Consequences of intravascular catheter sepsis. Clin Infect Dis. 1993;16:778. 21. Ellie E, Houang B, Louail C, Legrain-Lifermann V, Laurent F, Drouillard J, et al. CT and high-field MRI in septic thrombosis of the cavernous sinuses. Neuroradiology. 1992;34:22-4. 22. Komiyama M. Magnetic resonance imaging of the cavernous sinus. Radiat Med. 1990;8:136-44. 23. Raad I, Narro J, Khan A, Tarrand J, Vartivarian S, Bodey GP. Serious complications of vascular catheter-related Staphylococcus aureus bacteremia in cancer patients. Eur J Clin Microbiol Infect Dis. 1992;11:675-82. 24. Verghese A,Widrich WC,Arbeit RD. Central venous septic thrombophlebitis—the role of medical therapy. Medicine (Baltimore). 1985;64:394-400. 25. Golpe R, Marín B, Alonso M. Lemierre’s syndrome (necrobacillosis). Postgrad Med J. 1999;75: 141-4. 26. Centers for Disease Control and Prevention. Part 1. Intravascular device-related infection: An overview: Part 2. Recommendations for prevention of intravascular device-related infections. Fed Regist. 1995;60:4997-8.

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Part IV

Gastrointestinal Infections

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Chapter 8

Infectious Diarrhea and Gastroenteritis KEITH B. ARMITAGE, MD ROBERT A. SALATA, MD

Key Learning Points 1. With the notable exception of C. difficile associated diarrhea and illness in immunosuppressed patients, most diarrhea acquired in developing countries is self-limited. 2. Diarrhea in travelers is often due to bacterial pathogens, and responds to appropriate antimicrobial therapy. 3. Noroviruses are a common cause of self-limited gastrointestinal illness in developed countries. 4. Nosocomial diarrhea is almost never related to bacterial pathogens other than C. difficile, and should always raise concerns for this pathogen.

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nfectious gastroenteritis is one of the most common infections throughout the world and is a leading worldwide cause of infant death, with 4 million to 6 million deaths per year. In the United States, most cases of infectious gastroenteritis are self-limited, a sharp contrast to the state of affairs in the developing world where cases are more often chronic and debilitating. Diarrhea may be the most common symptom for travelers, immigrants, and refugees. The pathogens that cause diarrhea range from viruses that cause self-limited illness in adults and more serious syndromes in children to bacterial and protozoan pathogens that may cause significant illness and death in healthy and immunocompromised adults and children alike. New and emerging pathogens (e.g., Escherichia coli serotype 0157:H7, Cryptosporidium, Cyclospora) have received much attention from the lay press and the medical community. In this chapter, a general approach to the adult patient with acute diarrhea is followed by 143

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New Developments in Infectious Diarrhea and Gastroenteritis • Newer agents such as nitazoxanide (for giardiasis and cryptosporidiosis) and rifaximin (for traveler’s diarrhea) show promise as therapeutic alternatives. • Antimicrobial resistance among pathogens causing traveler’s diarrhea complicates the choices for presumptive therapy. • The incidence and morbidity of Clostridium difficile infection appears to be increasing; this appears to be related to the emergence of an epidemic strain that is more pathogenic and is highly resistant to fluoroquinolones and other antibiotics. • Recent studies have suggested a link between traveler’s diarrhea and the development of IBS. Abbreviation: IBS = irritable bowel syndrome.

a discussion of selected pathogens that cause diarrhea. Chronic diarrhea, food poisoning, and traveler’s diarrhea are discussed separately. The discussion generally excludes infectious diarrhea in patients with AIDS and/or HIV infection.

Epidemiology In the United States, most cases of infectious gastroenteritis go unreported, and the incidence of the disease is based on estimates. On average, adults in the United States and Europe have approximately 1 episode per year of infectious gastroenteritis (1). Annually in the United States, infectious diarrhea accounts for approximately 8 million visits to physicians, 250,000 hospitalizations, and 10,000 deaths (2). Together, gastroenteritis and acute diarrhea account for 1.5% of hospitalizations for inpatients younger than 20 years of age. In the developed world, most of the illness and death from infectious gastroenteritis occurs in the elderly. Exceptions to this rule occur with infection by E. coli 0157:H7, which produces hemolytic uremic syndrome [HUS] in children, and by rotavirus, which causes diarrhea leading to dehydration in young children. Although the United States has an average of 1 case of infectious gastroenteritis per adult, these cases are unevenly distributed in the population. Groups at special risk include adults who have small children in day care centers, international travelers, homosexual men, immunosuppressed patients, and individuals living in poor hygienic conditions. These risk groups account for a disproportionate number of cases of infectious gastroenteritis. Animal populations are the primary reservoir for most bacterial enteropathogens in the United States. Salmonella, Campylobacter, and pathogenic strains of E. coli usually enter humans from poultry, bovine, or porcine sources; and the route of illness is usually by means of undercooked or contaminated food. Infectious agents that rely on a human reservoir and are spread directly from one person to another or by human fecal contamination and include

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Salmonella typhi, Shigella, and Vibrio cholerae are much less common in the United States than in the developing world.

Pathogenesis Most microorganisms found in the human intestine are not pathogenic, but those that are rely on various virulence factors to produce disease. Microbial virulence factors include enterotoxins that alter intestinal salt and water transport mechanisms, adherence (and colonization) factors, and invasive and penetrability properties. Enterotoxins usually act in the upper small intestine to provoke fluid and electrolyte secretion and either cause no significant alteration in mucosal histology (e.g., cholera toxin) or are cytotoxins that can alter mucosal histology to the point of epithelial cell death (e.g., clostridial and staphylococcal enterotoxins). Adherence to the intestinal surface is required for many enteropathogens and involves specific cell-surface determinants. Invasive bacteria primarily colonize the colon and have the ability to invade and survive in host cells and bring about cell death. Gross mucosal ulceration can occur, particularly in shigellosis, and is responsible for dysenteric stools in that disease. In the case of systemic pathogens such as S. typhi, virulence factors include the ability to infect and persist in host immune cells, which permits access to the circulation and leads to extraintestinal disease. The role of host factors in the susceptibility to infectious gastroenteritis is discussed in the following text.

Etiology Infectious diarrhea can be classified as inflammatory or noninflammatory (2). This classification has practical application for the clinician, because examining the stool for fecal leukocytes (see Figure 8-1) can help distinguish the 2 conditions, and this distinction can alter the diagnostic and therapeutic approach. Noninflammatory diarrhea most often results from interference with absorption of fluid and electrolytes and does not involve pathogenic invasion of the intestinal mucosa. Virtually all viral and most protozoan pathogens give rise to a noninflammatory diarrhea. In most cases, these pathogens cause disease by interfering with the absorptive functions of enterocytes in the small intestine through the production of toxins that alter the handling of fluids and electrolytes (e.g., as in cholera, discussed in a later section) or cause villous damage. These processes result in the delivery of excess fluid and electrolytes to the large intestine. Once the absorptive capacity of the large intestine is exceeded, a high-volume, watery diarrhea results. In contrast with the aforementioned viruses and protozoans, many bacterial pathogens invade the intestinal mucosa (usually the colon), provoking

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Figure 8-1 Fecal leukocytes as seen on microscopy.

an inflammatory response that results in colonic malabsorption and the presence of leukocytes and blood in the stool. This diarrhea is characterized by mucus and blood and by a smaller volume of stool than is seen with noninflammatory diarrhea. E. coli can produce either syndrome, depending on the strain of the infecting organism (discussed in a later section). Other bacterial pathogens also cause noninflammatory diarrhea by producing preformed toxins that are ingested in contaminated food (see Food Poisoning Syndromes in the following text).

Diagnosis The risk of acquiring a gastrointestinal infection varies with the host and the potential for exposures to infectious agents. Host factors that influence susceptibility to infection include age, intestinal dysmotility, integrity of the normal intestinal flora, gastric acidity, and intestinal mucosal immunity. Potential for exposure to infectious agents varies with socioeconomic conditions and sanitation, travel to areas endemic to intestinal pathogens to which the host lacks immunity, and the occurrence of food- or water-borne outbreaks of disease caused by these agents. When evaluating a patient with diarrhea, it is impossible to overemphasize the importance of a careful history that focuses on issues such as travel, antibiotic use, illness in close contacts, exposure to potentially contaminated food or water, and the presence of decreased gastric acidity or gastrointestinal motility. A careful history also helps differentiate patients who are likely to have a self-limited viral process that requires only symptomatic therapy from

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those who have a bacterial or protozoan pathogen that might necessitate further testing and specific therapy. In adults, viral gastroenteritis typically lasts 24 to 36 hours and no longer than 72 hours. The illness usually is not associated with significant abdominal pain, and there is no (or only a lowgrade) fever. Viral gastroenteritis is associated with watery stools without blood or pus. In infants and small children, some viral pathogens (rotavirus, most notably) may produce a prolonged illness. Risk factors for infection by bacterial or protozoan pathogens also can be determined from a history of potential exposures. In tropical countries, acute diarrhea occurs endemically and epidemically, and any recent travel in a tropical country increases the likelihood of infection by a nonviral pathogen. In the United States, camping and hiking may be associated with exposure to Giardia. Exposure to imported fruits and undercooked meats or poultry products may be associated with infection by bacterial pathogens or Cyclospora. Antibiotic use, achlorhydria, or an immunocompromised state may influence the risk of infection by a bacterial pathogen. Patients whose history suggests either a bacterial process or risk factors for the acquisition of bacterial pathogens should have their stool examined for fecal leukocytes (see Figure 8-1); patients at risk for acquiring protozoan or other intestinal parasites should have a fresh stool specimen examined for ova and parasites. The presence of fecal leukocytes should prompt a stool culture and may lead to the initiation of specific therapy (see Treatment section in the following text). This approach is illustrated in Figure 8-2.

Treatment When treating patients with diarrhea, be aware that an otherwise healthy individual with a history that suggests a self-limited viral process and no risk factors for acquiring other pathogens does not require any further workup and should be treated with oral rehydration and symptomatic support. For patients with acute inflammatory diarrhea or those from whom a pathogen has been isolated, the decision to institute specific antimicrobial therapy is based on host factors and the specific pathogen. For most healthy adults, antimicrobial therapy has a limited role in the management of acute diarrhea. For many enteropathogens, such as Salmonella, and enterohemorrhagic E. coli, antimicrobial therapy has not been proven to have a benefit and may prolong the carrier state in Salmonella infection. Furthermore, antimicrobial resistance is a growing problem with some enteropathogens, such as Shigella and Salmonella. In contrast, antimicrobial therapy is indicated for dysentery caused by Shigella or Entamoeba histolytica; in cholera, antimicrobial therapy can decrease the volume of fluid lost and shorten the clinical syndrome. However, patients who are at high risk for bacteremia and other complications of bacterial gastroenteritis (e.g., the elderly, immunocompromised patients, patients with vascular grafts, patients with

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Evaluate severity and duration Obtain history and physical examination Treat hydration Report suspected outbreaks

Check all the following that apply

A. Community-Acquired or Traveler's Diarrhea (especially if accompanied by significant fever or blood in stool)

Culture or test for: Salmonella Shigella Campylobacter Escherichia coli O157:H7 (if there is blood in stool, also test for Shiga toxin; refer isolates if positive) Clostridium difficile toxins A±B (if patient has received antibiotics or chemotherapy in recent weeks)

Consider quinolone for suspected shigellosis in adults (e.g., fever, inflammation) Consider macrolide for suspected resistant strains of Campylobacter Avoid antimotility and certain antimicrobial drugs if suspected STEO (e.g., afebrile, bloody diarrhea)

B. Nosocomial Diarrhea (onset > 3 days in hospital)

Test for: C. difficile toxins A±B (in suspected nosocomial outbreaks, in patients with bloody stools, and in infants; also add hosts in panel A)

C. Persistent Diarrhea (lasting > 7 days, especially in immunocompromised patients)

Consider parasites: Giardia Cryptosporidium Cyclospora Isopora belli Plus inflammatory screen If HIV positive, also test for the following: Microsporida (Gram chromotrope) Mycobacterium avium complex All in panel A

Discontinue antimicrobials if possible Consider metronidazole if illness worsens or persists

Treat per test results

Figure 8-2 Approach to diagnosis and treatment when presence of fecal leukocytes has been determined.

sickle cell disease) benefit from antibiotic therapy. In these patients, empirical therapy is warranted in the setting of acute inflammatory diarrhea. In crowded conditions, such as refugee camps or areas of poor hygiene, epidemics of acute diarrhea caused by enteropathogens are common. In such settings, take steps to ensure the safety of the water supply, improve hygienic conditions, and decrease the interpersonal spread of disease. As with noninflammatory diarrhea, patients with inflammatory diarrhea require adequate hydration. In the past quarter century, oral rehydration ther-

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apy has revolutionized the treatment of various acute diarrheal illnesses. Oral rehydration formulas in which the addition of glucose increases the efficiency of absorption of fluid and electrolytes have decreased the need for intravenous hydration. Antimotility agents should be used with caution in patients with inflammatory diarrhea, particularly in children. In a small minority of patients with severe colitis, especially in the setting of infection with Shigella or E. histolytica, antimotility agents are associated with complications such as colonic perforation and death. Most experts advise caution in the use of antimotility agents in patients with fever and bloody diarrhea and do not recommend their use without concomitant antimicrobial therapy. The use of biotherapeutic agents to prevent and treat intestinal infections has been studied but not widely applied (3). Lactobacillus and Saccharomyces species have shown potential in placebo-controlled studies to effectively prevent or treat antibiotic-associated colitis, acute infantile diarrhea, recurrent Clostridium difficile diarrhea, and other diarrheal illnesses (4). These agents have not gained widespread use, but they have potential benefit in selected patients.

Specific Pathogens Viruses Norovirus or Norwalk-Like Viruses A family of viral pathogens known as Norwalk-like viruses or norovirus are the major cause of viral gastroenteritis in adults worldwide (5,6). They can be distinguished both clinically and epidemiologically from rotavirus (which is discussed in the following section). Noroviruses cause illness in adults and children and usually produce a mild clinical syndrome characterized by nausea, vomiting, and diarrhea that lasts no more than 24 to 36 hours. The diarrhea is watery and noninflammatory, and abdominal pain and fever are usually mild or absent. There have been large, well-documented outbreaks of such illness caused by interpersonal transmission of noroviruses as well as common-source outbreaks caused by food handlers. Norovirus-associated illness in schools, hospitals, and cruise ships and a multistate outbreak caused by contaminated oysters are testimony to the highly contagious and ubiquitous nature of these enteric viral pathogens (6). Illness caused by Noroviruses has a higher incidence in the winter and is often referred to as “wintervomiting disease.” Treatment consists of rehydration and symptomatic relief with antimotility agents. Rotavirus Rotavirus infection is much more common in children than is infection by Norwalk-like agents and produces a longer and more severe illness. Most studies show that rotavirus is the most common cause of pediatric diarrhea. An estimated 75 to 125 deaths and 65,000 to 75,000 hospitalizations for

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rotavirus infection occur each year in the United States. By the age of 2 years, most children are immune to rotavirus (7). Unlike the large, antigenically heterogeneous Norwalk virus family, only a few strains of rotavirus are antigenically heterogeneous; thus, infection leads to protective immunity. Trials of a rotavirus vaccine seem promising (8). In addition to infecting children, rotavirus has been associated with illness in parents of infected children and travelers, and water-borne and nosocomial outbreaks of rotavirus disease have been reported. Treatment consists of hydration and supportive care.

Bacteria Salmonella In the developed world, salmonellosis is primarily a food-borne gastrointestinal disease. Outside the developed world, systemic illness caused by S. typhi and Salmonella paratyphi is unusual (and is discussed briefly later in the text). Approximately 40,000 culture-proven cases of Salmonella gastroenteritis are reported to the Centers for Disease Control and Prevention each year (9). However, this is believed to represent only a small fraction of cases, because for each reported case 10 to 100 cases go unreported. Gastroenteritis related to different Salmonella species can be differentiated by a serotyping system; approximately 10 of these serotypes are responsible for most cases in the United States. Most Salmonella infections in the United States arise from an animal reservoir, and specific species of Salmonella are associated with particular food types and animals. Poultry, beef, and pork frequently have been associated with Salmonella. Undercooking meat products and inoculating food-preparation surfaces, which leads to cross-contamination, are common sources of Salmonella gastroenteritis. Although such gastroenteritis is associated most often with meat products and eggs, 2 recent large outbreaks were described in connection with ice cream and dry oat cereal, and there are case reports of other food products and animals having been contaminated with Salmonella (9). Interpersonal spread plays a small role in the transmission of Salmonella gastroenteritis. Clinically, Salmonella gastroenteritis is characterized by inflammatory diarrhea that may be accompanied by abdominal pain and fever. The illness may be more severe in the very young, the elderly, and the immunosuppressed (10). Clinically significant bacteremia associated with Salmonella gastroenteritis is unusual in healthy adults but is seen in elderly and, most significantly, in immunosuppressed persons. Severe and prolonged illness, including bacteremia, has been well described in patients with AIDS (11). Most cases of Salmonella gastroenteritis in otherwise normal hosts do not require antibiotic treatment. Antibiotic therapy has not been shown to have a significant benefit in such cases and has been associated with relapses and prolonged carriage of Salmonella. Very young, elderly, and immunosup-

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pressed persons and those with underlying illnesses (e.g., severe vascular disease, sickle cell disease) are at risk for complications or prolonged illness in Salmonella gastroenteritis and benefit from antibiotic therapy. Antimicrobial resistance is an increasing issue, but the fluoroquinolones, such as ciprofloxacin, and third-generation cephalosporins usually are reliable (12). S. typhi and related species produce a prolonged systemic illness characterized by invasion of the reticuloendothelial system and bacteremia. Patients may not have diarrhea during the illness, or it may be present only at the outset and may be mild. In contrast to nontyphoidal species of Salmonella, S. typhi and related species are highly adapted human pathogens and have no animal reservoir. Infection is based on humanto-human spread through direct contact or, more often, through fecal contamination of food and water. Typhoid fever is unusual in the United States, with fewer than 500 cases reported per year (70% or more of which occur in travelers or immigrants) (11). In addition to having fever, patients with typhoid fever can present with hepatosplenomegaly and a rash. The diagnosis is made by serology or by culturing S. typhi from the blood, stool, urine, or bone marrow. Antimicrobial therapy with quinolones or other agents improves survival and shortens the duration of illness (13). Most patients respond clinically to antimicrobial therapy within a week. Antimicrobial resistance is increasing worldwide, and knowledge of local resistance patterns should be used in selecting therapy for typhoid fever. From 1% to 3% of patients may become chronic fecal carriers of S. typhi. The fluoroquinolones or ampicillin (for ampicillin-sensitive strains) may be used to attempt eradication of the chronic carrier state in selected individuals such as health care workers and food preparers. Avoiding contaminated food and water supplies can prevent typhoid fever. Several vaccines for typhoid fever are available and have an efficacy of approximately 70% to 80%. In the United States, vaccination is given most often to travelers to areas where S. typhi is endemic, which includes most tropical destinations.

Campylobacter Before the 1970s, when selective culture media simplified the isolation of several enteropathogens, infection with Campylobacter was thought to be unusual. It is now recognized as the most common cause of bacterial gastroenteritis in the developed world. An estimated 2 million to 4 million cases occur every year in the United States, with a summer to fall seasonality (14). Campylobacter is by far the most common cause of bacterial gastroenteritis in young adults, causing gastroenteritis 10 times more often than does Salmonella. The primary animal reservoir of Campylobacter is the chicken, and most cases of infection with the organism are associated with undercooked poultry or cross-contamination of other foodstuffs. Contact with animals other than chickens, including kittens, also has been associated with Campylobacter infection. Most cases are sporadic, and large outbreaks and interpersonal spread are unusual.

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Campylobacter causes an acute inflammatory colitis that is indistinguishable from that caused by Salmonella or other bacterial enteropathogens. Diarrhea, abdominal pain, and fever are present in most patients. The illness usually lasts from 4 to 7 days. Severe prolonged colitis that mimics inflammatory bowel disease has been reported. Campylobacter also has been associated with pseudoappendicitis, and in rare instances has been believed to cause appendicitis. Hepatitis and pancreatitis also have been reported infrequently in association with campylobacteriosis. Bacteremia occurs in approximately 2% of culture-confirmed cases, and immunocompromised patients are at increased risk. Additionally, Campylobacter is associated with the Guillain-Barré syndrome and is by far the most common identified infection preceding this syndrome, with evidence of antecedent Campylobacter infection found in 20% to 40% of Guillain-Barré cases (14a,14b). The overall incidence of Guillain-Barré syndrome is much lower than that of campylobacteriosis, and the individual risk of acquiring the syndrome after this enteric infection is low. Most patients with Campylobacter enteritis require only supportive therapy with rehydration. In clinical trials, antimicrobial therapy has not been shown to be of benefit when given after several days of illness. However, when given at the onset of illness, antimicrobial therapy shortens the duration of illness and is clearly beneficial for patients with severe or prolonged disease, which can occur in immunosuppressed patients. Campylobacter is resistant to trimethoprim and most cephalosporins. Fluoroquinolones showed early promise as therapeutic agents against Campylobacter; however, resistance has developed during therapy and is spreading in fields in which quinolones are heavily used, such as animal husbandry. In Thailand, greater than 90% of strains of Campylobacter are quinolone resistant. Azithromycin remains the antimicrobial agent of choice for the treatment of Campylobacter enteritis.

Escherichia coli E. coli is the predominant nonpathogenic bacterial species in the human intestinal flora, but some strains have developed the ability to cause gastrointestinal disease. Diarrheagenic strains of E. coli cause disease through various mechanisms and produce varying clinical syndromes, including traveler’s diarrhea, hemorrhagic colitis, HUS, persistent watery diarrhea in infants, and persistent diarrhea (15). The genetic information responsible for the pathogenesis is often carried by plasmids or phages. During the past decade, the detailed pathogenic mechanisms associated with specific strains of E. coli have been perceived, but their details are beyond the scope of this chapter (15). We focus on the most common and clinically significant diarrheal syndromes caused by E. coli. Enterotoxigenic E. coli strains are responsible for more than one third traveler’s diarrhea cases. They produce diarrhea by the elaboration of a toxin that induces secretion of fluid and electrolytes by the small bowel.

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The strains are noninvasive and noninflammatory and are acquired by ingesting contaminated food and water. The illness that they cause is characterized by watery diarrhea (mild or severe) that usually lasts approximately 5 days but can be prolonged (rare). The illness is usually self-limited; but antimicrobial therapy, such as trimethoprim-sulfamethoxazole or quinolones, has been shown to significantly shorten the duration of illness. Antimotility agents used with antibiotics also have been shown to decrease the frequency of stools. (For treatment of traveler’s diarrhea, see section on Diarrhea in Travelers.) E. coli 0157:H7 and other enterohemorrhagic E. coli strains have gained prominence in the past 15 years by producing a severe syndrome in children characterized by bloody diarrhea and subsequent HUS (16). These strains also produce a nonbloody diarrhea and a hemorrhagic colitis (which may be severe, particularly in the elderly) without HUS. E. coli 0157:H7 and related strains produce 2 toxins that account for the intestinal and systemic pathogenesis of disease. Cattle are the primary reservoir for E. coli 0157:H7, and most cases of illness caused by the organism can be traced to the consumption of contaminated beef or of food products contaminated with bovine fecal matter. Interpersonal spread of the organism also has been documented. Diagnosis of E. coli 0157:H7 gastroenteritis is made by isolating the organism from stool. Managing the illness caused by E. coli 0157:H7 and related strains consists of supportive care. Antimicrobial therapy has not been shown to shorten the duration of illness, and there are inconclusive reports that suggest that antimicrobial therapy may increase the risk for HUS. Pending large clinical trials, no rational recommendation can be made for or against antimicrobial therapy. However, dialysis instituted early in the course of E. coli 0157:H7–related HUS may provide a survival advantage, increasing the importance of early recognition of the syndrome. Recent reports have indicated that the type of grain given to cattle in feedlots may dramatically increase the amount of E. coli 0157:H7 in the animals’ intestines, and many efforts are underway to prevent or minimize this. Preventing E. coli 0157:H7–related illness by thoroughly cooking meat and avoiding contamination of beef or other food products is also critical and is receiving increasing government attention. Two other types of pathogenic E. coli deserve brief mention. Enteroinvasive E. coli strains are pathogenically related to Shigella (see section in the following text) and produce a similar colitis or dysentery syndrome. Enteropathogenic E. coli strains are a heterogeneous subset of pathogenic E. coli strains. They have been responsible for large outbreaks of diarrhea in both the developed and developing world. Management of diarrhea caused by either of these types is similar to that for diarrhea caused by other bacterial enteropathogens. Decisions about the use of antimicrobial therapy for disease caused by these types of E. coli are based on the severity of illness at presentation and the characteristics of the host.

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Vibrio cholerae Cholera is a scourge of antiquity and an infection of immense historical significance that remains a major public health issue today. The seventh cholera pandemic, caused by the 01 El Tor strain of V. cholerae, began in 1961 and continues today. The World Health Organization (WHO) estimates that more than 3 million cases have occurred in the past 40 years (17). The Western Hemisphere was free of cholera for almost 100 years, but the disease has gained a foothold in the past decade, spreading from the coast of Peru to other areas of South and Central America (18). In the United States, cases have been seen in travelers and in consumers of raw food imported from South America. Cholera causes an acute and explosive diarrhea that can lead rapidly to loss of up to 10% of the body’s fluids and electrolytes. V. cholerae produces a toxin that acts on the enterocytes of the small bowel, causing derangement of the normal handling of solute and water, leading to hypersecretion of fluid and electrolytes. The resultant voluminous rice water diarrhea can lead to dehydration and death. The diagnosis is made by isolating the organism from the stool. The use of oral rehydration solutions, which contain glucose and electrolytes, has been associated with a marked decrease in illness and death from cholera. Intravenous or oral rehydration is the mainstay of therapy, along with use of antibiotics (particularly fluoroquinolones). Vibrio parahaemolyticus is a worldwide cause of food-borne illness, and is the most common pathogen associated with food in Japan (19). V. parahaemolyticus is a salt water–loving organism, and the illness it causes is associated with the consumption of seafood and exposure to salt water. In addition to producing gastrointestinal illness, V. parahaemolyticus causes the infection of wounds exposed to salt water and can produce a severe sepsis syndrome, particularly in patients with liver disease or other impaired host defenses. Shigella Shigella species differ from other common bacterial enteropathogens because it lacks an animal reservoir and relies instead on human-to-human contact or human fecal contamination for spread of the infection. As a result, Shigella infection is more common in areas of the world where living conditions are poor and have insufficient infrastructures for handling human waste and delivering safe drinking water. In the United States, children who attend day care facilities and homosexual men are identified as risk groups for shigellosis. There are 4 species of Shigella—Shigella dysenteriae, Shigella flexneri, Shigella boydii, and Shigella sonnei—all of which vary in their epidemiology and pathogenicity. S. sonnei is the major species that causes illness in the developed world. Shigella causes a spectrum of enteritis that ranges from mild self-limited disease to fulminant dysentery. Shigella requires the smallest inoculum size (102 organisms) to cause infection of any of the major bacterial entero-

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pathogens. In addition to severe dysentery, HUS, and bacteremia, obtundation and seizures are known complications of shigellosis. The diagnosis can be made by isolating the organism in stool culture. Empirical therapy should be considered when patients have dysentery. The other common infectious cause of dysentery syndrome in travelers and immigrants is amebiasis, which should be ruled out, particularly in adults. Resistance to antibiotics (e.g., ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones [less common]) among Shigella species is increasing around the world (20). If determining the antimicrobial resistance of an isolate is not possible, patients who fail to respond to antibiotic treatment within 48 hours should be switched to another antibiotic. There is no effective vaccine for Shigella.

Yersinia enterocolitica Infection with Yersinia enterocolitica most often leads to inflammatory diarrhea but also can produce septicemia, arthritis, and abdominal pain that mimics appendicitis (21). In the United States, infection with Y. enterocolitica is less common than infection with the bacterial enteropathogens discussed previously and accounts for approximately 1% of bacterial gastroenteritis cases. Swine are an important animal reservoir for Y. enterocolitica, and the consumption of undercooked pork or chitterlings (raw pork intestines) is an important epidemiologic clue to the presence of Y. enterocolitica. Cows and other animals are also hosts for the organism, and its spread from dogs to humans and from humans to humans has been documented. The diarrheal illness caused by Y. enterocolitica is similar to that caused by Salmonella or Campylobacter. Pseudoappendicitis is more common in older children and adults. In clinical trials, antimicrobial therapy was not helpful in self-limited cases of Y. enterocolitica infection in otherwise healthy individuals; however, in most studies, antibiotic therapy was not started until several days into the illness. Antibiotic therapy is indicated for severe presentations, patients with medical complications, or cases of septicemia. Y. enterocolitica is resistant to ampicillin and first-generation cephalosporins and is sensitive to doxycycline, aminoglycosides, fluoroquinolones, and trimethoprim-sulfamethoxazole. Another species of Yersinia, Yersinia pseudotuberculosis, is an animal pathogen that occasionally produces diarrheal illness in humans similar to that caused by Y. enterocolitica. Clostridium difficile The first decade of the new millennia has seen an epidemic of Clostridium difficile in North America, with the spread of strains that may be more pathogenic (22). C. difficile is harmless under normal environmental conditions in the colon, its growth suppressed by the normal colonic flora. Disruption of the normal colonic flora permits C. difficile to proliferate and produce cytopathic toxins that cause mild to severe diarrhea. Asymptomatic

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carriage of C. difficile is found in 7% of all patients admitted to hospitals (22). The carriage rate increases to more than 20% after hospitalization, with the organism being spread from 1 patient to another by the hands of health care workers. Therefore, C. difficile is both a community-acquired and a nosocomially acquired organism. Broad-spectrum antimicrobial agents, particularly those that are active against anaerobes, are the most common causes of alterations in the ecology of the colon that lead to C. difficile disease. The illness can develop after a single dose of antibiotics or at any time up to 2 months after cessation of therapy. Chemotherapeutic agents that alter the intestinal flora also have been implicated in C. difficile disease. Not all patients who carry C. difficile and receive antibiotics develop diarrhea, and most mild cases of antibiotic-associated diarrhea (75%) are not caused by C. difficile but instead result from alterations in the flora or other effects of the antibiotics that are given. Clinically, C. difficile diarrhea ranges from a mild, self-limited illness to the severe but less frequent syndrome of pseudomembranous colitis. The latter condition is characterized by the development of whitish-yellow plaques in the colon that can become confluent (23); and it can lead to colonic perforation, necrosis, and death. Patients with this syndrome are often febrile and seem ill. Although occurring in a minority of patients, extreme leukocytosis (with peripheral leukocyte counts more than 40,000 cells/mm3) can be an important clue to the presence of pseudomembranous colitis, particularly in elderly patients. The diagnosis of C. difficile diarrhea is made by the demonstration of toxin in a patient’s stools; several different assays exist for this purpose. Isolating the organism from the stool of symptomatic patients is considered presumptive but not definitive evidence of infection, because carriage of C. difficile is not always associated with illness. Fecal leukocytes may or may not be present (sensitivity 30%-60%). Endoscopic examination can be used to establish a diagnosis of pseudomembranous colitis, and the findings in computed axial tomographic scans of the abdomen are often characteristic. Treatment of mild cases of C. difficile diarrhea can consist of simply stopping the offending antibiotic, if possible. In more severe cases, antibiotic therapy with oral vancomycin or oral or intravenous metronidazole should be used. Oral vancomycin is not absorbed and is effective in inhibiting the growth of C. difficile. An oral dose of 125 mg given 4 times daily is recommended except for the most severe cases. Oral vancomycin therapy is expensive compared with metronidazole and has been linked to colonization of vancomycin-resistant enterococcus. Intravenous vancomycin does not reach measurable levels in the bowel and is not an effective treatment agent for colitis caused by C. difficile. Metronidazole is also active against C. difficile and has the advantages of lower cost and availability for intravenous delivery in patients who cannot take anything by mouth and/or have ileus. Clinical trials of vancomycin and metronidazole in severe cases of C. difficile diarrhea have been inconclusive; many experts favor oral

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vancomycin for the sickest patients; combinations of oral vancomycin and intravenous metronidazole have been used in severe cases. Oral vancomycin has not been shown to provide any advantage in less severe cases of C. difficile diarrhea, and most authorities recommend metronidazole as a cheaper alternative. Intravenous immunoglobulin has shown benefit in uncontrolled trials in treating patients with severe disease, and nitazoxanide has shown promise as an alternative to vancomycin and metronidazole. Probiotic therapy with Saccharomyces boulardii has shown promise in clinical trials but has not gained widespread popularity. Many experts recommend against antimotility agents because they may prolong exposure to C. difficile toxin. Relapsing C. difficile diarrhea occurs in 10% to 20% of patients (22). Neither vancomycin nor metronidazole is active against C. difficile spores. If the colonic milieu remains altered after successful therapy, C. difficile diarrhea may recur after sporulation and the production of metabolically active, toxinproducing bacteria. Many relapses are a particular problem in the elderly, perhaps because of the tendency for spores to persist in diverticula and to resist being removed from the bowel through normal peristalsis. Therapeutic approaches to relapsing C. difficile diarrhea have included long tapering or pulse-dosing courses of oral vancomycin (see Table 8-1) (24).

Protozoa Entamoeba histolytica Entamoeba histolytica is an enteric protozoan parasite that causes amebiasis, the third most deadly parasitic disease worldwide (after malaria and schistosomiasis). Infection with E. histolytica is highly endemic in Africa, South America, Mexico, and southern Asia. The infection is transmitted through contaminated food and water, and less frequently by direct fecal–oral contact with the cyst form of the organism. Although most infected individuals are asymptomatic, E. histolytica causes various intestinal and extraintestinal syndromes. The most common clinical presentation is a noninvasive colitis that is characterized by nonspecific abdominal pain and loose stools. Amebic colitis, which is caused when E. histolytica trophozoites invade intestinal epithelial cells, is characterized by abdominal pain and tenderness, with bloody stools and without fecal leukocytes. Fulminant amebic colitis, which may lead to toxic megacolon, is infrequent but can be seen in malnourished patients, children, and patients taking corticosteroids. This syndrome is characterized by fever, an outward appearance of toxicity, profuse diarrhea, and occasionally intestinal perforation. Intestinal amebiasis can be diagnosed by identifying amebic trophozoites and/or cysts in the stool; several stool specimens are often required for this, and at least 3 stool specimens should be examined before amebiasis is ruled out. Additionally, E. histolytica must be differentiated from nonpathogenic intestinal protozoans. The colitis caused by E. histolytica is inflammatory, but fecal

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Table 8-1 Recommended Antimicrobial Therapies for the Infectious Organisms That Cause Diarrhea Diseases

Infectious Organism Recommended Antimicrobial Therapy

Bacterial Shigellosis

Shigella species

Salmonellosis

Salmonella enteritidis

Campylobacteriosis

Campylobacter jejuni

ETEC, EPEC, EIEC EHEC

Adults: SXT 160–800 mg q12h for 3 days Fluoroquinolone: Ofloxacin 300 mg, norfloxacin 400 mg, or ciprofloxacin 500 mg q12h for 3 days Children: SXT 5–25 mg/kg/d in 2 divided doses for 3–5 days Adults*: SXT 160–800 mg q12h for 3 days (if susceptible); norfloxacin 400 mg, ciprofloxacin 500 mg, or ofloxacin 200 mg q12h for 5–7 days Children*: If ≤3 months of age, ceftriaxone 50 mg/kg/d; if >3 months and healthy, no treatment necessary; if >3 months with underlying illness, ceftriaxone <2 g/d Adults: Azithromycin 500 mg/d for 5 days; fluoroquinolones as for shigellosis above Children: Azithromycin 10 mg/kg/d for 5 days Same as for shigellosis above Role of antimicrobial therapy unclear

Escherichia coli E. coli O157:H7 and other enteric bacteria that produce Shigalike toxins Aeromonas Aeromonas Same as for shigellosis above Plesiomonas Plesiomonas diarrhea shigelloides Antibiotic-associated Clostridium difficile Metronidazole 500 mg tid for 10-14 days; vancomycin 125 mg qid for 10-14 days; diarrhea† bacitracin also has been used Yersiniosis Yersinia Antimicrobial therapy usually is not enterocolitica required except for severe infections or associated bacteremia Adults: combination of two of the following: doxycycline, aminoglycoside, SXT, fluoroquinolones Children: ceftriaxone 50 mg/kg/d q24h for 5 days Cholera Vibrio cholerae Doxycycline 300 mg PO in a single dose; tetracycline 500 mg qid for 3 days; SXT 160 mg/800 mg bid for 3 days A fluoroquinolone in a single dose Parasitic Giardiasis Giardia lamblia Metronidazole 250–750 mg q8h for 7–10 days Continued

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Table 8-1 Continued Diseases

Infectious Organism Recommended Antimicrobial Therapy

Amebiasis

Entamoeba histolytica

Cryptosporidiosis

Cryptosporidium species

Isosporiasis

Isospora species

Microsporidiosis

Microsporidium species Cyclospora species

Cyclosporiasis

Nitazoxanide 500g q12h x 3d Peds: 100–200g q12h x 3d Infants: furazolidone 7 mg/kg/d in 4 divided doses for 7 days Older children: metronidazole 20 mg/kg/d in 3 divided doses for 7 days Metronidazole 750 mg q8h for 5–10 days + diiodohydroxyquin 650 mg q8h for 20 days or paromomycin 500 mg tid for 10d For children: Metronidazole 50 mg/kg/d IV in 3 divided doses + diiodohydroxyquin 40 mg/kg/d in 3 divided doses for 20 days No treatment necessary except in severe cases or in patients with AIDS Severe cases: Paromomycin 500 mg q8h for 7 days Nitazoxanide 500g q12h x 3d Peds: 100–200g q12h x 3d AIDS patients: give 14–28 days then q12h indefinitely SXT 160–800 mg q12h for 7–10 days AIDS patients: SXT 320–1600 mg q12h for 2–4 weeks, then 160–800 mg/d indefinitely Children: SXT 10–50 mg/kg/d in 2 divided doses for 7 days Albendazole 400 mg q12h for 3 weeks SXT 160–800 mg q6h for 10 days AIDS patients: SXT 320–1600 mg q12h for 2–4 weeks, then 160–800 mg/d indefinitely Children: SXT 10–50 mg/kg/d in 2 divided doses for 7 days

* Treatment for salmonellosis is recommended only for severe cases, for patients aged <6 months or >50 years or for those with prostheses, valvular heart disease, severe atherosclerosis, malignancy, or uremia. † Discontinue the offending agent EHEC = Enterohemorrhagic E. coli; EIEC = Enteroinvasive E. coli; EPEC = Enteropathogenic E. coli; ETEC= Enterotoxigenic E. coli; SXT = sulfamethoxazole–trimethoprim.

leukocytes may be few or absent because the amebic form of E. histolytica can lyse host inflammatory cells. The most common extraintestinal site of amebiasis is a liver abscess. Amebic liver abscess can present acutely, with fever, abdominal pain, and weight loss; or it can have a more insidious course. Amebic liver abscesses most often occur from 2 to 6 months after exposure to E. histolytica and

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can be seen in refugees and immigrants with relatively remote exposures. Other extraintestinal sites of infection are rare and include brain abscesses, pleural and pericardial abscesses, and sites of cutaneous and genitourinary infection. Only a minority of patients with extraintestinal amebiasis have E. histolytica in their stool, in which cases the diagnosis of amebiasis is based on clinical suspicion, serologic findings (positive in >85% of patients with invasive infection), and imaging studies such as computed tomography and ultrasound. Treatment of amebiasis depends on the site of infection and other factors. Treatment of asymptomatic persons who pass cysts of E. histolytica in their stools is given only to patients who live in nonendemic areas or to those who are at high risk for colitis. Various luminal agents are available for treating asymptomatic persons who pass cysts of the organism, including diloxanide, paromomycin, and diiodohydroxyquin. Colitis is usually treated with a nitroimidazole, such as metronidazole, followed by a luminal agent to eradicate the cyst state. Metronidazole is the treatment of choice for extraintestinal amebiasis. Preventing amebiasis is an important consideration in situations of crowding and poor sanitation. The simple act of boiling water eliminates cysts of E. histolytica; however, treating drinking water with chlorine or iodine is ineffective.

Giardia lamblia Giardia lamblia is the most common parasitic cause of diarrhea in the developed world (25). Because most states in the United States do not mandate reporting giardiasis, data on the incidence of the disease in this country are not highly reliable. The annual incidence is estimated to be 50 cases per 100,000 population, with toddlers and young adults the major groups at risk. Infection is passed from person to person and by ingesting contaminated water or food. Outbreaks of waterborne G. lamblia infection have been well described and usually involve the ingestion of untreated river, lake, well, and occasionally municipal water. Giardiasis occurs in travelers, accounting for approximately 5% of cases of traveler’s diarrhea. G. lamblia is resistant to chlorine and can be reliably removed from water only by ultrafiltration. Person-to-person transmission of the organism has been demonstrated most often in day care centers. G. lamblia can be found in many large mammals; however, because the organism is difficult to subtype, the role of these animal reservoirs is unknown. G. lamblia causes a noninflammatory diarrhea characterized by watery stools, cramping, flatulence, and little or no fever. The illness usually lasts approximately 1 week but can persist in immunocompromised patients, including those with IgA deficiency who may otherwise not show manifestations of immunodeficiency. The diagnosis is made by demonstrating the organism in a wet mount of a fresh stool specimen. Some symptomatic patients may shed few organisms, and empirical therapy is warranted for

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patients in whom there is a high index of suspicion of giardiasis but who have negative stool specimens. Standard therapy consists of metronidazole in a dose of 250 to 750 mg orally thrice daily for 7 to 10 days. Lower doses are associated with treatment failure, and higher doses are associated with increased side effects. Nitazoxanide (Alinia) is a newer agent active against both G. lamblia and Cryptosporidium parvum and is an alternative to metronidazole. Other treatment options include quinacrine hydrochloride, furazolidone, and tinidazole, which is unavailable in the United States.

Microsporidia Microsporidia are an order of small, obligate, intracellular protozoal parasites found widely in animals and in the environment. In the past decade, they have been recognized as having a role in human disease, particularly in immunocompromised patients, including those with HIV infection and/or AIDS. At least 4 genera are known to cause human disease: Encephalitozoon, Enterocytozoon, Nosema, and Pleistophora (26). Cases of infection are most often recognized in residents of tropical countries and in travelers. The most common symptoms are chronic diarrhea and wasting. Infection also has been recognized at extraintestinal sites. Diagnosis requires electron microscopy of biopsy specimens. Clearly defined therapies are lacking; albendazole has been used successfully in some cases of infection with Enterocytozoon. Cryptosporidia Cryptosporidium parvum is a protozoan parasite found throughout the world but was not known as a human pathogen until the early 1980s. It is now recognized as a cause of sporadic cases of self-limited diarrhea in healthy individuals and of intractable diarrhea in immunocompromised patients (27). Groups at risk for acquiring the organism include travelers, animal handlers, and day care center personnel. In 1994, an outbreak of cryptosporidiosis in Milwaukee that was associated with contamination of the city’s water supply affected several hundred thousand residents. Illness caused by C. parvum follows the ingestion of spores and the infection of small-bowel enterocytes, leading to disruption of intestinal absorption and producing a watery, noninflammatory diarrhea. The duration of the illness is usually 10 to 14 days but can be chronic in immunocompromised patients; chronic cryptosporidial diarrhea has been well described in patients with HIV infection and/or AIDS. Cholecystitis has been reported in immunocompromised patients. Diagnosis is made by identifying oocysts in stool with a modified acid-fast stain. Treatment in immunocompetent patients consists of hydration and supportive care. Nitazoxanide has been shown to shorten the duration of illness, and may offer benefit in immunocompromised patients (28). Various other antimicrobial agents have been used in chronic, severe cases of cryptosporidiosis, with no consistent response.

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Cyclospora Cyclospora cayetanensis is a coccidian parasite recently recognized as a cause of acute and chronic diarrhea (29). Originally described in travelers and expatriates in Kathmandu who presented with prolonged diarrhea, Cyclospora has been linked to outbreaks of diarrhea in the United States associated with imported fruit, particularly berries. The clinical illness caused by Cyclospora is characterized by diarrhea, nausea, and weight loss that can persist for months or weeks if left untreated. Treatment with trimethoprim-sulfamethoxazole has been successful. An alternative therapy for patients with sulfa allergy has not been established (30).

Food-Poisoning Syndromes Food poisoning can result from the ingestion of various infectious agents, preformed bacterial toxins, and noninfectious substances; and it encompasses many clinical presentations. For the purposes of this section, food poisoning is defined as any illness occurring within 48 hours of food ingestion. Not all food poisoning syndromes produce gastrointestinal symptoms, and many (e.g., scombroid, ciguatera, shellfish, botulism) present with primarily neurological syndromes that are beyond the scope of this chapter. Bacteria cause 92% of food-borne illnesses for which a cause is identified (31). In the United States, most cases of food-borne illness go unreported, and the incidence of food-borne gastroenteritis is based on estimates. In 1996, the Centers for Disease Control and Prevention began active surveillance for Campylobacter, E. coli 0157:H7, Listeria, Salmonella, Shigella, Vibrio, Yersinia, Cyclospora, and Cryptosporidium in specific regions of the United States (the data include illnesses with onset after 48 hours). The incidence of illness was highest for Campylobacter (24.7 cases per 100,000 population), followed by salmonellosis (13.7) and shigellosis (7.8) (32). The major risk factors for foodborne disease are improper food storage and preparation, most often related to the temperature at which the food is stored before preparation or the temperature at which it is held between preparation and consumption. Poor personal hygiene of the food preparer, inadequate cooking, and contaminated equipment (including cross-contamination of food-preparation surfaces) are also important risk factors. Food poisoning syndromes are often suspected by patients who present with gastrointestinal illness. The presence of similar symptoms in 2 or more people who have consumed the same food should raise suspicion for food poisoning. Food poisoning syndromes can be categorized by incubation time and symptoms, such as the presence or absence of vomiting. Gastrointestinal symptoms that occur within 6 hours of food ingestion suggest the presence of a preformed bacterial toxin, such as those produced by Staphylococcus aureus or Bacillus cereus, or a chemical substance. Both S. aureus and

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B. cereus proliferate and produce toxins under conditions of improper food storage. Syndromes of food poisoning from both S. aureus and B. cereus present with prominent nausea and vomiting. S. aureus food poisoning occurs when food is contaminated with enterotoxin-producing strains of staphylococci under conditions favoring growth of the bacteria and with time for accumulation of enough toxin to produce illness. Because S. aureus enterotoxins are relatively heat stable, proper cooking is not protective against disease. Vomiting is the predominant symptom, but diarrhea and fever also can occur. The diagnosis is suggested by the history and time frame of illness occurrence and can be confirmed by isolating a toxinproducing strain of S. aureus from the suspected food. Large outbreaks of illness caused by S. aureus food poisoning have been well documented. Custards, other egg products, and potato salads are among the foods most commonly associated with staphylococcal food poisoning. B. cereus poisoning is similar to that caused by S. aureus and is frequently associated with the consumption of fried rice. The differential diagnosis of short-incubation food poisoning also includes Norwalk-like viral gastroenteritis, as discussed previously. The incubation period for this illness is usually longer than that for food poisoning caused by S. aureus or B. cereus (usually >8 hours), and diarrhea is usually a prominent feature of the illness. Heavy metal ingestion can produce upper intestinal symptoms within an hour of ingestion. Zinc ingestion caused by improper storage of acidic beverages in galvanized containers has been reported. Faulty fluoridation that results in high fluoride levels also has been shown to produce nausea and vomiting. Ingestion of poisonous mushrooms and raw fish containing helminths are also included in the differential diagnosis. The onset of nausea, vomiting, and abdominal pain within 8 to 16 hours after ingestion of food suggests illness caused by the ingestion of preformed toxins from Clostridium perfringens or B. cereus. The longer incubation time results from the production of toxins after the ingestion of food. Food poisoning caused by C. perfringens typically presents with abdominal cramping and noninflammatory diarrhea with little or no vomiting. The diagnosis of C. perfringens food poisoning is difficult to make because the organism is normally present in the intestinal flora. The diagnosis is based on the isolation of the toxin from stool. Food poisoning caused by C. perfringens resembles B. cereus food poisoning of long incubation. Diarrhea related to food-borne infection that occurs with an incubation period of more than 16 hours is usually caused by the bacterial enteropathogens discussed previously, including Salmonella, Campylobacter, E. coli, Yersinia, and V. parahaemolyticus. The management of food-borne gastroenteritis consists primarily of rehydration and supportive care. Treatment issues for bacterial pathogens have been discussed previously. Food-borne illnesses are largely preventable through proper handling, storage, and preparation of food.

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Diarrhea in Travelers A wide variety of enteropathogens cause diarrhea in travelers, including Salmonella, Shigella, E. coli, Campylobacter, rotavirus, and protozoan parasites. In the developing world, these enteric pathogens circulate in the community and, at times, are isolated from both symptomatic and asymptomatic individuals. Travelers are at increased risk for developing infectious gastroenteritis because they typically lack immunity to the local enteropathogens and are often exposed to infection by means of contaminated food or water. The increased incidence of bacteria and parasites in travelers should prompt a more aggressive approach should diarrhea or other gastrointestinal symptoms develop, especially if these are severe or chronic. Enterotoxigenic E. coli is the most common cause of diarrhea in travelers, followed by Salmonella, Shigella, and viral pathogens (33). G. lamblia is responsible for approximately 5% of cases of traveler’s diarrhea and should be suspected in patients who develop diarrhea after returning from short-term travel, have an illness characterized by bloating and flatulence, and have prolonged symptoms (>3 weeks). In counseling travelers about diarrhea, it is important to give advice that helps them avoid acquiring enteropathogens and develop a strategy in case they do develop illness. Travelers should be advised to drink only bottled or boiled water (and to use such water when brushing their teeth), to eat fruits and vegetables only if they have been cooked or if they are peeled by the travelers themselves, and to avoid ice cubes. These precautions should be maintained even on the way home, because the food and water on the airplane or on other transportation may be prepared locally. Travelers also should be advised that handheld filtration systems and purification tablets do not always work and should not be considered reliable protection against diarrhea. Experts in travel medicine advise presumptive therapy in the event of diarrhea. The traveler is given a prescription for an antibiotic (usually a quinolone, trimethoprim-sulfamethoxazole, or doxycycline) and is instructed to begin taking the antibiotic together with an antimotility agent if diarrhea develops. This strategy is effective for diarrhea caused by enterotoxigenic E. coli, the most common pathogen responsible for traveler’s diarrhea. In areas of the world where quinolone-resistant Campylobacter is the predominant pathogen in travelers (e.g., Thailand), azithromycin is the preferred agent for therapy for traveler’s diarrhea. Persistent fever or bloody stools should prompt the traveler to seek medical attention. Rifaximin is a luminal agent approved in 2004 for prophylaxis in travelers, and its use is still being evaluated. Use of other antibiotics to prevent diarrhea may be associated with side effects, may contribute to the pool of resistant pathogens worldwide, may put the traveler at increased risk for some pathogens owing to the disturbance of the normal flora, and is generally not recommended. Studies linking traveler’s diarrhea to the subsequent development of irritable bowel syndrome have refocused

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investigators on preventive strategies. Bismuth sulfates (e.g., Pepto-Bismol) work by coating the intestine, preventing bacterial adherence and colonization, and inhibiting production of bacterial toxin. They are effective only if taken at least 4 or 5 times per day, which most travelers find inconvenient.

Chronic Diarrhea A large number of conditions, both infectious and noninfectious, can lead to chronic diarrhea, which is defined as diarrhea that persists for more than 4 weeks. Patients with chronic diarrhea can be subclassified further according to whether or not they have malnutrition and/or blood in their stool. Patients with chronic diarrhea who do not have malnutrition but who do have blood in their stool should be evaluated for a colonic neoplasm or parasite-associated conditions, such as ameboma, whipworm colitis, chronic campylobacteriosis, and schistosomiasis. Inflammatory bowel disease also should be considered. Patients without blood in the stool but with signs or symptoms of malnutrition usually have an underlying malabsorption syndrome, which may stem from various conditions. Among the infectious causes of malabsorption syndromes are tropical sprue; bacterial overgrowth syndrome; and several parasites, including G. lamblia, Strongyloides stercoralis, Capillaria, and Cryptosporidium. Some cases of filariasis and intestinal pseudoobstruction from Chagas disease can cause lymphatic obstruction that can lead to chronic diarrhea. The term tropical enteropathy (or sprue) has been used to describe a syndrome of malabsorption and minor intestinal mucosal abnormalities seen in otherwise healthy individuals from tropical countries. Tropical enteropathy is thought to be an adaptation to frequent enteric infections. The wide variety of noninfectious causes of malabsorption is beyond the scope of this chapter. Chronic diarrhea, malnutrition, and wasting are common manifestations of HIV infection in tropical countries. Referred to as slim disease in many parts of Africa, this syndrome has not been linked to a single specific pathogen. It may be related to exposure to many enteric pathogens or to the involvement of the bowel mucosa by HIV infection. Many enteric pathogens cause diseases of more severe and prolonged course in patients with AIDS (see Chapter 39).

Nosocomial Diarrhea Diarrhea that occurs after 3 days of hospitalization is by definition considered nosocomial diarrhea. Patients with nosocomial diarrhea are unlikely to have the standard enteric pathogens, such as Campylobacter, Salmonella, and Shigella. The yield for ova and parasites is similarly low. In 15% to 20% of these patients, C. difficile toxin may be detected in the stool. Among hospitalized patients, it is recommended that stool cultures be made for the following groups:

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● ●

●

Patients who have diarrhea within 72 hours after admission Patients whose onset of diarrhea occurs more than 72 hours after admission and who are age 65 years or older, have preexisting disease that causes alteration of organ function, have HIV infection, or have a neutropenia of 500 cells/mm3 or less or when an outbreak of nosocomial infection is suspected Patients with a suspected nondiarrheal manifestation of enteric infection, such as erythema nodosum, mesenteric lymphadenitis, polyarthritis, or fever of unknown origin (34)

Additionally, testing for C. difficile toxin is an important part of the work-up for diarrhea (35,36).

Summary In the United States, most cases of gastroenteritis and diarrhea in adults are self-limited. A careful history helps identify patients at risk for complications of bacterial or protozoal infection. Specific antimicrobial therapy is indicated for some pathogens, and a subset of patients may benefit from therapy for bacterial pathogens that cause self-limited disease in normal healthy adults.

REFERENCES 1. Flint JA,Van Duynhoven YT,Angulo FJ, DeLong SM, Braun P, Kirk M, et al. Estimating the burden of acute gastroenteritis, foodborne disease, and pathogens commonly transmitted by food: an international review. Clin Infect Dis. 2005;41:698-704. 2. DuPont HL. Guidelines on acute infectious diarrhea in adults. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol. 1997;92: 1962-75. 3. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA. 1996; 275:870-6. 4. Roffe C. Biotherapy for antibiotic-associated and other diarrhoeas. J Infect. 1996;32:1-10. 5. Fankhauser RL, Monroe SS, Noel JS, Humphrey CD, Bresee JS, Parashar UD, et al. Epidemiologic and molecular trends of “Norwalk-like viruses” associated with outbreaks of gastroenteritis in the United States. J Infect Dis. 2002;186:1-7. 6. Kapikian A. Overview of viral gastroenteritis. Arch Virology. 1996;12:7-19. 7. Jin S, Kilgore PE, Holman RC, Clarke MJ, Gangarosa EJ, Glass RI. Trends in hospitalizations for diarrhea in United States children from 1979 through 1992: estimates of the morbidity associated with rotavirus. Pediatr Infect Dis J. 1996;15:397-404. 8. Vesikari T. Rotavirus vaccines against diarrhoeal disease. Lancet. 1997;350:1538-41. 9. Grisaru-Soen G,Wysoki MG, Keller N. Risk factors for development of nontyphoid Salmonella bacteremia. Clin Pediatr (Phila). 2004;43:825-9. 10. Varma JK, Molbak K, Barrett TJ, Beebe JL, Jones TF, Rabatsky-Ehr T, et al. Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations. J Infect Dis. 2005;191:554-61. 11. Aliaga L, Mediavilla JD, López de la Osa A, López-Gómez M, de Cueto M, Miranda C. Nontyphoidal salmonella intracranial infections in HIV-infected patients. Clin Infect Dis. 1997;25:1118-20. 12. Rankin SC, Coyne MJ. Multiple antibiotic resistance in Salmonella enterica serotype enteritidis [Letter]. Lancet. 1998;351:1740. 13. Vogel LP. Resistant bacteria in retail meats and antimicrobial use in animals [Letter]. N Engl J Med. 2002;346:777-9.

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14. Stutman HR. Salmonella, Shigella, and Campylobacter: common bacterial causes of infectious diarrhea. Pediatr Ann. 1994;23:538-43. 14a. McCarthy N, Giesecke J. Incidence of Guillain-Barré syndrome following infection with Campylobacter jejuni. Am J Epidemiol. 2001;153:610-4. 14b. Mishu B, Blaser MJ. Role of infection due to Campylobacter jejuni in the initiation of GuillainBarré syndrome. Clin Infect Dis. 1993;17:104-8. 15. Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin Microbiol Rev. 1998;11:142-201. 16. Slutsker L, Ries AA, Greene KD, Wells JG, Hutwagner L, Griffin PM. Escherichia coli O157:H7 diarrhea in the United States: clinical and epidemiologic features. Ann Intern Med. 1997;126:505-13. 17. Kuruvilla A, Jesudason MV, Mathai D, John L, John TJ. The clinical pattern of diarrhoeal illness caused by the new epidemic variant of non-O1 Vibrio cholerae. Trans R Soc Trop Med Hyg. 1994;88:438. 18. Begue RE, Castellares G, Hayashi KE, Ruiz R, Meza R, English CK, et al. Diarrheal disease in Peru after the introduction of cholera. Am J Trop Med Hyg. 1994;51:585-9. 19. Akeda Y, Nagayama K,Yamamoto K, Honda T. Invasive phenotype of Vibrio parahaemolyticus. J Infect Dis. 1997;176:822-4. 20. Materu SF, Lema OE, Mukunza HM, Adhiambo CG, Carter JY. Antibiotic resistance pattern of Vibrio cholerae and Shigella causing diarrhoea outbreaks in the eastern Africa region: 19941996. East Afr Med J. 1997;74:193-7. 21. Currie B. Yersinia enterocolitica. Pediatr Rev. 1998;19:250; discussion 251. 22. McDonald LC, Killgore GE, Thompson A, Owens RC Jr., Kazakova SV, Sambol SP, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-41. 23. Brazier JS. The diagnosis of Clostridium difficile-associated disease. J Antimicrob Chemother. 1998;41 Suppl C:29-40. 24. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother. 1998;41 Suppl C:41-6. 25. Cacciò SM, Thompson RC, McLauchlin J, Smith HV. Unravelling Cryptosporidium and Giardia epidemiology. Trends Parasitol. 2005;21:430-7. 26. Wanke CA, DeGirolami P, Federman M. Enterocytozoon bieneusi infection and diarrheal disease in patients who were not infected with human immunodeficiency virus: case report and review. Clin Infect Dis. 1996;23:816-8. 27. Tzipori S, Griffiths JK. Natural history and biology of Cryptosporidium parvum. Adv Parasitol. 1998;40:5-36. 28. Zulu I, Kelly P, Njobvu L, Sianongo S, Kaonga K, McDonald V, et al. Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial. Aliment Pharmacol Ther. 2005;21:757-63. 29. Brennan MK, MacPherson DW, Palmer J, Keystone JS. Cyclosporiasis: a new cause of diarrhea. CMAJ. 1996;155:1293-6. 30. Connor BA. Cyclospora infection: a review. Ann Acad Med Singapore. 1997;26:632-6. 31. Humphrey T. Food- and milk-borne zoonotic infections. J Med Microbiol. 1997;46:28-33. 32. Hogue A,White P, Guard-Petter J, Schlosser W, Gast R, Ebel E, et al. Epidemiology and control of egg-associated Salmonella enteritidis in the United States of America. Rev Sci Tech. 1997;16:542-53. 33. Steffen R,Tornieporth N, Clemens SA, Chatterjee S, Cavalcanti AM, Collard F, et al. Epidemiology of travelers’ diarrhea: details of a global survey. J Travel Med. 2004;11:231-7. 34. Wood M. When stool cultures from adult inpatients are appropriate. Lancet. 2001;357:901-2. 35. Guerrant RL,Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32:331-50. 36. Wilson M. Diarrhea in nontravelers: Risk and etiology. Clin Infect Dis. 2005;41:S541-6.

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Chapter 9

Biliary Tract Infections LAVINIA F. SMULTEA, DO CURTIS J. DONSKEY, MD

Key Learning Points 1. The development of biliary tract infection generally requires obstruction of bile ducts, and the most common cause of this obstruction is gallstones. Obstruction of the cystic duct results in acute cholecystitis, whereas obstruction of the common bile duct may result in cholangitis. 2. The differential diagnosis of right upper quadrant (RUQ) pain and fever includes acute cholecystitis, cholangitis, appendicitis, acute pancreatitis, liver abscess, renal colic or acute pyelonephritis, and pulmonary embolism. 3. Ultrasonography is the most useful imaging study in the initial evaluation of patients who present with acute RUQ pain and fever. 4. Acute acalculous cholecystitis refers to acute inflammation of the gallbladder in the absence of gallstones. The clinical presentation is often subtle, owing to the preponderant occurrence of the disease in elderly and postoperative or critically ill patients. 5. The classic clinical presentation of cholangitis includes Charcot’s triad of fever and chills, jaundice, and RUQ pain; however, the complete triad is seen in only 70% to 85% of patients. 6. ERCP is the “gold standard” procedure for the diagnosis of common bile duct stones, and this technique allows therapeutic drainage at the time of diagnosis.

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New Developments in Biliary Infections • A recent study observed a fivefold increase of postoperative complications in patients with culture-positive bile at the time of surgery for obstructive jaundice • Percutaneous tube cholecystotomy can be an appropriate temporizing measure in patients with severe concurrent medical conditions that significantly increase the risk of surgery.

B

iliary tract infections are common causes of illness and death throughout the world. Although most of these infections are complications of gallstone disease, biliary infections in the absence of gallstones are increasingly recognized in immunocompromised and critically ill patients and as complications of biliary tract instrumentation. The clinician must distinguish infection of the biliary system from other illnesses that can have a similar presentation. Additionally, clinicians must determine whether urgent surgical or endoscopic drainage of such infections is indicated. New imaging, endoscopic, and surgical drainage techniques have improved the diagnosis and management of biliary tract infections; however, they have also increased the complexity of decision making with regard to these conditions. The biliary system includes the gallbladder and bile ducts. In the healthy biliary system, bile is sterile. In the presence of biliary tract pathology, however, bactibilia (the presence of bacteria in the biliary system) is common. Bacteria can reach the biliary tract from the portal circulation or by ascending from the small intestine through the ampulla of Vater. Bactibilia was demonstrated in 12% of patients who underwent elective cholecystectomy for gallstones (i.e., chronic cholecystitis) (1) in approximately one fourth to one third of patients with common bile duct (CBD) obstruction caused by malignancy, and in up to 80% of patients with CBD stones or strictures (2). Additional factors associated with bactibilia include diabetes mellitus, jaundice, advanced age, and instrumentation of the biliary tree. Bactibilia most often represents colonization rather than infection. The development of biliary tract infection generally requires obstruction of bile ducts, and the most common cause of this obstruction is gallstones. Culture-positive bile at the time of surgery for obstructive jaundice is associated with a fivefold increase in the incidence of postoperative infection and with higher incidence of septic complications (3). Cholelithiasis (gallstone disease) is present in 10% to 15% of adults in the Western industrialized countries and in approximately 25 million adults in the United States (4). Cholelithiasis increases in frequency with age and is approximately two times more common in women than in men. By 75 years of age, approximately 35% of women and 20% of men in the United States have developed gallstones. Seventy-five percent of these stones are cholesterol stones, and 25% are black (more common) or brown pigment

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stones. Risk factors for cholesterol gallstones include female gender, genetic predisposition, obesity, pregnancy, rapid weight loss, total parenteral nutrition, and certain medications (e.g., estrogens, clofibrate). Risk factors for black pigment stones include chronic hemolysis, cirrhosis, and pancreatitis. The clinical manifestations of gallstones are illustrated in Figure 9-1. Seventy-five percent of individuals with gallstones remain asymptomatic. The most common presenting symptom of cholelithiasis is biliary pain or colic, a visceral pain caused by transient or partial obstruction of the bile ducts that is not associated with inflammation or secondary infection. In the classic study by Gracie and Ransohoff of people with asymptomatic gallstones, the annual risk of new biliary pain was 2% within the first 5 years after gallstone diagnosis, falling to approximately 0.5% annually thereafter.

Asymptomatic stone (75%)

Long-standing cholelithiasis, resulting in gallbladder carcinoma (<0.1%)

Stone intermittently obstructing cystic duct, causing intermittent biliary colic (20%) Stone impacted in cystic duct, causing acute cholecystitis (10%)

Stone in cystic duct compressing common bile duct, causing Mirizzi syndrome (<0.1%)

Stone eroding through gallbladder into duodenum, resulting in cholecysteneric fistula (prerequisite for gallstone ileus) (<0.1%)

Stone impacted in distal common bile duct, causing jaundice, biliary colic-type pain, and risk of ascending cholangitis or acute biliary pancreatitis (5%)

Figure 9-1 Schematic depiction of the complications of gallstones. The percentages, based on natural history data, approximate the frequency of gallstones occurring in untreated patients. As shown, the most frequent outcome is for gallstones to remain asymptomatic throughout life. Biliary colic, acute cholecystitis, and cholangitis are the most common complications: Mirizzi syndrome, cholecystenteric fistula, and gallbladder cancer are relatively rare. (Republished with permission from Bilhartz LE, Horton JD. Gallstone disease and its complications. In: Sleisenger and Fordtran’s gastrointestinal and liver disease: Pathophysiology, diagnosis, management. Vol. 2. 6th ed. Philadelphia: WB Saunders; 1988.)

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Once biliary pain develops, the likelihood of infection and other complications of gallstone disease increases (4). Obstruction of the cystic duct results in acute cholecystitis, whereas obstruction of the CBD can result in cholangitis. Approximately 10% of gallstone patients have stones in the CBD. Although these can be asymptomatic, the incidence of serious complications (e.g., obstructive jaundice, pancreatitis, cholangitis) ranges from approximately 25% to 50%.

Acute Calculous Cholecystitis Pathogenesis and Bacteriology Cholecystitis refers to inflammation of the gallbladder, which is or is not secondarily infected. It occurs in 1% to 3% of persons with symptomatic gallstones. In more than 90% of patients with acute cholecystitis, a gallstone obstructs the cystic duct (acute calculous cholecystitis). This obstruction leads to bile stasis and to increased intraductal pressures, with subsequent gallbladder distension, a compromised blood supply, and impaired lymphatic drainage. Damage to the gallbladder mucosa from ischemia and bile stasis in the setting of supersaturated bile promotes further inflammation through the production of inflammatory mediators, such as prostaglandins I2 and E2, and lysolecithin. The pathologic changes in cholecystitis range from mild acute inflammation with edema to necrosis and perforation. Although bacteria do not play a direct role in initiating cholecystitis, enteric bacteria can be cultured from approximately 50% of patients with acute cholecystitis. Early reports suggested that bacterial infection was often a late complication of cholecystitis, but one study found that 81% of patients who had cholecystectomy within 2 days of symptom onset had positive gallbladder cultures, whereas patients from whom cultures were made after symptoms of a longer duration had lower rates of positive cultures (5). The organisms isolated from bile in acute cholecystitis are usually members of the normal intestinal flora. Approximately half are aerobic gram-negative rods such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter species, approximately 30% are enterococci or streptococci, and 15% are anaerobes (5). Anaerobes (most common are Bacteroides followed by Clostridia) are more frequent after common duct or complex previous biliary procedures and in the elderly. In 70% of cases, the infection is polymicrobial. When polymicrobial infection is present, aerobic gram-negative rods are the organisms most likely to be cultured from the blood. Fungal organisms, predominantly Candida species, are isolated occasionally. When Candida species are isolated from the gallbladder of a nonneutropenic patient without evidence of candidemia or of candidiasis outside the biliary tract, cholecystectomy without antifungal therapy is reported to be adequate therapy (6).

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However, severe cases of acalculous cholecystitis caused by Candida species are reported (7). Consultation with an infectious diseases specialist is recommended when Candida species are isolated from bile cultures.

Clinical Manifestations Seventy-five percent of the patients who present with acute calculous cholecystitis (ACC) had previous episodes of biliary pain. Biliary pain is rather constant, (contrary to what is implied by the term colic), poorly localized (although usually in the epigastrium or right upper quadrant [RUQ]), and typically lasts from 1 to 6 hours. Pain that lasts longer than 6 hours suggests acute cholecystitis. As inflammation of the gallbladder develops, the pain localizes to the RUQ and becomes more severe. It is often associated with nausea and mild vomiting. Physical examination commonly reveals fever in patients with acute calculous cholecystitis, but the temperature rarely exceeds 38.8˚C (102˚F) unless complications, such as gangrene or perforation, are present. Mild jaundice is seen in 20% of patients and in 40% of the elderly. RUQ tenderness is detected on abdominal examination, and a palpable gallbladder is detected in one third of patients, most frequently in association with their first attack. In patients who have had many attacks of cholecystitis, the gallbladder is often not palpable because it has become fibrotic and unable to distend. Murphy sign refers to pain and inspiratory arrest during palpation of the right subcostal region and is relatively specific for acute cholecystitis. Elderly patients or debilitated patients with acute cholecystitis often present with minimal localizing signs or symptoms, and the diagnosis is often delayed. Compared with younger populations, the elderly population has a greater incidence of complications, such as perforation, gangrene, and empyema. As a result, the death rate from acute cholecystitis in the elderly is approximately 7% compared with 1.6% in younger persons (8).

Complications Risk factors for the development of complications in gallstone disease include: age, male gender, diabetes, high fever, and significant leukocytosis. Perforation of the gallbladder occurs in approximately 5% to 10% of untreated acute cholecystitis cases. The most common form of perforation is subacute with walling off of the process as a pericholecystic abscess. A small percentage of untreated acute cholecystitis cases (approximately 1%) result in free perforation with diffuse peritonitis. Persistent fever and abdominal pain can be noted in these cases, but the signs and symptoms are not distinctive. Many cases are diagnosed late or are missed, which accounts for the 30% to 50% death rate among patients with free perforation. Empyema or suppurative cholecystitis occurs when gross pus is present in the gallbladder. The reported frequency of this condition varies from 1%

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to 9%. Fever, leukocytosis, and a tender mass are typical; however, as with perforation, minimal signs and symptoms can be present, especially in elderly patients. Emphysematous cholecystitis occurs when gas-forming bacteria infect the gallbladder wall and produce pockets of gas that are visible by plain radiography, ultrasonography, or computed tomography (CT) (9). Approximately two thirds of patients affected with this condition have poorly controlled diabetes. Bacteria associated with emphysematous cholecystitis include Clostridium perfringens, anaerobic streptococci, and Escherichia coli. Early cholecystectomy is indicated because of the high risk of perforation. All three of the aforementioned complications occur most commonly in the elderly, in men with diabetes mellitus, and in patients with acalculous cholecystitis. A cholecystenteric fistula develops when a large gallstone erodes through the wall of the gallbladder and into the adjacent intestinal tract, usually at the duodenum. The presentation is similar to that of acute cholecystitis. The presence of air in the biliary tree (pneumobilia) suggests the diagnosis. Obstruction of the small bowel (gallstone ileus) can occur when a large gallstone fills the lumen of the bowel, usually at the ileocecal valve. Biliary tract infections are the source of liver abscess in the United States in 40% to 50% of the cases. In patients with cholecystitis, contiguous spread of infection can result in liver abscess. In patients with cholangitis, now the major identifiable cause of pyogenic liver abscesses, infection ascends through the biliary tree. Liver abscesses from a biliary source are commonly multiple. Finally, cholangitis can occur in association with or as a complication of acute calculous cholecystitis (discussed in more detail later).

Differential Diagnosis Clinicians who evaluate patients with pain in the RUQ and fever must consider many conditions in addition to acute cholecystitis (Table 9-1). In one prospective study of 100 patients who had suspected acute cholecystitis, Table 9-1 Differential Diagnosis of Right Upper Quadrant Pain and Fever Acute cholecystitis Cholangitis Myocardial infarction or ischemia Right lower lobe pneumonia Pulmonary embolism or infarction Intestinal obstruction Hepatitis Perihepatitis (Fitz-Hugh–Curtis syndrome) Liver abscess Pancreatitis Right-sided nephrolithiasis or pyelonephritis Appendicitis Peptic ulcer disease

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the diagnosis was correct in only two thirds of cases (4). Cholangitis must always be considered in the differential diagnosis because the spectrum of clinical and laboratory findings for this condition overlaps that of acute cholecystitis. High fever or frank jaundice, stones in the CBD or a dilated CBD (as seen with ultrasound), and bilirubin concentration that exceeds 4 mg/dL should suggest cholangitis. Appendicitis can cause pain in the RUQ if the appendix is retrocecal or if the cecum is positioned in the subhepatic area. Appendicitis is the disease most often confused with ACC. Acute pancreatitis is difficult to distinguish from cholecystitis based on the physical examination and history alone because the two conditions can present similarly, and the serum amylase and lipase concentrations can be nonspecifically increased in cholecystitis. However, an amylase level above 1000 U/dL should suggest pancreatitis as a concurrent or alternative diagnosis. Renal colic and acute pyelonephritis that involves the right kidney are usually easily excluded by urinalysis. Small bowel obstruction usually causes more prominent nausea and vomiting than does cholecystitis and can be excluded by plain abdominal radiography. Myocardial infarction, pulmonary embolism, and Fitz-Hugh and Curtis syndrome (perihepatitis caused by infection with Neisseria gonorrhoeae or Chlamydia trachomatis) should be considered if risk factors for these conditions are present. Finally, liver abscess must also be considered in the differential diagnosis of RUQ pain, and, as noted earlier, liver abscess can occur as a complication of cholecystitis.

Diagnosis In a patient with suspected acute cholecystitis, judicious laboratory testing and imaging are needed to confirm the diagnosis and to exclude complications and other conditions that are part of the differential diagnosis. Initial laboratory testing for all patients with RUQ pain should consist of a complete blood count with differential; measurement of aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, and serum amylase activities; serum bilirubin concentration; urinalysis; and blood culture. Ultrasound or radionuclide imaging of the RUQ should be performed on all patients (see discussion later in this section). On the basis of the previously described findings in the differential diagnosis and of the history and findings on physical examination, selected patients should undergo cardiac isoenzyme assays, electrocardiography, abdominal plain radiography, chest radiography, pelvic examination with cervical cultures, and total abdominal ultrasonography or CT. Common laboratory findings seen in acute cholecystitis include mild leukocytosis with a left shift and mild increases in alkaline phosphatase, aminotransferase, and amylase activities. The bilirubin level is increased in 20% of patients, usually into the 2- to 4-mg/dL range. Plain abdominal radiography is rarely useful in the diagnosis of acute cholecystitis. In Western

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countries only 10% to 25% of gallstones are visible on plain radiography; however, it can help in the diagnosis of bowel obstruction, emphysematous cholecystitis, and cholecystenteric fistula. Ultrasonography is the most useful imaging study in the initial evaluation of patients who present with acute RUQ pain and fever (10). It is the best method for detecting gallstones within the gallbladder, with sensitivity and specificity both exceeding 95% for stones larger than 2 mm or stones with acoustic shadows. Because gallstones are highly prevalent and usually asymptomatic, abdominal pain in a patient with gallstones should not be attributed to acute cholecystitis without other supportive evidence. Radionuclide imaging of the biliary system (cholescintigraphy) can be used as an initial diagnostic technique for acute cholecystitis, but is most useful as an adjunct to ultrasonography (10). CT is approximately 75% sensitive for the detection of CBD stones and is superior to ultrasound for the detection of obstructing malignancy and abscesses. It is not, however, indicated in the management of most cases of ACC. The role and limitations of each diagnostic imaging method is outlined in Table 9-2.

Table 9-2 Diagnostic Imaging in Biliary Tract Infections Method

Ultrasonography Acute calculous cholecystitis

Cholangitis/ choledocholithiasis

Advantages EUS Cholangitis

Advantages

Disadvantage Cholescintigraphy Acute calculous cholecystitis

Comments

Method of choice; thickening of the gallbladder wall >4 mm (in the absence of hypoalbuminemia) and presence of pericholecystic fluid (in the absence of ascites) strongly suggest ACC; sonographic Murphy sign (focal gallbladder tenderness under the transducer) US only 50% sensitive in detecting CBD stone; in 75% of the cases where stones not seen the diagnosis is suggested by a dilated CBD (>6 mm); thus a normal US does not exclude cholangitis Absence of radiation, portability, ability to evaluate for other causes of abdominal pain Comparable with ERCP in terms of accuracy of confirming /excluding CBD stones (95% concor-dance rate); sensitivity ~95% and specificity ~97% Safer, less expensive than ERCP, thus ideal for excluding CBD stone in patients with low pretest probability Not readily available at all institutions, requires operator expertise Involves the intravenous administration of technetium-99m-labeled iminodiacetic acid derivatives (HIDA, DISIDA) which, in normal scans, is excreted into Continued

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Table 9-2 Continued Method

Disadvantage

ERCP Choledocholithiasis/ cholangitis Advantage

CT/MRCP Advantage

Comments

the gallbladder, CBD, and small intestine within 30-60 min; a positive scan is defined as nonvisualization of the gallbladder with normal excretion into the CBD and the duodenum; sensitivity ~95%, specificity ~90%; a normal scan essentially excludes ACC False positives are likely in severely ill or fasting patients, thus not indicated if acalculous cholecystitis suspected; if bilirubin >20 mg /dL the scan requires use of DISIDA Remains the gold standard for diagnosis of stones in CBD with sensitivity and specificity of ~95% Ability to extract stones/drain infected bile, emergently decompress the biliary tree in severely ill patients, thus reducing the necessity for invasive CBD exploration Not indicated in the management of most cases of ACC; mainly useful in detection of complications (gallbladder perforation, abscess formation, pancreatitis) and to exclude other intraabdominal pathology of diagnosis in doubt; sensitivity for detection of CBD stones is ~75% superior in detection of obstructing malignancy; MRCP is a safe procedure most useful for excluding CBD stones in those with low pretest probability of disease

Abbreviations: ACC, acute calculous cholecystitis; CBD, common bile duct; CT, computed tomography; DISIDA, diisopropyl iminodiacetic acid; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; HIDA, hepatoiminodiacetic acid; MRCP, magnetic resonance cholangiopancreatography; US, ultrasonography.

Treatment The management of acute calculous cholecystitis requires a combined medical and surgical approach. Initial medical management of all patients should include administration of intravenous fluids and parenteral analgesics. Nasogastric suctioning can be used if persistent vomiting occurs. Early surgical consultation is recommended.

Antibiotic Therapy Antibiotic therapy is recommended in complicated or severe cases of acute cholecystitis and for perioperative prophylaxis of all patients (Table 9-3). The role of antibiotics in the initial management of uncomplicated acute cholecystitis is not clear. One retrospective study of a series of patients with acute cholecystitis suggested that preoperative administration of antibiotics did not affect the incidence of local complications (e.g., pericholecystic abscess, empyema) but did decrease the incidence of postoperative wound infections and sepsis in elderly, debilitated patients and in those with local septic complications (11). The inability of antibiotics to reach significant

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Table 9-3 Common Bacterial Pathogens Isolated from Biliary Tract Infections and Recommended Empirical Antimicrobial Therapy* Infections

Cholecystitis Cholangitis Bacterial Isolates

Enterobacteriaceae (50%) Enterococci (30%) Anaerobes (15%) Polymicrobial (70%) Suggested Regimens

Mild-moderatea Ampicillin 2g IV q 8 h Cefazolin 1-2 g q 8 h Cefoxitin 2g q 6-8 h Cefotaxime 1-2 g q 8 h Ceftriaxone 2 g q 24 h Ampicillin–sulbactam 3 g IV q 6 h Piperacillin–tazobactam 3.375 g IV q 6 h Ampicillin 2 g IV q 4-6 h + gentamicin Ciprofloxacin 200-400 mg IV q 12 h +/− metronidazole 500 mg IV q 8 h Severeb Ampicilin 5 mg/kg IV q 24 h + metronidazole Piperacillin–tazobactam 3.375 g IV q 6 h Imipenem 0.5-1.0 g IV q 8 h Complex nosocomialc Piperacillin + aminoglycoside + metronidazole or clindamycin 600 mg q 6-8 h Imipenem + aminoglycoside * All empirical antimicrobial regimens should provide coverage for Enterobacteriaceae. For severely ill patients with cholecystitis or cholangitis, the initial antimicrobial regimen includes coverage of anaerobes (including Bacteroides fragilis) and enterococci. The antimicrobial regimen should be adjusted appropriately based on information gained from cultures of blood and bile. The dosages listed are for healthy adults and can require adjustment for patients with abnormal renal or hepatic function. The recommended duration of antimicrobial therapy for uncomplicated cases of cholangitis is 7-14 days. a Elderly patients, patients with chronic conditions, patients without chronic conditions but with fever, leukocytosis, tachycardia, and those who fail to improve after 12 hours of conservative management. b Critically ill and those with infectious complications such as perforation. c Prior common bile duct or complex biliary procedures. Abbreviations: IV, intravenous; q, every.

concentrations within the gallbladder when the cystic duct is obstructed can explain the lack of effect of antibiotics on the incidence of local complications. The favorable results of antibiotic treatment in decreasing septic complications, however, seems to depend on adequate serum concentration rather than tissue concentration. Table 9-3 describes our position and practice vis-à-vis the empiric therapy for ACC. Bacterial cultures should be obtained at the time of surgery, and antimicrobial therapy can be adjusted on the basis of the results. In patients undergoing early uncomplicated cholecystectomy, prolonging the antibiotic therapy more than 1 day beyond

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the surgery has not been shown to be beneficial (4), but treatment for 3 to 5 days after surgery for uncomplicated cholecystitis remains an acceptable practice.

Surgical Therapy Cholecystectomy is the definitive therapy for acute cholecystitis. In cases of severe and complicated disease, cholecystectomy should be performed at an early point if possible. The timing of cholecystectomy in cases of uncomplicated disease is controversial. Randomly assigned controlled trials done before and after the advent of laparoscopic cholecystectomy (LC) of early (within days following presentation) compared with delayed (>6-8 weeks) cholecystectomy for acute cholecystitis have shown that early operation is preferred in most cases because it reduces illness and total hospitalization time and costs (4,12-14). These studies did not show that the death or complication rates are different for early versus delayed surgery (4). LC is a safe and feasible alternative to open surgery in patients with chronic cholecystitis undergoing elective surgery and in most patients with uncomplicated acute cholecystitis (4). Findings from several recent trials seem to favor LC within 48 to 72 hours of onset of symptoms over surgery after 3 to 5 days of conservative management (interval surgery) or surgery delayed 6 to 12 weeks (delayed surgery) (4). In patients with severe concurrent medical conditions that significantly increase the risks of illness and death of surgery, percutaneous tube cholecystotomy can be an appropriate temporizing measure (15).

Acute Acalculous Cholecystitis Acute acalculous cholecystitis refers to acute inflammation of the gallbladder in the absence of gallstones and accounts for 2% to 15% of all cases of acute cholecystitis (1) and 5% to 10% of all cholecystectomies done in the United States. In Western industrialized countries, most cases of acalculous cholecystitis are seen in critically ill patients and after any surgery. Acalculous cholecystitis can also occur in children, outpatients (especially elderly with underlying vascular disease), bone marrow transplant patients, patients with vasculitis syndromes, as well as AIDS patients (16). Additionally, patients with AIDS can develop acalculous cholecystitis as a result of infection with many organisms, including cytomegalovirus, Cryptosporidium species, and microsporidia (17). As a group, patients with acalculous cholecystitis tend to be older men (c.f. acute calculous cholecystitis).

Pathogenesis and Bacteriology In most cases of acalculous cholecystitis, the gallbladder mucosa is injured by ischemia in combination with bile stasis. A disturbed microcirculation

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plays a critical role and is caused by hypoperfusion in critically ill patients or by vascular insufficiency in patients with vasculitis or atherosclerosis. Bile stasis occurs in fasting patients because the gallbladder does not receive a cholecystokinin stimulus to empty itself. As in calculous cholecystitis, inflammatory mediators such as prostaglandins and Hageman factor promote further injury in acalculous cholecystitis. The bacteria that secondarily infect the gallbladder in this condition are similar to those seen in calculous cholecystitis, but anaerobic flora are more commonly seen. As noted previously, Candida species have been associated with occasional cases of acalculous cholecystitis (7). Rare cases of acalculous cholecystitis have been associated with various illnesses, including typhoid fever and leptospirosis.

Clinical Manifestations Although acute acalculous cholecystitis can have a presentation similar to that of calculous cholecystitis, the presentation is more often subtle, owing to the preponderant occurrence of the disease in elderly and postoperative or critically ill patients. RUQ tenderness is initially absent in three fourths of cases. Acalculous cholecystitis should always be considered when unexplained fever, leukocytosis, or hyperamylasemia occurs in a critically ill or postoperative patient. Delays in diagnosis contribute to the much higher rates of gangrene and perforation seen in acalculous cholecystitis compared with calculous cholecystitis; death rates are also higher in the former disease (10%-50% vs. 1%).

Diagnosis The fulminant course of the disease and its high death rate make an early diagnosis crucial, thus a high index of suspicion for this illness is needed in patients at risk for it. Mildly increased amylase, alkaline phosphatase, or aminotransferase activities can be seen but are nonspecific. Ultrasonographic findings are similar to those in calculous cholecystitis (i.e., a gallbladder wall thickened to >4 mm in the absence of ascites or hypoalbuminemia, pericholecystic fluid collection, and a sonographic Murphy sign). The sensitivity of ultrasonography for detection of acute acalculous cholecystitis ranges from 67% to 92%, and its specificity is greater than 90% (18). CT scanning is also useful for detecting acalculous cholecystitis. Radionuclide scintigraphy is of limited use in most cases owing to the high incidence of false-positive tests caused by viscous bile in fasting, critically ill patients.

Management Antibiotic coverage for patients with acalculous cholecystitis should include aerobic gram-negative organisms and anaerobes. Urgent surgical intervention is needed because of the high risk of progression to gangrene or perforation.

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Open cholecystectomy is the preferred procedure in most cases. Surgical or percutaneous cholecystotomy coupled with antibiotics have been used successfully as definitive therapy in patients at high surgical risk and it has been shown to obviate the need for cholecystectomy. For those who cannot tolerate the percutaneous approach, a novel technique of transpapillary endoscopic cholecystectomy can be considered.

Prevention In patients who receive total parenteral nutrition, the use of intravenous cholecystokinin to promote gallbladder contraction has been shown to reduce the formation of gallbladder sludge, which is a risk factor for acalculous cholecystitis (19). Daily cholecystokinin administration in critically ill patients has been proposed as a means of preventing acalculous cholecystitis. The effectiveness of this measure has not been established.

Cholangitis The term cholangitis refers to inflammation of the biliary ducts, which can be caused by infection, induced iatrogenically, or mediated immunologically (e.g., primary sclerosing cholangitis). A wide variety of infectious agents have been associated with cholangitis, including bacteria, parasites, viruses, and fungi. This chapter focuses primarily on acute bacterial cholangitis.

Pathogenesis and Bacteriology The central event in the pathogenesis of acute cholangitis is biliary obstruction and stasis caused by calculi or benign strictures. Cholangitis occurs much more commonly in patients with biliary obstruction from gallstones or strictures than in patients with malignant obstruction. In 80% to 90% of cases, a gallstone obstructs the CBD (4). In most of the remaining cases, obstruction of the CBD is caused by malignancy, biliary strictures, or instrumentation. Rare cases are caused by congenital abnormalities of the bile ducts, parasites, or sclerosing cholangitis. Chronic obstruction results in increased bile stasis, which promotes growth of the bacteria that colonize the bile ducts, and raises the intraluminal pressure, which promotes entry of these organisms into the bloodstream. Bacteria invade the biliary tract by ascension from the duodenum and only rarely by means of the hepatic portal venous blood. The mechanisms of entry are complex and involve breakdown of several host defense mechanisms (hepatic tight junctions, Kupffer cells, bile flow, IgA production). Culture of bile, stones, or biliary tract stents are positive in more than 90% of patients, yielding a mixed growth of gram-positive and gramnegative bacteria. Most commonly isolated are bacteria of colonic origin that

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mirror those associated with bacterial colonization of the biliary tree and that seen with acute cholecystitis: E. Coli (25%-50%), Klebsiella (15%-20%), and Enterobacter species (5%-10%). The most common gram-positive are Enterococcus species (10%-20%) (2). Anaerobic bacteria (Bacteroides and Clostridia) are cultured from bile in up to 40% of cases of cholangitis, usually as part of a polymicrobial infection. Infections are often polymicrobial. Positive blood cultures are seen in approximately 50% of cases of cholangitis; in most such cases, gram-negative rods are isolated. In hospitalized patients or in those who have undergone instrumentation of the biliary tract, infection with more resistant organisms is common, as is the recovery of anaerobes. Ascending cholangitis is also the most common infectious complication of endoscopic retrograde cholangiopancreatography (ERCP) and frequently seen because of occluded stents. This intervention can introduce intestinal flora into the biliary tract and promote the dissemination of bile bacteria through the blood (20). Postprocedural biliary tract sepses in this setting are caused by incomplete drainage of an infected biliary system. The most frequent organisms responsible for cholangitis/sepsis are enteric bacteria; blood cultures usually yield single organisms. Nosocomial infections with Pseudomonas aeruginosa seen in the past caused by ERCP equipment contamination are now rare.

Clinical Manifestations Acute cholangitis has a wide range of clinical presentations, from a mild illness that can be self-limiting to a fulminant illness with septic shock (4,21). The classic clinical presentation of cholangitis includes Charcot triad of fever and chills, jaundice, and RUQ pain; however, the complete triad is seen in only 70% to 85% of patients. Fever occurs in more than 90% of cases. Jaundice is seen in 60% to 80% of cases. Abdominal pain is described by approximately 70% of patients but can be mild and is not always localized to the RUQ. Elderly or debilitated patients can present only with fever or altered mental status as an indication of illness. In contrast with acute cholecystitis, cholangitis is seen as often in men as in women.

Differential Diagnosis The differential diagnosis of cholangitis includes the same previously discussed entities in the differential diagnosis of cholecystitis (see Table 9-1) as well as other illnesses associated with fever and jaundice. The abdominal pain associated with cholangitis is often less severe than that of acute cholecystitis, whereas fever and other signs of systemic illness are often more pronounced. Liver abscess must be considered in the differential diagnosis of cholangitis but also can occur concurrently as a complication of cholangitis. Jaundice associated with sepsis caused by gram-negative or gram-positive bacteria (i.e., the hepatopathy of sepsis or hyperbilirubinemia of sepsis) also

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must be considered in the differential diagnosis. In cholangitis, systemic infection results in increased serum levels of conjugated bilirubin caused by a defect in the excretion of conjugated bilirubin from hepatocytes (22). Other infectious diseases associated with fever and jaundice (e.g., viral hepatitis, malaria, babesiosis, leptospirosis, typhoid fever) must be considered if relevant risk factors are present.

Diagnosis Routine testing typically reveals leukocytosis with left shift and a cholestatic pattern of liver function tests with elevation of alkaline phosphatase, gammaglutamyl transferase, and bilirubin. Aminotransferase levels approaching 1000 IU/L suggest liver microabscess formation and necrosis of hepatocytes. The bilirubin level is increased in more than 80% of patients. A bilirubin level above 4 mg/dL suggests cholangitis rather than cholecystitis as a cause of fever and RUQ pain. In cholangitis, the sensitivity of ultrasonography for the detection of CBD stones is 50%, whereas it is 75% for the detection of dilated CBDs (4). The bile ducts may not be significantly dilated early in the illness and may never become dilated in patients with chronic inflammation related to sclerosing cholangitis or recurrent infection. Ultrasound should always be followed by ERCP. ERCP is the gold-standard procedure for the diagnosis of CBD stones, with both sensitivity and specificity of 95% (4). Additionally, this technique allows therapeutic drainage at the time of diagnosis. If the Charcot triad is present, the ERCP should not be delayed. Percutaneous transhepatic cholangiography is an alternative diagnostic technique to ERCP if the latter is unavailable or cannot be performed but is contraindicated in those with suppurative cholecystitis, because it can lead to sepsis. Recently, magnetic resonance imaging cholangiography has been shown to be as accurate in detecting CBD stones larger than 1 cm as ERCP. Its overall sensitivity exceeds 90% (23).

Treatment The management of acute cholangitis usually includes both decompression of the obstructed CBD and antibiotic therapy. Eighty percent of the patients with acute cholangitis respond to supportive measures and antibiotic therapy, allowing a delay of definitive surgical or radiologic procedures to relieve the obstruction until the acute illness is resolved. However, in 15% to 20% of the cases cholangitis does not alleviate after 12 to 24 hours of antibiotic therapy alone, thus requiring emergent decompression of the CBD. Indications for urgent biliary tract decompression include persistent abdominal pain, hypotension, confusion, and fever greater than 39ºC (102.2ºF). In recent years, endoscopic drainage techniques have become the initial procedure of choice in managing acute cholangitis. In a prospec-

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tive randomly assigned trial, initial endoscopic drainage for severe cholangitis caused by choledocholithiasis was associated with significantly lower illness (34% vs. 66%) and death (10% vs. 32%) than was initial surgical decompression (24). If emergent surgery is necessary in acute cholangitis, then a choledochotomy with T-tube placement is preferred over cholecystectomy with CBD exploration because it carries a lower death rate. When cholangitis is suspected, antibiotic therapy should be started promptly after blood specimens are drawn for culture. Initial antibiotic therapy should include an agent that is active against aerobic gram-negative rods, including E. coli and Klebsiella species. It is unclear whether antimicrobial activity directed against Enterococcus species and anaerobes is necessary in the initial management of patients with cholangitis. Anaerobes are unlikely in those without previous instrumentation of the biliary tract. Antibiotic agents with little or no activity against these organisms (e.g., ciprofloxacin) have been shown to be as effective in managing cholangitis as a ceftazidime/ampicillin/metronidazole regimen. No studies have shown that a particular antibiotic regimen is superior to others in the management of cholangitis (2). Our practice is to include coverage for Enterococcus species and anaerobes for most patients with moderate to severe illness. Preferred antibiotic choices for covering these organisms, in addition to gram-negative rods that include piperacillin–tazobactam, imipenem, ampicillin–sulbactam, are preferred over ampicillin in combination with metronidazole and an aminoglycoside or quinolone owing to their low potential for nephrotoxicity. Antibiotic therapy usually can be directed at specific organisms when the results of blood and biliary cultures are available. Antibiotic therapy for 7 to 14 days is usually recommended, but the duration of therapy is measured on the basis of the patient’s clinical course, adequacy of drainage, and the presence of bacteremia. REFERENCES 1. Chetlin SH, Elliott DW. Biliary bacteremia. Arch Surg. 1971;102:303-7. 2. van den Hazel SJ, Speelman P,Tytgat GN, Dankert J, van Leeuwen DJ. Role of antibiotics in the treatment and prevention of acute and recurrent cholangitis. Clin Infect Dis. 1994;19:279-86. 3. Namias N, Demoya M, Sleeman D, Reever CM, Raskin JB, Ginzburg E, et al. Risk of postoperative infection in patients with bactibilia undergoing surgery for obstructive jaundice. Surg Infect (Larchmt). 2005;6:323-8. 4. Bilhartz LE, Horton JD. Gallstone disease and its complications. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger and Fordtran’s gastrointestinal and liver disease, 7th ed. Philadelphia: WB Saunders; 2002:1019-1040. 5. Claesson BE, Holmlund DE, Mätzsch TW. Microflora of the gallbladder related to duration of acute cholecystitis. Surg Gynecol Obstet. 1986;162:531-5. 6. Morris AB, Sands ML, Shiraki M, Brown RB, Ryczak M. Gallbladder and biliary tract candidiasis: nine cases and review. Rev Infect Dis. 1990;12:483-9. 7. Diebel LN, Raafat AM, Dulchavsky SA, Brown WJ. Gallbladder and biliary tract candidiasis. Surgery. 1996;120:760-4; discussion 764-5. 8. Morrow DJ, Thompson J, Wilson SE. Acute cholecystitis in the elderly: a surgical emergency. Arch Surg. 1978;113:1149-52. 9. Mentzer RM, Golden CT, Chandler JG, et al. A comparative appraisal of emphysematous cholecystitis. Am J Surg. 1975;125:10-5. 10. Saini S. Imaging of the hepatobiliary tract. N Engl J Med. 1997;336:1889-94. 11. Kune GA, Burdon JG. Are antibiotics necessary in acute cholecystitis? Med J Aust. 1975;2:627-30.

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12. van der Linden W, Sunzel H. Early versus delayed operation for acute cholecystitis. A controlled clinical trial. Am J Surg. 1970;120:7-13. 13. McArthur P, Cuschieri A, Sells RA, Shields R. Controlled clinical trial comparing early with interval cholecystectomy for acute cholecystitis. Br J Surg. 1975;62:850-2. 14. Järvinen HJ, Hästbacka J. Early cholecystectomy for acute cholecystitis: a prospective randomized study. Ann Surg. 1980;191:501-5. 15. Yusoff IF, Barkun JS, Barkun AN. Diagnosis and management of cholecystitis and cholangitis. Gastroenterol Clin North Am. 2003;32:1145-68. 16. Savoca PE, Longo WE, Zucker KA, McMillen MM, Modlin IM. The increasing prevalence of acalculous cholecystitis in outpatients. Results of a 7-year study. Ann Surg. 1990;211: 433-7. 17. French AL, Beaudet LM, Benator DA, Levy CS, Kass M, Orenstein JM. Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases. Clin Infect Dis. 1995;21: 852-8. 18. Mirvis SE, Vainright JR, Nelson AW, Johnston GS, Shorr R, Rodriguez A, et al. The diagnosis of acute acalculous cholecystitis: a comparison of sonography, scintigraphy, and CT. AJR Am J Roentgenol. 1986;147:1171-5. 19. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet. 1990;170:25-31. 20. Westphal JF, Brogard JM. Biliary tract infections: a guide to drug treatment. Drugs. 1999;57:81-91. 21. Hanau LH, Steigbigel NH. Cholangitis: Pathogenesis, diagnosis, and treatment. Curr Clin Trop Infect Dis. 1995;25:153-78. 22. Miller DJ, Keeton DG,Webber BL, Pathol FF, Saunders SJ. Jaundice in severe bacterial infection. Gastroenterology. 1976;71:94-7. 23. Lee MG, Lee HJ, Kim MH, Kang EM, Kim YH, Lee SG, et al. Extrahepatic biliary diseases: 3D MR cholangiopancreatography compared with endoscopic retrograde cholangiopancreatography. Radiology. 1997;202:663-9. 24. Lai EC, Mok FP,Tan ES, Lo CM, Fan ST,You KT, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326:1582-6.

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Chapter 10

Viral Hepatitis HECTOR BONILLA, MD ARJUN VENKATARAMANI, MD, MPH

Key Learning Points 1. Hepatitis A is the commonest hepatitis infection in the US. 2. Hepatitis B can progress to malignancy in the absence of cirrhosis. 3. Hepatitis C infection rates are especially high in prison and HIV populations. 4. Hepatitis D infection cannot occur in the absence of chronic Hepatitis B infection. 5. Hepatitis E can be responsible for fulminant hepatitis in pregnant women.

T

he most common viruses associated with hepatitis are A, B, C, D, and E. In addition, other viruses such as Epstein-Barr virus, Cytomegalovirus, yellow fever, dengue fever, Lassa virus, Marburg virus, Ebola virus, and Rift Valley fever virus, are associated with hepatitis (1). This chapter discusses the various syndromes associated with the heterogeneous alphabetized group of viruses A through E. The virology, epidemiology, transmission, and treatment of hepatitis A through E viruses covered in this chapter are summarized in Table 10-1. According to the Centers for Disease Control (CDC), in 2003 there were an estimated 130,000 cases of infection with hepatitis A, B, and C in the United States. Most of the cases were caused by hepatitis A virus (HAV) infection (2). Chronic viral liver disease, reported only with the B, C, and D viruses, is now the leading cause of cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation. More than 4 million Americans are infected with the hepatitis C virus (HCV), and more than a million are chronically infected with the hepatitis B virus (HBV). 185

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New Developments in the Management of Viral Hepatitis ●

●

Newer nucleoside analogs hold promise for suppression and possible eventual clearance of hepatitis B infections. Specification of genotypes will be increasingly important in predicting the clinical course and response to therapy in hepatitis C infections.

Table 10-1 Hepatitis Virology, Epidemiology, and Treatment for A-E Viruses Incubation (days) Transmission

Virus

Type

A

Picornavirus ssNA (+)

B

Hepadnavirus 30-180 dsDNA

C

Flavivirus ssRNA (+)

15-150

D

Deltaviridae ssRNA (−)

Few weeks

E

Caliciviridae ssRNA (+)

15-45

Contaminated food Raw fish, green onions (fecal-oral) IDU, blood/ blood products Needlestick, sex, etc. IDU, blood/ blood products, needlestick IDU, blood/ blood products Contaminated water (fecaloral)

History

Chronic Treatment Infection of Infection

Childcare, No Supportive household care exposure, travel to endemic areas Promiscuous, 5%-10% INF, PEGMSM INF, lamivudine adefovir, entecavir Promiscuous, 70%-90% INF, PEGMSM INF/ Ribavirin Promiscuous, 50% MSM

INF

Travel to endemic area

Supportive care

No

Abbreviations: IDU, intravenous drug use; INF, interferon; MSM, men who have sex with men; PEG-INF, pegylated interferon; PEG-INF.

Hepatitis A The hepatitis A virus (HAV) is a single (+) stranded nonenveloped RNA virus, genus Herpetovirus and belonging to the Picornaviridae family. Seven genotypes have been identified, but only one serotype has been associated with human disease (3-5). Certain nucleotide changes in the HAV genome have been associated with more severe disease (6).

Epidemiology Hepatitis A is the major cause of hepatitis in the United States. In 2003, the CDC estimated approximately 61,000 new cases of HAV infection in the United States. Approximately 6% of these cases are caused by travel to

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developing countries. Almost 40% of Americans have antibody evidence of past HAV infection. Historically, Native Americans, Alaskan natives, and Hispanics are the ethnic groups with the highest incidence of HAV infection (2). Approximately 100 deaths from fulminant HAV infection occur annually. The risk of death increases with age and with coexistent liver disease. The route of transmission is predominantly fecal-oral (food or water contamination) with an incubation period of 30 days (range of 15-60 days). After oral ingestion, HAV crosses the gastrointestinal mucosa and replicates in liver cells. It is excreted through bile into the gastrointestinal tract (7). Its lack of an envelope can make HAV more stable in bile. It can be excreted in feces 2 weeks before any clinical illness becomes apparent and for another 2 weeks after the onset of jaundice (8). Therefore, the peak of infectivity of HAV occurs 2 weeks before the onset of jaundice or elevation of the aminotransferases. HAV can survive and remain infectious for 3 to 10 months in water. The course of disease is shown in Figure 10-1.

Clinical Manifestations The spectrum of the disease varies from severe acute illness to asymptomatic disease (9). Most children younger than 5 years of age have asymptomatic infection. Characteristically HAV has an abrupt onset of symptoms that include fever, malaise, anorexia, abdominal discomfort, dark urine, and jaundice. The severity of the symptoms increases with increasing age (jaundice occurs in 10% of children younger than 6 years of age, 40% to 50% in older children, and 70% to 80% in adults) (10).

Clinical illness

Infection

ALT

Response

IgM

IgG

Viremia

HAV in stool

0

1

2

3

4

5

6 Week

7

Figure 10-1 Clinical course of hepatitis A infection.

8

9

10

11

12

13

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HAV can present as a fulminant hepatitis in less than 0.1% of the cases, with a fatality rate greater than 50%, as a cholestatic hepatitis with the persistent high levels of bilirubin, or as a relapsing hepatitis manifested by elevation in the aminotransferases that can occur weeks or months after recovery (10).

Diagnosis and Treatment HAV presents with a rapid elevation in the serum aminotransferases during the prodromal phase followed by elevation in bilirubin levels. Serologic tests are diagnostic. A HAV-positive IgM is almost always found at clinical presentation and can remain positive for several months. Development of the antibody leads to abatement of the clinical illness and infectivity (Table 10-2). The presence of the antibody leads to lifelong protection against reinfection. HAV-specific IgG can be used to test for past exposure, need for vaccination, and ongoing protection against the virus. There is no specific treatment of HAV; supportive care only is indicated.

Prevention Proper food handling and good agricultural and food processing practices are recommended by the Food and Drug Administration (FDA), and the adherence to the current CDC guidelines for viral hepatitis should be universally implemented to prevent outbreaks of hepatitis A (11). Prevention is also possible through passive or active immunization. Prophylaxis with a single dose of immunoglobulin (IG) at 0.02 mg/kg is recommended after exposure to HAV from close personal or household contacts of index cases. The use of IG is 80% to 90% effective in preventing acute clinical hepatitis. Vaccination is recommended for preexposure protection against HAV in trav-

Table 10-2 Antibodies in Viral Hepatitis (A-E) Stage of Infection Virus Type

Acute

Chronic

Resolved

A B

Anti-HA IgM + Anti-HBc IgM +

C

Anti-HCV +*

D

HBsAg + Anti-HD IgM + HD RNA + Anti-HE IgM +

– HB DNA + Anti-c IgG Persistent HCV RNA Persistent HD RNA +** HBsAg –

Anti-HA IgG + HB DNA − Anti-c IgG + HCV RNA − Anti-HCV + HD RNA −

E

Anti-HE IgG +

* Could be negative during acute infection. RNA viral is positive 1 to 2 weeks after exposure and antiHCV is positive 7 weeks after exposure. ** Both HDV IgG and IgM can be present Abbreviations: anti, antibody; HA, hepatitis A; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HD, hepatitis D; HE, hepatitis E; IgM, immunoglobulin M.

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Table 10-3 Vaccines and Dosing Schedules Vaccine

Hepatitis A vaccine Havrix Vaqta Hepatitis B vaccine Engerix-B Recombivax HB Hepatitis A/B vaccine Twinrix

Dose

Dosing Schedule

1,440 ELISA units 50 U

2 doses 6 to 12 months apart 2 doses 6 to 12 months apart

20 Ug 10 Ug

3 doses at 0, 1, and 6 months 3 doses at 0, 1, and 6 months

720 ELISA U/20 Ug

3 doses at 0, 1, and 6 months

Abbreviation: ELISA, enzyme-linked immunoabsorbent assay.

elers to endemic areas that include Mexico, Central and South America, Africa, and southern parts of Asia and Greenland; in the United States the highest incidence of hepatitis A has been reported on the West Coast. Also vaccination has been recommended in sexually active homosexual men, injection drug users, persons with preexisting liver disease, and health care workers. Infants should also be universally vaccinated. Two inactivated (formalin-killed) vaccines (Havrix or Vaqta) are available (Table 10-3). These two vaccines are highly immunogenic. Approximately 100% of the vaccines develop protective antibodies within 1 month after the first dose, and protective levels can persist for at least 20 years. Therefore postvaccination testing is not recommended. In 2001 the FDA approved the combined hepatitis A and hepatitis B vaccine (Twinrix) for persons older than 18 years of age who need both vaccines. The vaccination schedule is 0, 1, and 6 months with a similar immunogenicity of the single hepatitis vaccine (A or B) (10).

Hepatitis B The hepatitis B virus (HBV) is a member of the Hepadnaviridae family. These viruses are double-stranded DNA viruses with lipid envelope (12). Viral replication in hepatocytes is not cytopathic. In contrast, the specific T-cell host response to the many viral proteins causes hepatocellular damage. Eight different genotypes have been identified (A-H). The most prevalent genotypes in the United States are A and G (13-15). Preliminary data suggests that genotype B is associated with spontaneous seroconversion. Genotypes A and B respond better to interferon (INF) therapy, and genotype C is associated with hepatocellular carcinoma. However, the role of genotypes in the pathogenesis and response to therapy needs further study (16-19). HBV serologies are based on the detection of antigens and antibodies to specific parts of the virus including the surface, envelope, and core. Two strains of HBV have been identified; one that produces hepatitis B early antigen (HBeAg) and the other that does not produce HBeAg, also

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called the core-mutant strain. This hepatitis B virus mutant is associated with either progressive or fulminant cases of HBV (20).

Epidemiology Worldwide, approximately 2 billion people have been infected with HBV; 350 million people experience chronic infection, and 500,000 to 1.2 million cases result in death each year. The problem is especially acute in sub-Saharan Africa, East Asia, and China (21). The CDC reports approximately 1.2 million people in the United States have chronic HBV infection. Approximately 73,000 acute cases were identified in 2003 (22). The highest incidence is in the South, and the lowest is in the Midwest. The incidence of HBV has declined by 67% since the 1980s, presumably because of routine vaccination in children and adolescents. The risk factors for transmission include injection drug use (IDU), sexual contact (especially multiple sex partners or men who have sex with men [MSM]), vertical transmission (from mother to child), and unvaccinated health workers. Blood transfusions and repeated use of hypodermic needles continue to be another source of infection in some developing nations The chronically infected individual with HBV has a 100 times greater risk for HCC (23),especially when both hepatitis B surface antigen (HBsAg) and HBeAg are positive (24). Therefore, it is very important these individuals be screened for evidence of HCC by doing imaging studies of the liver and measuring the alpha-fetoprotein (tumor marker) twice a year (25). Also, HBV coinfection with HCV or hepatitis delta virus (HDV) leads to a greater incidence of cirrhosis and HCC (26).

Clinical Manifestations HBV can cause both an acute and a chronic infection. The acute illness can be asymptomatic. The classic features of malaise, fatigue, anorexia, and nausea followed by jaundice, dark urine, and pale stools occurs after an incubation period of 45 to 160 days. A serum sickness–like illness (maculopapular rash, arthralgias, and fever) precedes clinical hepatitis in a minority of patients. Findings on examination include jaundice, tender hepatomegaly, splenomegaly, and lymphadenopathy. The clinical illness typically lasts 1 to 2 months but can last longer. Children usually have asymptomatic infection or a mild illness. Occasionally, the acute hepatitis can be prolonged or can take a relapsing course. Rarely, a fulminant fatal hepatitis occurs (12). Chronic infection occurs in 1% to 20% of cases after an acute infection. Infection early in life or in the context of an immunosuppressed state is a clear risk factor for chronic infection. In chronically infected adults, serious complications such as cirrhosis and HCC can develop. Extrahepatic manifestations of chronic HBV infection include membranous glomerulonephritis, vasculitis, and polyarteritis nodosa (27).

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Diagnosis Acute HBV infection is characterized by elevated aminotransferases and bilirubin, a positive HBsAg, IgM against the HBV core (HBcIgM), HBeAg, and active viremia measured by commercially available HBV-DNA assays (Figure 10-2). The hepatitis B infection is a dynamic process that can proceed as follows (28), shown in Table 10-4. Serology in chronic HBV is illustrated by Figure 10-3.

Treatment The goal of therapy is to prevent progression of liver disease to cirrhosis and HCC by suppressing the virus to the lowest possible level. Before making a decision to initiate therapy for hepatitis B, the following three variables need to be considered: 1. Alanine aminotransferase (ALT) levels 2. HBV-DNA copies/mL 3. The HBeAg status Therapy is indicated for patients with positive HBeAg, elevated ALT, and HBV-DNA viral loads greater than 105 copies/mL and for patients with negative HBeAg with elevated ALT and HBV-DNA viral load greater than 104 copies/mL (29). In the cases where ALT is normal a liver biopsy needs to be considered before initiation of HBV therapy (28). Decompensated cirrhosis is not a contraindication to therapy with nucleoside analogs and is almost an urgent indication for institution of therapy.

Symptoms HBeAg

anti-HBe

Titer

Total anti-HBc

0

4

anti-HBs

IgM anti-HBc

HBsAg

8

12 16 20 24 28 32 36

52

100

Weeks after Exposure Figure 10-2 Typical serologic course of acute hepatitis B infection with recovery.

+ + − −

+

+ +

+

I. Immune-Tolerance

II. Immune-Active III. Inactive-Carrier

IV. Reactivation

+

− +

−

Anti-HBe

>105 Copies (fluctuating) Nondetected low levels + (fluctuating)

>10

5 Copies

HB-DNA

50-200 U/L

50-200 U/L Normal

Normal

ALT

Chronic hepatitis Mild/moderate hepatitis-fibrosis Active hepatitis

Normal

Biopsy

Vertical transmission, low risk HCC and cirrhosis Higher risk HCC and cirrhosis May persist inactive indefinitely Occur after inactive-carrier

Comment

Source: Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: What we knew in 1981 and what we know in 2005. Hepatology. 2006;43S(1):S173-81. Abbreviations: ALT, alanine aminotransferase; HB, hepatitis B; HBe, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma.

HBe Ag

HBs Ag

Phase

192

Table 10-4 Clinical Phases of Chronic Hepatitis B

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Acute (6 months)

193

Chronic (Years) HBeAg

anti-HBe HBsAg

Titer

Total anti-HBc

IgM anti-HBc

0 4 8 12 16 20 24 28 32 36

52

Years

Weeks after Exposure Figure 10-3 Typical serologic course of hepatitis B infection in progression from acute to chronic infection.

Pegylated interferon alfa, and nucleoside analogs such as lamivudine (Epivir), adefovir (Hepsera), and entecavir (Baraclude) are all currently FDAapproved drugs for initial therapy for HBV. Lamivudine therapy is ideal for initiation because of the lack of side effects, availability, and lower cost. However, the high rate of development of resistance (YMDD mutant) with prolonged use of lamivudine has led to recommendations for the use of adefovir or entecavir for at least 48 weeks. The doses of these last two nucleoside analogs must be adjusted according to the individual’s renal function. Therapy with pegylated INF is limited by the many physical, psychological, and hematological side effects. It is likely that combination therapy (nucleoside analogs with INF) will be the mainstay in the future treatment of HBV infection, but this remains to be confirmed by extensive studies (28,30). Decompensated cirrhotic patients who do not respond to nucleoside analogs need to be considered for liver transplantation. Post-transplant immunoprophylaxis with HBV-specific immunoglobulin (HBIG) is necessary. Results of therapy with nucleoside analogs in this population are very encouraging.

Prevention The best form of prophylaxis against HBV is immunization. Candidates for vaccination include all infants and children younger than 19 years of age, adults in high-risk groups that include multiple sex partners or sexually transmitted diseases (STDs), MSM, IDU, incarcerated persons, sexual contact with someone with chronic hepatitis B, health care workers with blood exposure in the workplace, hemodialysis patients (31), and patients with

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other chronic liver diseases. However there has been a trend toward universal HBV vaccination. A routine course of three injections of recombinant hepatitis B vaccine, Engerix-B or Recombivax, (scheduled at 0, 1, and 6 months) provides immunity in 90% to 95% of cases (see Table 10-3). Postvaccination testing of people at high risk for HBV infection is worthwhile to determine appropriate prophylaxis if an exposure occurs. For those nonresponders to a primary vaccination a new series of the vaccine in the deltoid area is recommended. Booster doses of HBV vaccine have not been recommended for healthy adults or children with normal immune status, but recommended for hemodialysis patients. The need for a booster dose in these individuals should be considered when the antibody level declines below 10 mIU/mL (10). Decreased exposure to a known risk factor for HBV is also crucial in preventing the disease. HbsAg-positive health care workers (HCWs) need to adopt universal precautions; actively viremic HCWs should not be allowed to do invasive procedures. The two most commonly encountered clinical situations in which passive immunization against HBV are indicated are vertical transmission and needlestick injury. In the case of vertical transmission, the combination of active and passive immunization provides approximately 95% protection. HBIG in a dose of 0.5 mL should be given to the neonate in the delivery room, and active vaccination should begin within a week of delivery. In cases of known nosocomial exposure of unimmunized or nonimmune people, the recommended dose of HBIG is 0.06 mL/kg within 48 hours of exposure; again, active immunization should be given concurrently (30,32).

Hepatitis C HCV is an enveloped single-stranded RNA virus of the Flaviviridae family. There are six major genotypes and many subtypes of HCV. Genotype 1 is the most common in the United States. Additionally, variants referred to as quasispecies develop in individual patients. It is hypothesized that the development of quasispecies are associated with chronic infection and resistance to therapy (32).

Epidemiology The estimated prevalence of HCV infection in the world is 2% to 3%. Approximately 123 million people are infected with HCV (33). According to the CDC, the prevalence in the United States is approximately 1.8% of the population representing 3.9 million cases. Sixty-five percent of the afflicted individuals are between the ages of 30 to 49 years (34). More than 80% of patients infected with HCV develop chronic infection, which can lead to cirrhosis in 20% and HCC in 1% overall (35).

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In 2003 the CDC estimated 4900 cases of clinical symptomatic acute hepatitis C and 30,000 new infected cases (2). The genotype 1 was present in 73.7% of the infected population. The strongest risk factors associated with HCV infection were illegal drug use and high-risk sexual behavior. However, other methods of transmission include tattoos, body piercing, and needlestick injury. Breast-feeding does not seem to be a risk factor. The risk of sexual transmission of HCV is estimated at 5% over a 10- to 20-year period. The risk of vertical transmission is slightly lower. However, in approximately 30% of patients, a convincing risk factor is not identified (34,35). In the U.S. correctional system it has been estimated that 39% of its population has HCV infection. In the human immunodeficiency virus (HIV) population, the prevalence of coinfection HIV/HCV is on average 35% (36). Worldwide, contaminated equipment and syringes seem to be the major risk factor for HCV infection (33).

Clinical Manifestations After acute HCV infection, clinical manifestations can appear after 7 to 8 weeks of exposure with either mild symptoms (malaise, nausea, or vomiting) or no symptoms at all and in very rare cases fulminant hepatitis (23). Transition to chronic hepatitis is the usual pattern. Chronic hepatitis is usually asymptomatic or associated with nonspecific symptoms. Besides the clinical manifestations associated with liver disease (cirrhosis or HCC), HCV can present with several extrahepatic manifestations that include cryoglobulinemia (37), membranoproliferative glomerulonephritis, cognitive dysfunction, non-Hodgkin lymphoma, sicca syndrome, porphyria cutanea tarda, and lichen planus (38-44). Approximately 15% to 20% of the chronic infected cases develop hepatitis and some degree of fibrosis and cirrhosis, HCC, and death (31,32). The median time of progression to cirrhosis in untreated HCV infection is 30 years (13 years for men and 42 years for women after infection). Factors that increase the rate of progression of fibrosis are age older than 40 years, alcohol use (greater than 50 g/day), male gender, and coinfection with HBV or HIV infection (45).

Diagnosis The diagnosis of hepatitis C is based on detection of antibodies by enzyme immunoassay against viral antigens (46). These serologies do not distinguish acute from chronic or active from resolved disease and must be interpreted in the context of the overall clinical picture. Consequently, the determination of the HCV RNA, either qualitatively or quantitatively by polymerase chain reaction (PCR) confirms the diagnosis of HCV infection (47). However, the magnitude of the viral load does not correlate with progression of HCV but does correlate with the response to therapy (48).

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Newer generation PCR tests have reduced the lower limit of detection to well below 100 copies per mL (47,48). The value of serum ALT is limited by the fact that it can be normal in up to 60% of infected patients (49). The HCV genotype is an integral part of the workup that should be done before instituting therapy because the genotype can predict the response and duration of therapy. For example, genotypes 2 and 3 have a higher likelihood of response and require a shorter course of IFN/ribavirin therapy (6 months vs. 12 months for the other genotypes) (50). Liver biopsy is considered the gold standard in evaluation of the activity (inflammation) and stage (fibrosis) of the liver disease (51). Because of complications associated with biopsy and sampling error (52), alternatives to liver biopsy have been proposed such as the use of biochemical markers for fibrosis and necrosis (alpha-2 macroglobulin, haptoglobulin, gamma-glutamyl transpeptidase [GGT], total bilirubin, apolipoprotein A and ALT) also called the Fibrospect II test (fibrosis marker) and Acti test (necrosis marker). The accuracy of these markers needs to be validated in different study populations (53,54).

Treatment The treatment of choice for chronic HCV infection is the combination of weekly subcutaneous pegylated IFN and daily oral ribavirin. Studies have shown sustained response (defined as absence of virus 6 months after cessation of a standard course of therapy) to be 42% to 46% for genotype 1infected patients and 76% to 82% in cases involving genotypes 2 and 3 (50). For genotype 1-infected patients, the duration of therapy is 48 weeks. The HCV-RNA PCR is quantitatively measured before and 12 weeks into therapy. If the patient does not demonstrate early virologic response (defined as undetectable viral load or at least a two-log decrease in the viral load), therapy is usually discontinued at this point. The daily dose of ribavirin is weight based (1200 mg in patients weighing more than 75 kg [165 lb], 1000 mg in patients between 70-75 kg [154-165 lb], and 800 mg or less in patients weighing less than 70 kg [154 lb]). In genotypes 2 or 3, the duration of therapy is only 24 weeks. Unfortunately, therapy is fraught with physical, psychological, and hematological side effects that can lead to dose reduction or adjunctive therapy with hematologic growth factors. Therapy is unsafe in patients with decompensated cirrhosis and should be offered only through research protocols. HCV-related cirrhosis is the most common reason for liver transplantation in the United States. Unfortunately, recurrence is universal (50). As noted, the genotype predicts the response and duration of HCV therapy (response rate is higher and shorter for genotypes 2 and 3). However, all genotypes can be associated with cirrhosis and HCC (50). Studies done in African American populations treated with IFN and ribavirin have shown lower rates of response to treatment when compared to

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non-Hispanic white patients, a difference that cannot be explained by the genotype distribution alone (55).

Prevention The principles of prophylaxis for HCV infection are similar to those for HBV infection. The sheer number of subtypes and quasispecies complicates development of vaccines. To date there is no effective vaccine or postexposure prophylaxis available. Therefore, primary prevention to decrease the risk of contracting the infection to reduce liver disease should be advised (needle-exchange programs, HAV and HBV vaccination where indicated, reduced alcohol use, etc.). Secondary prevention (counseling patients about their infectivity) is mandatory and should include advice about sharing toothbrushes, razors, nail clippers, and hypodermic needles (30). Protected sexual intercourse is not necessary in the context of a monogamous relationship (10,56). In acute hepatitis C infection, the use of IFN has been shown to be effective by clearing the infection in 98% of the cases (57).

Hepatitis D HDV is a defective small-RNA virus belonging to the delta family. HDV is a chimera that contains RNA and enveloped proteins consisting of HDV antigen and HBsAg. Three different genotypes have been identified with a geographic distribution; genotype 1a is the predominant strain in the United States. The HDV infection can occur as a superinfection (HBV infection predates HDV) or as a coinfection of both viruses. There is no evidence of replication of HDV outside the liver (58).

Epidemiology Geographical distribution of this virus is broad and includes southern Italy; Okinawa, Japan; Northern India; China; Albania; the Sahara; European Russia; and parts of South America (59,60). In the United States, more than 10,000 new infections occur annually, and a few acute infections are fatal. Additionally, approximately 1000 people die annually in the United States from chronic HDV infection. The parenteral route, which is the most efficient way of transmission of HDV, leads to a high incidence rate in injection drug users and hemophiliacs. Sexual transmission has been documented (58,61,62).

Clinical Manifestations The clinical manifestations of acute HDV infection are similar to other types of hepatitis ranging from subclinical to fulminant hepatitis. Acute HDV

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infection can occur as a coinfection (HBV/HDV) that resolves in 95% of the cases or as a superinfection (after HBV infection) that often has a more severe course leading to a chronicity in 70% of the cases. The chronic HDV infection is defined by the presence of IgG anti-HDV antibody, the increase of IgM anti-HDV titer and persistent HDV RNA in blood samples. These chronically infected HDV patients have a faster progression to cirrhosis than those with HBV infection alone eventually requiring liver transplantation. HCC is another complication of chronic HDV infection, and the rate is approximately 40%, which is similar to patients with cirrhosis and chronic HBV infection (58).

Diagnosis During the acute HDV infection, serological markers such as HDV-RNA levels and HDV antigen can be detected (36). During the primary HDV infection, there are increased titers of the IgM antibody that declines in a few weeks followed by an IgG antibody response. The diagnosis of coinfection (HBV/HDV) is made by detection of IgM antibody against HBcAg, HBeAg, and anti-HBe antibody and IgM anti-HDV (Figure 10-4). In contrast, superinfection is diagnosed by the presence of chronic hepatitis B [HBsAg (+), IgG anti-HBc antibody and anti-HBe antibody], superimposed by acute HDV infection (anti-HDV IgM and HDV RNA) (58). The HDV test should be considered in patients who present with acute hepatitis, excluding acute viral hepatitis A, B, and C, such as HAV IgM (−), HBc IgM (−), HCV antibody (Ab) (−), and HBsAg (+).

Symptoms

Titer

ALT Elevated Anti-HBs IgM anti-HDV

HDV RNA HBsAg

Total anti-HDV

Time after Exposure

Figure 10-4 Typical serologic course in HBV-HDV coinfection.

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Treatment Therapy for HBV should be effective in the sense that it eliminates the infection that is essential for HDV to survive and replicate. IFN is the only licensed drug for treatment of chronic HDV infection. In patients with liver failure, liver transplantation is an option with excellent survival rates (62,63).

Prevention The principles of prophylaxis for HDV infection are similar to those for HBV infection. HBV and HDV can be prevented by pre- and postexposure prophylaxis for hepatitis B and education to reduce the risk factors for superinfection (IDU and sexual contact) (10,30).

Hepatitis E The hepatitis E virus (HEV) is a single-stranded, nonenveloped, RNA virus that belongs to the Calciviridae family. HEV has been classified in four major genotypes (1, 2, 3, and 4) (59,64).

Epidemiology HEV spreads by means of the fecal-oral route. Outbreaks of hepatitis E have been associated with contaminated water. Several genotypes are identified with geographical distribution: genotype 1 in Asia and Africa; genotype 2 in Mexico, Nigeria, and Chad; genotype 3 in Asia, Europe, Oceania, North and South America; and genotype 4 exclusive from Asia (59). During the recent conflicts in Sudan and Iraq, several suspected cases of hepatitis E have been reported (65).

Clinical Manifestations The incubation period of HEV ranges from 15 to 60 days. The symptoms are similar to those of HAV and include fever, abdominal discomfort, jaundice, dark urine, and pale stools. Less commonly, diarrhea, arthralgias, and an urticarial rash develop. The disease is self-limited, but fulminant cases of HEV have developed in 10% of the women, especially during the third trimester of pregnancy (66). HEV is not associated with chronic hepatitis although preexisting chronic liver disease can be associated with more severe HEV disease.

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Symptoms IgG anti-HFV

ALT

Titer

IgM anti-HFV

Virus in stool 0

1

2

3

4

5

6

7

8

9

10 11 12 13

Time after Exposure Figure 10-5 Typical serologic course in hepatitis E infection.

Diagnosis and Treatment The diagnosis is made by serology (IgM antibodies), stool antigen detection, or by HEV genome amplification by PCR techniques (10,60). The serologic course of HEV is shown in Figure 10-5. No specific therapy has shown to be of benefit for HEV.

Prevention The prevention of HEV depends on the provision of clean water supplies. Individuals should avoid drinking water (also beverages with ice) of unknown purity, raw shellfish, and raw fruit and vegetables not peeled or prepared by traveler (10, 30). Research on vaccines for HEV is evolving.

REFERENCES 1. Sherlock S, Dooley J. Virus hepatitis. In: Sherlock S, Dooley J, eds. Diseases of the liver and biliary system. 10th ed. London: Blackwell Science; 1997:303. 2. Centers for Disease Control. Summary of notable diseases. United States. 2002. MMWR. 2003:51-3. 3. Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science. 1973;182:1026-8. 4. Sánchez G, Villena C, Bosch A, Pintó RM. Hepatitis a virus: molecular detection and typing. Methods Mol Biol. 2004;268:103-14. 5. Robertson BH, Khanna B, Nainan OV, Margolis HS. Epidemiologic patterns of wild-type hepatitis A virus determined by genetic variation. J Infect Dis. 1991;163:286-92. 6. Fujiwara K,Yokosuka O, Ehata T, Saisho H, Saotome N, Suzuki K, et al. Association between severity of type A hepatitis and nucleotide variations in the 5′ non-translated region of hepatitis A virus RNA: strains from fulminant hepatitis have fewer nucleotide substitutions. Gut. 2002;51:82-8.

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7. Mathiesen LR, Møller AM, Purcell RH, London WT, Feinstone SM. Hepatitis A virus in the liver and intestine of marmosets after oral inoculation. Infect Immun. 1980;28:45-8. 8. Menon KV, Zein NN. What do we need to know about non-A-to-E viral hepatitis? Curr Gastroenterol Rep. 2000;2:33-9. 9. Lednar WM, Lemon SM, Kirkpatrick JW, Redfield RR, Fields ML, Kelley PW. Frequency of illness associated with epidemic hepatitis A virus infections in adults. Am J Epidemiol. 1985;122: 226-33. 10. Centers for Disease Control. Hepatitis A-E, report of the division of viral hepatitis. Available at: www.cdc.gov/ncidod/diseases/hepatitis/slideset/slide_.htm. Accessed May 16, 2003. 11. Centers for Disease Control. Prevention of hepatitis A through active or passive immunization practices (AICIP). MMWR. 1999;48(RR12):1-37. 12. Robinson WS, Lutwick LI. The virus of hepatitis, type B (first of two parts). N Engl J Med. 1976;295:1168-75. 13. Summers J, O’Connell A, Millman I. Genome of hepatitis B virus: restriction enzyme cleavage and structure of DNA extracted from Dane particles. Proc Natl Acad Sci U S A. 1975;72:4597-601. 14. Kao JH. Hepatitis B viral genotypes: clinical relevance and molecular characteristics. J Gastroenterol Hepatol. 2002;17:643-50. 15. Kidd-Ljunggren K, Miyakawa Y, Kidd AH. Genetic variability in hepatitis B viruses. J Gen Virol. 2002;83:1267-80. 16. Chu CJ, Lok AS. Clinical significance of hepatitis B virus genotypes [Editorial]. Hepatology. 2002;35:1274-6. 17. Chu CJ, Hussain M, Lok AS. Hepatitis B virus genotype B is associated with earlier seroconversion compares with compare with hepatitis B virus genotype C. Gastroenterology. 2002;120: 1756-62. 18. Kao JH,Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J. Hepatology. 2000;33:998-1002. 19. Fujie H, Moriya K, Shintani Y, Yotsuyanagi H, Iino S, Koike K. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan [Letter]. Gastroenterology. 2001;120:1564-5. 20. Liu CJ, Kao JH, Lai MY, Chen PJ, Chen DS. Precore/core promoter mutations and genotypes of hepatitis B virus in chronic hepatitis B patients with fulminant or subfulminant hepatitis. J Med Virol. 2004;72:545-50. 21. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97-107. 22. Centers for Disease Control. Incidence of acute hepatitis B—United States, 1990-2002. MMWR. 2004;52:1252-4. 23. Farci P,Alter HJ, Shimoda A, Govindarajan S, Cheung LC, Melpolder JC, et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med. 1996;335:631-4. 24. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988;61:1942-56. 25. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology. 2001;34:1225-41. 26. Liaw YF, Chen YC, Sheen IS, Chien RN,Yeh CT, Chu CM. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology. 2004;126:1024-9. 27. French Vasculitis Study Group. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84: 313-22. 28. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004;2:87-106. 29. Chen G, Lin W, Shen FM, et al. Viral load as a predictor of liver disease in chronic hepatitis B infection. Hepatology. 2004;40:594 (abstract 996). 30. Centers for Disease Control. Guidelines for viral hepatitis surveillance and case management. Available at: www.cdc.gov. Accessed January, 2005. 31. Centers for Disease Control. Update: Recommendations to prevent hepatitis B virus transmission—United States. JAMA. 1999;281:790. 32. Centers for Disease Control. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the immunization practices advisory committee (AICP). MMWR. 1991;40(RR-13):1-19. 33. Shepard CW, Finelli L,Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558-67.

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Expert Guide to Infectious Diseases

34. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-62. 35. Seeff LB. Natural history of hepatitis C. Am J Med. 1999;107:10-15. 36. Verucchi G, Calza L, Manfredi R, Chiodo F. Human immunodeficiency virus and hepatitis C virus coinfection: epidemiology, natural history, therapeutic options and clinical management. Infection. 2004;32:33-46. 37. Horcajada JP, García-Bengoechea M, Cilla G, Etxaniz P, Cuadrado E,Arenas JI. Mixed cryoglobulinaemia in patients with chronic hepatitis C infection: prevalence, significance and relationship with different viral genotypes. Ann Med. 1999;31:352-8. 38. Tsukazaki N,Watanabe M, Irifune H. Porphyria cutanea tarda and hepatitis C virus infection. Br J Dermatol. 1998;138:1015-7. 39. Ramos-Casals M, Font J. Extrahepatic manifestations in patients with chronic hepatitis C virus infection. Curr Opin Rheumatol. 2005;17:447-55. 40. Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther. 2005;21:653-62. 41. Silvestri F, Pipan C, Barillari G, Zaja F, Fanin R, Infanti L, et al. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood. 1996;87:4296-301. 42. Zuckerman E,Zuckerman T,Levine AM,Douer D,Gutekunst K,Mizokami M,et al. Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med. 1997;127:423-8. 43. Fargion S, Piperno A, Cappellini MD, Sampietro M, Fracanzani AL, Romano R, et al. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology. 1992;16:1322-6. 44. Haddad J, Deny P, Munz-Gotheil C, Ambrosini JC, Trinchet JC, Pateron D, et al. Lymphocytic sialadenitis of Sjögren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet. 1992;339:321-3. 45. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825-32. 46. Vrielink H, Reesink HW, van den Burg PJ, Zaaijer HL, Cuypers HT, Lelie PN, et al. Performance of three generations of anti-hepatitis C virus enzyme-linked immunosorbent assays in donors and patients. Transfusion. 1997;37:845-9. 47. Beld M, Habibuw MR, Rebers SP, Boom R, Reesink HW. Evaluation of automated RNA-extraction technology and a qualitative HCV assay for sensitivity and detection of HCV RNA in poolscreening systems. Transfusion. 2000;40:575-9. 48. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-92. 49. Esteban JI, López-Talavera JC, Genescà J, Madoz P,Viladomiu L, Muñiz E, et al. High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus. Ann Intern Med. 1991;115:443-9. 50. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C. Hepatology. 2004;39:1147-71. 51. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24:289-93. 52. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614-8. 53. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (Fibro Test, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;23:3-8. 54. Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C, et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology. 2005;41:1376-82. 55. Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265-71. 56. Wejstål R. Sexual transmission of hepatitis C virus. J Hepatol. 1999;31 Suppl 1:92-5. 57. German Acute Hepatitis C Therapy Group. Treatment of acute hepatitis C with interferon alfa2b. N Engl J Med. 2001;345:1452-7.

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58. Smedile A, Ciancio A, Rizzetto. Hepatitis D virus. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical virology. 2nd ed. Herndon, VA: ASM Press; 2002:1227-40. 59. Lu L, Li C, Hagedorn CH. Phylogenetic analysis of global hepatitis E virus sequences: Genetic diversity, subtypes and zoonosis. Rev Med Virol. September 21, 2005. 60. Anderson DA, Shrestha. Chapter 48. In: Richman DD, Whitley RJ, Hayden FG, eds. Clinical virology. 2nd ed. Herndon, VA: ASM Press; 2002:1061-74. 61. Ponzetto A, Forzani B, Parravicini PP, Hele C, Zanetti A, Rizzetto M. Epidemiology of hepatitis delta virus (HDV) infection. Eur J Epidemiol. 1985;1:257-63. 62. Ciancio A, Ottobrelli A, Marzano A, et al. A long-term follow-up in patients treated with orthotopic liver transplantation (OLT) for hepatitis delta virus (HDV). J Hepatol. 2001;34:28. 63. Rosina F, Pintus C, Meschievitz C, Rizzetto M. A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study. Hepatology. 1991;13:1052-6. 64. Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE, et al. Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. Virology. 1991;185:120-31. 65. Emerson SU, Purcell RH. Running like water—the omnipresence of hepatitis E. N Engl J Med. 2004;351:2367-8. 66. Khuroo MS,Teli MR, Skidmore S, Sofi MA, Khuroo MI. Incidence and severity of viral hepatitis in pregnancy. Am J Med. 1981;70:252-5.

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Chapter 11

Peritonitis JENNIFER A. HANRAHAN, DO ROBERT A. BONOMO, MD

Key Learning Points 1. Spontaneous bacterial peritonitis (SBP) is the most common type of primary peritonitis, and usually occurs in the setting of liver cirrhosis. 2. SBP should be considered in any patient with ascites who experiences a clinical deterioration, and diagnostic paracentesis should be performed as soon as possible. 3. An ascitic fluid neutrophil count greater than 250 is considered indicative of infection even in the absence of positive cultures. 4. SBP and secondary peritonitis can be difficult to distinguish by history and physical exam, and management differs. 5. Initial antimicrobial therapy for SBP should be directed at enteric organisms. 6. Secondary peritonitis can be treated with a short course of antibiotics once adequate source control is obtained, unless there is persistent evidence of infection. 7. Peritonitis in the setting of peritoneal dialysis usually presents with cloudy dialysate fluid, and any change in the appearance of the fluid should be investigated.

P

eritonitis is the condition of acute or chronic inflammation of the abdominal cavity from any cause. It can result from diffuse or localized infection, chemical irritation, or malignancy and can be associated with an intra-abdominal infection such as an abscess. The cause of peritonitis differs depending on whether the infection is acquired in the health care setting or in the community, and by route of infection. Generally, peritonitis 204

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New Developments in the Management of Peritonitis • Prophylaxis for SBP is recommended for all cirrhotics with gastrointestinal

hemorrhage. The recommended antibiotic is norfloxacin 400 mg every 12 hours for at least 7 days. • Prophylaxis for SBP is also recommended for individuals with cirrhosis and a prior history of SBP. • Individuals with cirrhosis and ascites who have not had an episode of SBP are at high risk for developing peritonitis. However, those most likely to benefit from prophylaxis have not been clearly identified, and no consensus exists on whom should be offered prophylaxis in the absence of prior SBP. • Oral moxifloxcin 400 mg orally daily can be prescribed to those individuals with SBP who are not severely ill and can be managed as outpatients, provided that they have not had quinolone prophylaxis. This should be done after paracentesis is performed. • Ertapenem is a newer antibiotic that can be considered for community-acquired intra-abdominal infections.

can be divided into the three main categories of primary, secondary, and tertiary peritonitis. Primary peritonitis is a diffuse bacterial peritonitis that occurs in the absence of disruption of hollow viscera. An apparent source of infection is not evident in primary peritonitis. Examples of primary peritonitis include spontaneous bacterial peritonitis (SBP) in patients with liver disease, spontaneous peritonitis in children, and tuberculous peritonitis (TBP). In contrast, secondary peritonitis results from intra-abdominal infection, usually as a result of rupture of hollow viscera. Secondary peritonitis can be localized with abscess formation, or it can be diffuse. This type of peritonitis can result from many conditions, including a ruptured appendix, perforated gastric ulcer, intestinal ischemia, ruptured diverticula, perinephric abscess, anastomotic leak, and trauma. Tertiary peritonitis is a term used to describe peritonitis that occurs after secondary peritonitis, in the setting of chronic illness or prolonged hospitalization and can involve fungi or highly resistant nosocomial pathogens.

Primary Peritonitis Primary peritonitis is a diffuse infection in the peritoneal cavity that occurs in the absence of another source of infection. Examples of primary peritonitis include primary peritonitis in children, fungal peritonitis, TBP, and SBP. SBP is currently the most common type of primary peritonitis and involves the infection of ascitic fluid in patients with ascites. This condition most commonly occurs with ascites from liver disease but also can occur with ascites caused by many other diseases, including nephrotic syndrome, congestive heart failure (especially chronic constrictive pericarditis), systemic lupus

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erythematosus, rheumatoid arthritis, and Budd-Chiari syndrome. SBP also has been described in patients with chronic active hepatitis, acute viral hepatitis, and lymphedema (1).

Epidemiology Primary peritonitis is rare other than SBP in individuals with underlying liver disease. The incidence of primary peritonitis in children has decreased after the introduction of antibiotics, and TBP peritonitis is an unusual manifestation of tuberculosis. SBP in individuals with ascites is the most common type of primary peritonitis seen today. It is unusual to find SBP in asymptomatic outpatients, however, the prevalence in patients hospitalized with ascites ranges from 10% to 30% (2,3). The 2-year death rate after SBP is high and ranges from 44% to 95% (4-6). Risk factors for development of SBP in individuals with ascites include an elevated serum bilirubin concentration, ascitic fluid protein content of 1 g/dL, and a previous episode of SBP (2,3,7,8). In addition, cirrhotics with gastrointestinal bleeding are at increased risk of peritonitis, whether or not ascites is present (3). Patients who developed SBP in one series were found to have a 69% recurrence rate at 1 year and a 1-year survival probability of only 38% (5). Patients who survive an initial episode of SBP, often go on to die of liver failure and complications of portal hypertension.

Pathogenesis Various mechanisms have been proposed for the pathogenesis of SBP. When SBP was initially described, the infection was presumed to result from transient enteric bacteremia followed by sepsis (6). More recently, it has been demonstrated in an animal model that a combination of intestinal bacterial overgrowth and increased bowel-wall permeability lead to translocation of bacteria to the lymphatic system (9), which can lead to bacteremia. Direct translocation of bacteria from the gut is thought to be less likely given that SBP is usually monomicrobial. If direct translocation from the gut were responsible, polymicrobial infection would be expected to occur, and anaerobes would be expected to play a greater role in SBP. Another likely factor in the development of SBP is delayed clearance of bacteria from the hepatic reticuloendothelial system in individuals with portal hypertension.

Etiology Organisms usually recovered in SBP include normal enteric flora. As noted previously, SBP is generally a monomicrobial infection. Aerobic gramnegative bacilli are responsible for most cases, with Escherichia coli and Klebsiella pneumoniae causing more than 70% of cases (Table 11-1) (4,10).

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Table 11-1 Classification and Microbiology of Peritonitis Classification

Primary Peritonitis Diffuse bacterial peritonitis with no disruption of hollow viscera Examples: SBP TB peritonitis Fungal peritonitis ● ● ●

Secondary Peritonitis Localized (abscess) or diffuse peritonitis from rupture of hollow viscus Examples: Ruptured appendix Ischemic bowel Perforated gastric ulcer ● ● ●

Tertiary Peritonitis Persistent peritonitis not responding to therapy or peritonitis in patients with multiple organ failure Examples: Peritonitis with lowgrade pathogens Fungal peritonitis ●

●

Microbiology ●

●

● ●

SBP: Escherichia coli, E. coli and anaerobes Klebsiella pneumoniae, including: streptococci, enterococci, Bacteroides species anaerobes and Streptococci Staphylococcus aureus rare Clostridium species TB: Mycobacterium tuberculosis Fungal: blastomycosis Coccidioidomycosis, histoplasmosis ●

●

● ●

●

●

●

Staphylococcus epidermidis Candida species Enterococci including VRE Pseudomonas aeruginosa Stenotrophomonas maltophilia Aspergillus

Abbreviations: SBP, spontaneous bacterial peritonitis; TB, tuberculosis; VRE, vancomycin-resistant Enterococcus.

Gram-positive organisms (e.g., enterococci, streptococci [including pneumococcus]) account for an additional 25% of cases of SBP. Anaerobes are rare and account for less than 5% of cases. Additionally, polymicrobial infection is unusual, and secondary peritonitis should be considered when this is found. Staphylococcus aureus is rarely isolated from patients with SBP, accounting for only 2% to 4% of all cases (4), and has been found in patients with erosion of an umbilical hernia. Other sites of infection should be sought when this organism is recovered.

Clinical Manifestations The diagnosis of SBP should be considered in any patient with ascites who exhibits clinical deterioration, and diagnostic paracentesis should be done in such cases. The clinical findings in SBP can be quite subtle. Up to one third of patients with SBP can be asymptomatic. Furthermore, although all patients with SBP have ascites, it is not evident on physical examination. If a small amount of ascites is present, ultrasonography can be helpful in localizing fluid for paracentesis. Approximately 50% to 75% of patients with SBP have fever (2), and approximately half have abdominal pain. Hypotension and hypothermia can occur but are uncommon. Hepatic encephalopathy is often present, and worsening encephalopathy can occur in the absence of other signs.

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Diagnosis A diagnostic paracentesis confirms the diagnosis of SBP. This procedure is safe, even in the presence of thrombocytopenia and prolonged prothrombin time (11). Most patients do not require correction of the coagulopathy before paracentesis (12). The neutrophil count is the single best predictor of infection, and one greater than 250 to 500 cells/mm3 is indicative of infection, even in the absence of positive cultures. It is recommended that antibiotic therapy be started when the ascitic fluid neutrophil count is greater than or equal to 250 cells/mm3 (3). Although a Gram stain is usually negative, it is a simple and useful diagnostic test and can help guide empirical antibiotic administration and identify bowel perforation. Cultures should be obtained by directly inoculating from 10 to 15 mL of ascites fluid into blood culture bottles. Runyon and coworkers (13) found that the diagnostic yield for positive cultures increased from 42% to 91% when blood culture bottles were inoculated at the bedside as opposed to using conventional plating methods. The pH of ascitic fluid is also helpful in making the diagnosis; however, this generally reflects the neutrophil count. The ascitic fluid albumin and total protein concentrations should be obtained, because they help establish both the diagnosis of portal hypertension and the risk of recurrence of SBP. Although peritoneal fluid cytology is rarely diagnostic of SBP, it can be done in a search for tumor cells. The amylase concentration can help establish the diagnosis of pancreatic ascites and bowel perforation. Other optional tests that should be done when TBP is suspected include smears for acid-fast bacilli and mycobacterial cultures. Studies to be performed on ascitic fluid are listed in Table 11-2. Blood culture can be positive in one third to one half of cases of SBP and can be particularly helpful in patients whose ascitic fluid cultures are negative. Urine culture is not usually helpful in the diagnosis of SBP because culture results rarely coincide with ascites fluid culture.

Differentiating Spontaneous Bacterial Peritonitis from Secondary Peritonitis Although most patients who present with infected ascitic fluid are found to have primary peritonitis, approximately 15% have secondary peritonitis (14). Because the management of primary peritonitis differs from that of secondary peritonitis, it is important to distinguish the two. A history and physical examination are insufficient for differentiating primary from secondary peritonitis. Secondary peritonitis can be present when patients do not respond to antibiotic therapy for SBP, polymicrobial Gram stain or culture is present, or if the following ascitic fluid characteristics are present: 1. Total protein concentration is greater than 1 g/dL, 2. Glucose concentration is less than 50 mg/dL, and/or

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Table 11-2 Evaluation of Ascites Fluid Recommended Tests

Optional Tests

Cell count and differential Albumin (serum and ascites fluid) Total protein Gram stain Bacterial culture

Glucose Amylase Lactate dehydrogenase pH Ziehl-Neelsen stain Mycobacterial and fungal culture Cytology Bilirubin (ascites fluid and serum)

3. Ascitic-fluid lactate dehydrogenase concentration is greater than the upper limit of normal (2). Additionally, if the ascitic fluid is deeply bile stained with a bilirubin concentration greater than 6 mg/dL and if the ascitic fluid-to-serum bilirubin ratio is greater than 1, then biliary perforation should be suspected. Patients who meet these criteria should undergo evaluation to rule out perforation of a hollow viscus. Plain radiographs of the abdomen can be obtained to look for free air under the diaphragm. If these are unrevealing, a contrastenhanced computed tomography (CT) scan of the abdomen should be done on patients with suspected secondary peritonitis. Secondary peritonitis also can have other causes than those previously named, which are not as readily distinguishable. Repeat paracentesis is helpful in these situations. Akriviadis and Runyon (14) found that all patients with the disease had a decrease in their peritoneal fluid neutrophil count at 48 hours. Furthermore, all patients who had positive ascitic fluid cultures with organisms susceptible to the initial antibiotic regimen had negative cultures at 48 hours. All patients who were found to have secondary peritonitis had persistently positive ascitic fluid cultures at 48 and 96 hours despite antibiotic therapy, and more than half had multiple organisms. It is recommended that repeat paracentesis be done at least once after 48 hours of therapy in patients being treated for SBP (3). If the neutrophil count fails to decline or if the ascitic fluid culture remains positive, further evaluation is indicated, and antibiotic therapy can be changed.

Treatment Initial treatment of SBP should include the administration of antibiotics with activity against enteric flora. After the infecting organism has been identified by culture and susceptibility testing, treatment should be

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pinpointed to the specific pathogen. Cefotaxime has been the most extensively studied drug for treatment of SBP, and should be considered for empirical treatment (Table 11-3) (3,8). Other cephalosporins have also been found to be effective for treatment of SBP and can be considered along with ampicillin-sulbactam, piperacillin-tazobactam, and quinolones for individuals who have beta-lactam hypersensitivity. Oral antibiotic therapy with moxifloxacin 400 mg orally every 24 hours can be considered for individuals who are not severely ill and who have not had prophylaxis with a quinolone (3). Most patients with SBP have sterile ascitic fluid soon after beginning antibiotic therapy. Often, the ascitic fluid becomes sterile after the initial dose of an antibiotic agent (14). In an evaluation of 90 patients with SBP and culture-negative neutrocytic ascites (CNNA), who were randomly assigned to receiving either 5 or 10 days of intravenous cefotaxime, no difference between the two groups was found in the death rate, bacteriologic cure, or recurrence of infection (15). Although antibiotic therapy is often continued for 10 to 14 days, a shorter course of therapy is acceptable and more cost-effective. Currently, 5 to 7 days of therapy is considered standard, as long as repeat paracentesis at 48 hours demonstrates improvement. If ascitic fluid neutrophil counts remain high or if resistant organisms are found on culture, then a longer course of therapy can be necessary.

Prophylaxis The risk of recurrence of SBP within 1 year is 40% to 70% (3), and the death rate is high. Both primary and secondary prevention strategies have been used with nonabsorbable antibiotics to selectively decontaminate the gut. Norfloxacin at 400 mg/day has been used for prophylaxis; however, although this has been shown to be effective in reducing the occurrence of SBP, it can select for quinolone resistance (16). Trimethoprim-sulfamethoxazole has also been demonstrated to be effective at preventing SBP (17). Studies of both primary and secondary prophylaxis have shown a substantial decrease in the incidence of SBP, but whether death rates are affected is less clear (2,4,17, 18). Oral ciprofloxacin at 500 mg twice daily has been demonstrated to decrease the risk of bacterial infection in individuals with acute upper gastrointestinal bleeding when administered for 7 days (19). Although individuals with cirrhosis and ascites are at high risk for development of SBP, in those with no previous episodes of SBP, those most likely to benefit from prophylaxis have not been clearly identified, and no consensus exists on whom should be offered prophylaxis (18). The current recommendation is that individuals with upper gastrointestinal bleeding receive antibiotic prophylaxis, independent of presence of ascites (3), and that individuals with a previous episode of SBP receive prophylaxis with norfloxacin or trimethoprim-sulfamethoxazole (2,3).

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Culture-Negative Neutrocytic Ascites and Bacterascites In 1984, Runyon and Hoefs (20) originally described a variant of SBP, that is CNNA. This entity was described as existing when a neutrophil count of more than 500 cells/mm3 is present in the absence of positive ascitic fluid cultures. Negative ascitic fluid cultures were found in up to 35% of suspected cases of SBP that were otherwise clinically indistinguishable from diagnosed SBP. The diagnosis of CNNA should be made only when patients have not received antibiotics in the recent past and when no alternate explanation exists for an increased neutrophil count. The clinical presentation, laboratory findings, death rate, and response to treatment are similar in patients with SBP and CNNA. Despite the negative cultures, CNNA is thought to be caused by bacterial infection, and can be a precursor to SBP. Repeat paracentesis usually shows improvement after initiation of antibiotic therapy. It is possible that the number of organisms present in CNNA is below the threshold of detection for culture. Although the original case series defined CNNA in patients with a neutrophil count of more than 500 cells/mm3, a neutrophil count of more than 250 cells/mm3 is used as a cutoff (4,21). Patients occasionally have positive ascites fluid culture, but a neutrophil count less than 250 cells/mm3. This clinical situation is called bacterascites, and can be caused by colonization of ascitic fluid either because of extraperitoneal infection or as precursor to SBP, or perforation of the intestine with the paracentesis needle. When perforation of the intestine during paracentesis occurs, the culture will generally be polymicrobial. Although CNNA should be treated with antibiotics, bacterial agglutination (BA) may not require treatment (4). In the setting of bacterascites, symptoms of peritonitis correlate with progression to SBP, whereas asymptomatic patients often do not experience this progression (10). If culture of ascitic fluid is positive, then repeat paracentesis is recommended at the time the culture result is obtained to determine whether evidence of peritonitis exists, and whether antibiotic therapy is indicated (3).

Secondary Peritonitis Pathogenesis Secondary peritonitis is a distinct clinical entity that results from the rupture or spillage of an abdominal viscus into the normally sterile abdominal cavity. Predisposing factors include abdominal trauma, perforation, or intraperitoneal spread from an infected abdominal organ or abscess. Perforation of a gastric or duodenal ulcer, cholecystitis, rupture of diverticula, rupture of the appendix, and penetrating abdominal wounds are all common causes. Subsequent infection can either be localized, as with an abscess, or consist of generalized peritonitis. Chemical peritonitis also can occur, especially after rupture of the stomach.

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Etiology The number and types of bacteria increases progressively as one proceeds distally in the gastrointestinal tract. Therefore, the bacteria involved in secondary peritonitis depend on the level at which the rupture takes place. Proximally, there are sparse aerobes and oral anaerobes, whereas the colon contains the largest concentration of bacteria. The stomach in the fasting state contains relatively few microorganisms; however, many organisms are found after colonic perforation. If an organ ruptures below the ligament of Treitz, anaerobes constitute 99% of the organisms isolated. Bacteroides fragilis is the predominant anaerobe isolated from culture, and E. coli is the predominant facultative aerobe in gastrointestinal perforation (1). B. fragilis is present in approximately 75% of postoperative infections but accounts for less than 5% of fecal flora (22). Meleney and coworkers (23) recognized early on that microbial synergy plays an important role in establishing infection within the peritoneum. It was noted that the clinical course of illness was much more severe if two or more organisms were found. Because synergy plays an important role in infection, it is usually not necessary to treat all the organisms that are isolated from a culture.

Clinical Manifestations The signs and symptoms of secondary peritonitis are generally more pronounced than those of SBP. Most patients present with pain, either over a localized area (as can be seen with appendicitis) or as generally within the abdomen. Usually, the area of pain tends to extend as the inflammation progresses. Examination reveals tenderness over the involved area. Vomiting can be present at an early stage or can develop later if ileus or bowel obstruction develops. Fever and diarrhea also can be present, and abdominal rigidity, guarding, or rebound tenderness can be present. Immunocompromised or elderly patients can have more subtle symptoms. Peritonitis can be more difficult to diagnose in patients who are paralyzed and in those undergoing mechanical ventilation.

Diagnosis Patients who present with abdominal pain should have the usual laboratory tests to aid in establishing a diagnosis, including a complete blood count, electrolyte measurements, and plain radiography of the abdomen. Blood cultures are not useful in patients with community-acquired intraabdominal infection, and are not recommended (24). Although laboratory tests can be helpful in raising the index of suspicion for peritonitis, the definitive diagnosis can be made only surgically. Therefore, any patient suspected of having secondary peritonitis should undergo evaluation by a surgeon.

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Patients should have aerobic and anaerobic cultures sent from intraabdominal infection at the time of surgery. Gram stain is not useful in patients with community-acquired infection, but can be useful in those with health care-associated infections to help guide antibiotic therapy (24).

Treatment Secondary peritonitis is usually a surgical disease. The most important aspect of its treatment is the evacuation of pus and fecal contamination from the abdominal cavity. The principles of therapy involve supportive measures, followed by operative intervention. The surgical approach involves controlling the source of infection, evacuating contaminated material, decompressing the abdomen, and preventing or treating persistent infection. Antimicrobial therapy is recommended in established infections, but is not recommended to exceed 24 hours in the following situations (24,25): 1. There is bowel perforation, either traumatic or iatrogenic when the operation is done within 12 hours. 2. There is acute perforation of the stomach and duodenum in the absence of antacid therapy. 3. There is acute appendicitis and cholecystitis without perforation, abscess, or peritonitis. Patients with the previously listed clinical situations should be given prophylactic antibiotics only, not extended courses of therapy. If infection is suspected with cholecystitis, antibiotic therapy aimed at Enterobacteriaceae should be administered, and surgical consultation should be obtained (24). In individuals with established intra-abdominal infection for whom adequate source control is achieved at the time of operation, antibiotics can be administered until the resolution of signs and symptoms of infection. The duration of therapy can be limited to 5 to 7 days unless there is evidence of persistent infection (24,25). If persistent signs of infection occur, diagnostic investigation should take place. Antibiotic therapy should be aimed at potential organisms. For patients with community-acquired infections that are mild-to-moderate in severity, options include ampicillin/sulbactam, ticarcillin/clavulanic acid, ertapenem, cefazolin or cefuroxime plus metronidazole, or a quinolones plus metronidazole (24). For patients who are severely ill or are immunocompromised, broad-spectrum antibiotics are recommended including the following: piperacillin/tazobactam, imipenem/cilastatin, meropenem, a third or fourth-generation cephalosporin plus metronidazole, or aztreonam plus metronidazole (24). Aminoglycosides are not recommended for communityacquired infections because less toxic agents are now available. Postoperative infections are more likely to involve resistant pathogens including resistant gram-negative and gram-positive organisms, and Candida species. Antibiotic therapy should be tailored according to local antibiograms (Table 11-3).

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Table 11-3 Empiric Antibiotics for Peritonitis Dosage for Normal Renal Function, Can Require Adjustment for Renal and Hepatic Insufficiency

Primary Peritonitis

Cefotaxime Ampicillin/sulbactam Piperacillin/tazobactam For beta-lactam allergy: Monifloxicin

2.0 g IV q 8 h 3.0 g IV q 6 h 3.375 g IV q 6 h 400 mg PO or IV q 24 h

Secondary Peritonitis: Community-Acquired

Ampicillin/sulbactam Ticarcillin/clavulanic acid Ertapenem For beta-lactam allergy: ciprofloxacin and metronidazole

3.0 g IV q 6 h (ampicillin/sulbactam) 3 g ticarcillin and 100 mg clavulanic acid IV q 4-6 h 1 gram IV q 24 h 400 mg IV q 12 h (ciprofloxacin) and 500 mg IV or PO q 8 (metronidazole)

Secondary Peritonitis: Health Care-Associated

Piperacillin/tazobactam Meropenem Imipenem/cilastatin Cefepime plus metronidazole

3.375 g IV q 6 h 1 g IV q 8 h 500 mg IV q 6 h 2.0 g IV q 8 h plus 500 mg IV or PO q 8 h

Tertiary Peritonitis

Meropenem Imipenem/cilastatin Cefepime and vancomycin Fluconazole Amphotericin

1 g IV q 8 h 500 mg IV q 6 h 2.0 g IV q 8 h and 1 g IV q 12 h 200-400 mg IV q 24 h 0.5-1.0 mg/kg IV q 24 h

Abbreviations: h, hour; IV, intravenous; PO, orally; q, every.

Even though fungi can be recovered from patients with acute gastrointestinal tract perforation, therapy is not necessary unless the patient has recently received immunosuppressive therapy for malignancy or inflammatory disease, has undergone transplantation, or has postoperative or recurrent intra-abdominal infection (24). Likewise, enterococci do not need to be treated in community-acquired infections, but should be treated in health care-associated infections (24).

Tertiary Peritonitis Tertiary peritonitis is a syndrome that occurs in patients who have inadequate host defenses and who often have multiple-organ failure. The term tertiary peritonitis was originally used in the 1980s to describe patients who died of sepsis and multiple-organ failure caused by a delay in management

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or by iatrogenic factors (26). These patients were sometimes found to have peritoneal fluid that was free of microorganisms or that contained low-grade pathogens at the time of surgery. The term tertiary peritonitis has been used largely to describe a situation that presents as sepsis late in the postoperative phase, but also can describe patients with complicated peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). Persistent peritonitis with systemic inflammation ensues after what usually would be an adequate course of antimicrobial therapy.

Pathogenesis Microorganisms can gain access to the abdominal cavity by translocation of intestinal flora, which can result from malnutrition, alteration of the intestinal wall from CAPD, intestinal ischemia, or growth of resistant bowel flora through antibiotic selection pressure. Additionally, selection among the initial polymicrobial peritoneal inoculum can occur through antibiotic therapy, direct contamination during surgery, or direct access along peritoneal catheter devices. Patients develop a sepsis syndrome with hypotension, fever, low systemic vascular resistance, high cardiac output, and multiorgan failure. The death rate for patients with nonlocalized postoperative intra-abdominal sepsis approaches 100% when medical therapy alone is given (27). This death rate can be reduced somewhat by repeated laparotomy. The microorganisms involved in tertiary peritonitis are often highly resistant nosocomial pathogens, and include resistant gram-negative and gram-positive organisms and Candida species. As previously discussed, peritoneal fluid culture also can be negative.

Diagnosis Patients with tertiary peritonitis will usually have signs and symptoms of sepsis, and many will have obvious clinical signs of peritonitis. In contrast to secondary peritonitis, blood cultures can be positive in more than 30% of patients with tertiary peritonitis (28). An abdominal CT scan is useful to determine whether an intra-abdominal abscess is present.

Treatment Tertiary peritonitis is a health care-associated infection, and involves highly resistant organisms. Empiric therapy should be based on local resistance data, and can require several antibiotics. Broad-spectrum antibiotic therapy should be started and should be tailored according to culture results from blood and infected peritoneal fluid. Patients can also require surgical intervention or CT-guided drainage if a localized intra-abdominal abscess is present.

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Peritonitis in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis Epidemiology Peritonitis in patients who are undergoing CAPD is a distinct clinical entity and is the main complication of CAPD. The incidence has decreased from 1.0 to 1.3 episodes per patient per year (14,15,24) to 1 episode per 20 to 30 patient-months (29). The incidence is lower in centers with more experience and higher in those with less. Peritonitis is a major complication in CAPD and is the main reason for loss of the dialysis catheter and for changing to hemodialysis. Unlike with SBP, the recurrence of which is common, CAPD is estimated to recur in only approximately 25% of cases (30).

Pathogenesis The main factor in the development of CAPD peritonitis is usually a violation of sterile technique during the four or five daily fluid exchanges that occur in CAPD. The pathogenesis of this infection is similar to that of infections that result from intravascular devices, when organisms migrate along the catheter groove, and the catheter serves as an entry point for microorganisms into the normally sterile peritoneal cavity. Other host factors also can play a role. Recurrent CAPD peritonitis is thought to be associated with some type of impairment in host bactericidal activity (31).

Etiology Given that they are consequences of a laxity in sterile technique, most infections are caused by skin flora. Gram-positive organisms account for up to 70% of CAPD peritonitis, gram-negative organisms for 15% to 25%, and fungi for 2% to 3% (29). Anaerobes rarely cause CAPD peritonitis, and the infection is generally monomicrobial. Similar to SBP, when polymicrobial infection is found, or when anaerobes are present, secondary peritonitis from a gastrointestinal perforation should be sought.

Clinical Manifestations Although signs and symptoms of CAPD peritonitis are variable, the onset of the disease is usually noted by the presence of cloudy dialysate fluid. Additionally, most patients have abdominal pain and tenderness on examination. Other signs and symptoms of CAPD peritonitis are much less frequent. Only approximately 35% of patients have fever, and only approximately one quarter of patients have nausea and vomiting (30). CAPD patients are taught that they should be able to read newsprint through the dialysate fluid as a means of ensuring the absence of infection. If turbidity

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is present, it should always be taken seriously; the presence of infection should be assumed until proven otherwise.

Diagnosis The diagnosis of CAPD peritonitis is established by evaluating the dialysate fluid, as discussed in the following section on Laboratory Findings. Laboratory evaluation of the dialysate fluid should be undertaken in any patient who notes a change in the appearance of this fluid. Peritonitis is diagnosed when two or more of the following are present: 1. There is cloudy dialysate fluid with more than 100 leukocytes/ mm3 2. Abdominal pain is present. 3. There is positive culture from dialysate fluid (29). Cloudy dialysate fluid can also result from conditions other than infection, such as malignancy or allergic reaction.

Laboratory Findings The initial evaluation of turbid dialysate fluid includes a leukocyte count with differential. Generally, a leukocyte count of 100 cells/cm3 or more, with more than 50% polymorphonuclear leukocytes, is considered indicative of infection. It is important to obtain a differential count along with the leukocyte count because conditions such as eosinophilic peritonitis, which occurs as an allergic reaction to the dialysis catheter, also can cause cloudiness of the dialysate fluid. A Gram stain is useful in evaluating peritonitis and is positive in 20% to 30% of cases. It is recommended that 10 to 20 mL of effluent be centrifuged for the Gram stain. Although the Gram stain is positive in less than 30% of cases, the procedure is simple and can give an early clue to the presence of fungal peritonitis. Culture of infected peritoneal dialysate fluid is positive in more than 90% of cases (32). Various approaches have been tried for culture. As with SBP, 10 to 15 mL of fluid can be injected directly into blood culture bottles. Alternately, many dialysis centers send the entire bag of effluent to the microbiology laboratory, where the number of organisms can be concentrated either by filtration or by centrifugation. In contrast to other types of peritonitis, blood cultures in CAPD peritonitis are often negative and are not routinely helpful in making a diagnosis. In patients who are hospitalized with fever, blood cultures are indicated to rule out other sources of infection.

Treatment Treatment of CAPD peritonitis can be based on Gram stain results when the Gram stain is positive. Gram-positive organisms should be treated with a

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first-generation cephalosporin, and gram-negative organisms should be treated with a third-generation cephalosporin (29,33). Intraperitoneal therapy is preferred for CAPD peritonitis, although oral therapy has also been successful. For patients whose Gram stains are negative, empiric therapy should include a first- and third-generation cephalosporin or vancomycin and a third-generation cephalosporin (29,33). In patients known to be colonized with methicillin-resistant Staphylococcus aureus (MRSA), it is reasonable to treat empirically with vancomycin until cultures are available. Individuals who have recurrent peritonitis within 4 weeks from the same organism, or who have fungal peritonitis require catheter removal. Catheter salvage can be attempted in those with gram-positive organisms, but should not be considered in those with Pseudomonas or fungi. If recurrent S. aureus peritonitis occurs, an intraabdominal abscess or other occult infection should be looked for. The clinical response of CAPD peritonitis to such therapy is generally rapid, and symptoms alleviate within 48 hours after treatment is begun. If the culture of the dialysate fluid is negative but the patient is responding to empirical therapy, empirical therapy can be continued for the duration of therapy. Most cases of CAPD peritonitis can be treated with 7 to 10 days of intraperitoneal antimicrobial therapy; however, S. aureus and gramnegative organisms should be treated for 10 to 14 days. S. aureus often causes severe peritonitis, and is often present from catheter-related infection. Successful eradication of S. aureus often requires catheter removal (33). Uncomplicated CAPD peritonitis can be treated on an outpatient basis. Hospitalization is indicated when patients exhibit signs of sepsis, when there is suspicion of abscess formation or perforation, or when there is concern about resistant organisms. Tunnel- or exit-site infections usually require the removal of the dialysis catheter and temporary hemodialysis. Certain microorganisms, including P. aeruginosa and fungi, are often associated with tunnel-site infections. Infection with these organisms tends to have a higher illness rate and usually does not resolve without the removal of the dialysis catheter. Aminoglycosides can be given to those individuals whose residual urine output is less than 100 cc/day. Treatment should be given for at least 2 weeks, or until the catheter exit site looks completely normal (29,33). There have been anecdotal reports of successful treatment of fungal peritonitis with maintenance of the CAPD catheter; however, fungal peritonitis is associated with a high illness rate, and it is recommended that the catheter be removed. Fungal peritonitis also carries a high risk of adhesion formation, which can preclude future peritoneal dialysis. In addition to being relatively inefficacious in peritoneal dialysate fluid, amphotericin B is poorly tolerated intraperitoneally and causes severe inflammation in the patient. After catheter removal, patients with fungal peritonitis require a period of systemic antimicrobial therapy.

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Tuberculous Peritonitis The differential diagnosis of peritonitis should include consideration of TBP. This entity is not commonly seen in the United States, but is characterized by an insidious onset, often over a period of more than 1 month. Progressive ascites, fever, and abdominal pain are present. Night sweats, vomiting, chills, and weight loss also can occur. Active pulmonary tuberculosis is associated with TBP in approximately 20% of cases (34). A “doughy” abdomen caused by tuberculous adhesion can sometimes be found on physical examination, and an abdominal mass can be palpable in up to 50% of cases. TBP can present either as a chronic condition (plastic TBP)—in which there tends to be more abdominal pain, little ascites, and adhesions—or as a more acute condition (serous TBP) with ascites of rapid onset and fever (35). Tuberculous peritonitis usually results from the rupture of a caseous necrotic abdominal lymph node with contents that spill into peritoneal fluid. Occasionally, a characteristic calcified abdominal node can be seen on plain radiographs of the abdomen. This entity should be suspected when a predominantly lymphocytic exudate is found on evaluation of ascitic fluid and in conjunction with an increased total protein concentration. The organism is rarely seen on a Ziehl-Neelsen stain but can be cultured in up to 69% of cases. The yield of culture is improved if a large volume of fluid is concentrated for culture. Culture of peritoneal fluid can give positive results in more than 80% of cases if 1 L of fluid is cultured (34). A polymerase chain reaction test probably aids in the diagnosis of TBP but is not currently approved as a diagnostic tool in the disease in the United States. Ascitic adenosine deaminase levels can be useful in the diagnosis of TBP, but false-negative tests can occur (36). Peritoneoscopy and peritoneal biopsy often are used to examine the abdomen for evidence of characteristic pathology. Caseating granulomas, tissue that contains acid-fast bacilli, or granulomas (including epithelioid giant cells) must be found to make a definitive diagnosis histologically. When tubercles are seen studding the peritoneum, the yield on biopsy is approximately 75%. (Other chronic granulomatous diseases can produce an identical studding.) Because fluid cultures are often positive, it is recommended that they be done even when no characteristic features are seen on peritoneoscopy. Death from TBP has declined substantially since the advent of drugs to treat tuberculosis. The treatment of this disease consists of standard antimycobacterial drugs in regimens that resemble those used for treating pulmonary tuberculosis.

Summary Peritonitis is a relatively common condition that results from various underlying problems. The most common type of peritonitis seen in adults is SPB

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in the presence of liver disease with ascites. SBP can present with various signs and symptoms, and thus any clinical deterioration in a patient with liver disease and ascites warrants diagnostic paracentesis. These individuals can also develop secondary peritonitis, and clues are evident from examination of ascitic fluid. Individuals with very low ascitic glucose, high total protein, or polymicrobial Gram stain should be promptly investigated for secondary peritonitis. If secondary peritonitis is suspected, surgical consultation should be considered. Secondary peritonitis occurs most commonly because of a perforated viscus and requires surgical intervention. With adequate control of the source of peritonitis at the time of surgery, antibiotic therapy can be given for a short period of time, unless there is persistent evidence of infection. In both primary and secondary peritonitis, antimicrobial therapy should be aimed at enteric organisms. Both enterococci and candida species usually do not require therapy in community-acquired infections. Tertiary peritonitis represents a less common situation in which individuals with inadequate host defenses go on to develop ongoing sepsis and peritonitis after what would normally be adequate therapy for peritonitis. These cases often involve resistant pathogens including fungi. CAPD peritonitis is an entity that often presents initially with few systemic symptoms, but a change in the appearance of the dialysate is generally noted. This should be promptly investigated, and antibiotic therapy can be given by means of peritoneal dialysis. Finally, TBP is an uncommon disease in the United States, but should be considered in individuals with chronic abdominal pain, ascites, and fever. The diagnosis can be difficult to establish, and it is important to remain vigilant for this entity. Peritonitis is a disease that can be often be managed with appropriate antimicrobial therapy. However, diagnostic tests are necessary to establish the cause of peritonitis as treatment varies based on the underlying cause for peritonitis.

REFERENCES 1. Johnson CC, Baldessarre J, Levison ME. Peritonitis: update on pathophysiology, clinical manifestations, and management. Clin Infect Dis. 1997;24:1035-45; quiz 1046-7. 2. Sheer TA, Runyon BA. Spontaneous bacterial peritonitis. Dig Dis. 2005;23:39-46. 3. Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol. 2000;32:142-53. 4. Gilbert JA, Kamath PS. Spontaneous bacterial peritonitis: an update. Mayo Clin Proc. 1995;70:365-70. 5. Titó L, Rimola A, Ginès P, Llach J,Arroyo V, Rodés J. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology. 1988;8:27-31. 6. Conn HO, Fessel JM. Spontaneous bacterial peritonitis in cirrhosis: variations on a theme. Medicine (Baltimore). 1971;50:161-97. 7. Andreu M, Sola R, Sitges-Serra A,Alia C, Gallen M,Vila MC, et al. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. Gastroenterology. 1993; 104:1133-8.

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8. Guarner C, Solà R, Soriano G, Andreu M, Novella MT, Vila MC, et al. Risk of a first communityacquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology. 1999;117:414-9. 9. Guarner C, Runyon BA,Young S, Heck M, Sheikh MY. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol. 1997;26:1372-8. 10. Bhuva M, Ganger D, Jensen D. Spontaneous bacterial peritonitis: an update on evaluation, management, and prevention. Am J Med. 1994;97:169-75. 11. Grabau CM, Crago SF, Hoff LK, Simon JA, Melton CA, Ott BJ, et al. Performance standards for therapeutic abdominal paracentesis. Hepatology. 2004;40:484-8. 12. Runyon BA. Care of patients with ascites. N Engl J Med. 1994;330:337-42. 13. Runyon BA, Umland ET, Merlin T. Inoculation of blood culture bottles with ascitic fluid. Improved detection of spontaneous bacterial peritonitis. Arch Intern Med. 1987;147: 73-5. 14. Akriviadis EA, Runyon BA. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis. Gastroenterology. 1990;98:127-33. 15. Runyon BA, McHutchison JG,Antillon MR,Akriviadis EA, Montano AA. Short-course versus longcourse antibiotic treatment of spontaneous bacterial peritonitis. A randomized controlled study of 100 patients. Gastroenterology. 1991;100:1737-42. 16. Bauer TM, Follo A, Navasa M,Vila J, Planas R, Clemente G, et al. Daily norfloxacin is more effective than weekly rufloxacin in prevention of spontaneous bacterial peritonitis recurrence. Dig Dis Sci. 2002;47:1356-61. 17. Singh N, Gayowski T,Yu VL,Wagener MM. Trimethoprim-sulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med. 1995;122:595-8. 18. Frazee LA, Marinos AE, Rybarczyk AM, Fulton SA. Long-term prophylaxis of spontaneous bacterial peritonitis in patients with cirrhosis. Ann Pharmacother. 2005;39:908-12. 19. Hsieh WJ, Lin HC, Hwang SJ, Hou MC, Lee FY, Chang FY, et al. The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding. Am J Gastroenterol. 1998;93:962-6. 20. Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis. Hepatology. 1984;4:1209-11. 21. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis. 1998;27:669-74; quiz 675-6. 22. Wilson SE, Hopkins JA. Clinical correlates of anaerobic bacteriology in peritonitis. Clin Infect Dis. 1995;20 Suppl 2:S251-6. 23. Meleney FL, Harvey HD, Zaytseff-Jern H. Peritonitis: The correlation of the bacteriology of the peritoneal exudates and the clinical course of the disease in one hundred six cases of peritonitis. Arch Surg. 1931;22:1-23. 24. Infectious Diseases Society of America. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect Dis. 2003;37:997-1005. 25. Mazuski JE, Sawyer RG, Nathens AB, et al. Therapeutic Agents Committee of the Surgical Infections Society. The surgical infection society guidelines on antimicrobial therapy for intra-abdominal infections: An executive summary. Surg Infect (Larchmt). 2002 Fall;3(3): 161-73. 26. Wittmann DH, Schein M, Condon RE. Management of secondary peritonitis. Ann Surg. 1996;224: 10-8. 27. Munson JL. Management of intra-abdominal sepsis. Surg Clin North Am. 1991;71:1175-85. 28. Malangoni MA. Evaluation and management of tertiary peritonitis. Am Surg. 2000;66: 157-61. 29. Teitelbaum I, Burkart J. Peritoneal dialysis. Am J Kidney Dis. 2003;42:1082-96. 30. Saklayen MG. CAPD peritonitis. Incidence, pathogens, diagnosis, and management. Med Clin North Am. 1990;74:997-1010. 31. Holmes CJ. Peritoneal host defense mechanisms in peritoneal dialysis. Kidney Int. 1994;46(suppl 48):S58-70. 32. Diagnosis and management of peritonitis in continuous ambulatory peritoneal dialysis. Report of a working party of the British Society for Antimicrobial Chemotherapy. Lancet. 1987;1: 845-9. 33. ISPD Ad Hoc Advisory Committee. Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int. 2005;25:107-31. 34. Moreyra E, Rollhauser CA,Tenner SM. Tuberculous peritonitis: clinical manifestations, diagnosis, and treatment. Res Staff Phys. 1994;40:29-32.

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35. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 3-1998. A 31-year-old woman with a pleural effusion, ascites, and persistent fever spikes. N Engl J Med. 1998;338:248-54. 36. Fernandez-Rodriguez CM, Perez-Arguelles BS, Ledo L, Garcia-Vila LM, Pereira S, RodriguezMartinez D. Ascites adenosine deaminase activity is decreased in tuberculous ascites with low protein content. Am J Gastroenterol. 1991;86:1500-3.

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Chapter 12

Intra-Abdominal Abscess FARID F. MUAKKASSA, MD WILLIAM C. PAPOURAS, MD DANIEL P. GUYTON, MD

Key Learning Points 1. Control of infection in intra-abdominal abscesses can be accomplished with either percutaneous drainage or with surgical debridement of devitalized and necrotic tissue. 2. Both monotherapy and combination therapy can be effective in treatment of intra-abdominal abscesses with source control. 3. Empiric antimicrobial therapy should include coverage for aerobic gram positive, aerobic gram negative, and anaerobic organisms. 4. Therapy in general can be discontinued after 5-7 days or after the resolution of clinical signs of sepsis. If no improvement in one week then source is not controlled and further radiologic evaluation or surgical re-exploration may be warranted. 5. Antifungal prophylaxis may be considered in cases of gastrointestinal perforations, anastomotic leaks or severe acute necrotizing pancreatitis with treatment duration of 2-3 weeks for confirmed fungal sepsis.

I

ntra-abdominal abscesses are walled-off collections of pus surrounded by inflammatory adhesions that occur either within or outside the abdominal viscera. In abscesses that occur outside the abdominal viscera, the abscess wall can be surrounded by adhesions, loops of small or large bowel and their mesenteries, or the omentum; sometimes they are retroperitoneal. The formation of a well-defined intra-abdominal abscess may take several days to a week, depending on the cause of the responsible insult. Formation of abscesses in the peritoneal cavity usually follows 1) the resolution of a diffuse peritonitis, of which a remaining small, infected focus becomes walled off by 223

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New Developments • The epidemiology of healthcare associated intra-abdominal abscess is evolving to

include more antimicrobial resistant pathogens. • Intra-abdominal abscesses (especially pyogenic liver abscess) remain important

causes of unexplained fever particularly in the elderly. • Antimicrobial coverage for Enterococcus spp. Is controversial but is more

important in patients with healthcare acquired infection, those with septic shock, those who have received prior cephalosporins and in those with prosthetic heart valves.

the host-defense system; 2) a perforation in a viscus; or 3) a postsurgical anastomotic leak. More than 80% of intra-abdominal abscesses occur after an abdominal operation. Postoperative intra-abdominal abscesses in the upper gastrointestinal tract are largely caused by anastomotic leaks, whereas those in the lower tract are caused by the bacterial load in the colon. In contrast, most visceral abscesses result from hematogenous or lymphatic spread of organisms. Retroperitoneal abscesses can result from perforations of retroperitoneal organs, from the retroperitoneal portion of an organ, or from lymphatic or hematogenous seeding by infectious organisms. The approach to the diagnosis and treatment of intra-abdominal abscesses may vary with the cause of the etiologic disease process and with the involved organs. Although this chapter takes an organ-focused approach to the diagnosis and management of intra-abdominal abscesses, a broader initial perspective sometimes is needed before focusing on a specific organ.

Liver Abscesses Liver abscesses can be divided into 2 major categories—pyogenic and amebic abscesses—and share many clinical manifestations. Although liver abscesses are uncommon, their early diagnosis and management are crucial because of their high rate of death. The incidence of hepatic abscesses is rising, possibly as a result of increased instrumentation of the biliary tree, transplantation and immunosuppression, and improved diagnosis The incidence of pyogenic liver abscess ranges between 8 and 22 cases per 100,000 hospital admissions (1). In the United States, approximately 80% of liver abscesses are pyogenic, 10% are amebic, 10% are caused by superinfections, and less than 10% are caused by fungal and other organisms (2). Liver abscesses are solitary in 50% to 60% of cases and multiple in the remainder. Pyogenic abscesses tend to be multifocal, especially when they originate from sepsis or pyelophlebitis, whereas amebic abscesses are usually solitary. Abscesses are more common in the right lobe of the liver (60%) than in the left lobe (10%-15%) and are bilobar in 20% of cases. Their high prevalence in the right

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lobe may be caused by the laminar drainage of the superior mesenteric vein into this lobe of the liver. Pyogenic liver abscesses affect both sexes and all age groups. Amebic abscesses of the liver occur in 10% of cases of amebic colitis and in a male-to-female ratio that ranges from 9:1 to 10:1.

Etiology The cause of liver abscesses varies worldwide and is changing in some countries as a result of better health care and increased recognition through more advanced diagnostic techniques. Although pyogenic liver abscesses are the type preponderantly seen in most of the United States, amebic liver abscesses are endemic in many areas of the world. Other, less common abscesses involve fungi, infected echinococcal cysts, and other organisms. Bacteria may spread to the liver through the following routes (3): ●

●

●

●

●

● ●

Biliary tree: from cholecystitis, choledocholithiasis, cholangitis, obstructing biliary or pancreatic malignancies, occluded stents, or Ascaris lumbricoides migrating into the biliary tree Portal vein: from appendicitis, pancreatitis, omphalitis, diverticulitis, inflammatory bowel diseases, or pelvic inflammatory diseases Hepatic artery: from hematogenous spread from other foci in the body Adjacent organs: from direct extension from organs such as the gallbladder, kidney, or subhepatic or subdiaphragmatic infections Direct trauma: from penetrating trauma or seeding of bacteria in blunt hepatic hematomas Necrosis of hepatic neoplasms: including embolizations Cryptogenic infection: infection without an identifiable source

The bacteriology of liver abscesses shows that most cases (79%) are polymicrobial, and enteric gram-negative bacilli (usually E. coli and Klebsiella pneumoniae) are the most common pathogen. Other less common gramnegatives are Pseudomonas, Proteus, Enterobacter, Citrobacter, and Serratia. Common gram-positives are Streptococcus (anginosus group also called Streptococcus milleri), Enterococcus species and other viridans streptococci. Less common gram-positives are Staphylococcus aureus and β-hemolytic streptococci. (4). With recent progress in anaerobic culture techniques, the frequency of anaerobe involvement in hepatic abscess has been found to be approximately 50% (5). The involved anaerobes include species of Bacteroides (most common), Fusobacterium, Actinomyces, Peptostreptococcus, Clostridium, Lactobacilli, and Prevotella (4). Fungal liver abscesses, especially those caused by Candida albicans, are usually many; stem from systemic fungemia; and are prevalent in patients with cancer and immune-deficiency syndromes (6). Rare causes of hepatic abscess are Yersinia enterocolitica and tuberculosis.

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Clinical Manifestations Symptoms of pyogenic liver abscesses are variable and, in some cases, entirely absent. Clinical findings include fever, chills, malaise, abdominal pain mostly localized to the right upper quadrant, nausea, anorexia, and weight loss usually of less than 2-weeks’ duration but in some cases lasting several months. Because of the nonspecific symptoms of pyogenic liver abscesses, a significant number of patients with prolonged illness caused by such abscesses may have had a previous diagnosis of fever of unknown origin. Physical findings include right-upper-quadrant tenderness with hepatomegaly in 50% to 70% of patients, pleural dullness on percussion, and jaundice (7). Abscesses located high in the right upper lobe may cause respiratory symptoms, including cough, pleuritic pain that may radiate to the right shoulder, and a pleuritic rub. Patients with amebic abscesses have a presentation similar to that of those with pyogenic abscesses but additionally may have a history of diarrhea and radiographic chest findings and, in some series, have lacked the spiking temperature of the latter group. Rarely, patients with amebic abscesses may present with left-upper-quadrant pain if the abscess involves the left lobe of the liver and extends into the pericardium.

Diagnosis Radiologic evaluation is the key to diagnosing liver abscesses in more than 95% of cases. Ultrasonography is the most helpful screening test for liver abscess because of its high sensitivity (85%-95%), better biliary tree imaging than with computed tomography (CT), and therapeutic applicability to the biopsy or drainage of abscesses. Ultrasonography has its limitations in heterogeneous livers, lesions high in the chest cavity, and obese patients. CT is the most sensitive of all imaging modalities for liver abscess (95%-100%) and can be used for therapeutic intervention. It also can provide information about other abdominal lesions that may have caused a liver abscess. In some cases, CT reveals an enhancing rim around an abscess. Because the Kupffer cells within the abscess and the Kupffer cells that surround the abscess differ in their ability to engulf the technetium-99m–labeled colloid, this scanning technique widely and effectively diagnoses and locates liver abscesses. However, limitations of the technique include the inability to detect lesions smaller than 2 cm, differentiate solid from cystic lesions, and allow planning for therapeutic interventions. Chest and abdominal radiography reveal nonspecific abnormalities in approximately 50% of cases. Although hepatic arteriography also has been used to image hepatic abscesses, it is invasive and does not offer any benefits over CT. Magnetic resonance imaging (MRI), although accurate in detecting liver abscesses, offers no advantage over CT scanning and does not allow percutaneous aspiration for diagnosis or treatment.

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Most patients with liver abscesses have leukocytosis and increased liver enzyme activity, with alkaline phosphatase the enzyme most severely affected. Half of patients with pyogenic abscesses have positive blood cultures. The presence of viridans streptococci, especially S. anginosus group, and increased liver enzyme activities in the absence of endocarditis is an important clue to the diagnosis of pyogenic liver abscesses. Amebiasis and amebic abscesses of the liver may be difficult to diagnose, because amebae may not be recovered from pus and are more often found on the wall of the abscess. CT and ultrasonography can be used to aspirate these lesions for rapid diagnosis. Both aerobic and anaerobic cultures should be obtained. A sterile, brownish aspirate without a foul smell is characteristic of an amebic abscess. However, fluid in amebic abscesses can be yellow or green and secondarily infected, rarely, with other organisms. Finding Entamoeba histolytica trophozoites on direct microscopy or culture is diagnostic of an amebic abscess. The diagnosis of amebic abscess can be confirmed by the finding of increased serum antiamebic antibody titers with an indirect hemagglutination test, for which results are readily available within 24 hours in most major medical centers. The serologic test for amebiasis indicates either past or current exposure to ameba and is positive in 90% of cases of amebic liver abscess. In areas of the world where such disease is endemic, high titers may be found in a high percentage of the population. If the diagnosis is in doubt, a trial or inclusion of amebicidal therapy is helpful in reaching a conclusion.

Treatment Pyogenic Liver Abscess The keystones of treatment of pyogenic liver abscesses are drainage and antibiotic therapy in addition to eliminating the underlying source of the condition if it is known (8). Untreated pyogenic hepatic abscesses carry a 95% to 100% death rate. When a pyogenic hepatic abscess is suspected, the patient should be given broad-spectrum antibiotic therapy directed against gram-negative rods, Streptococcus species, and anaerobes. Appropriate initial antibiotics may include an aminoglycoside, clindamycin or metronidazole for anaerobes, and a penicillin. Antibiotic coverage is then adjusted according to the results of culture of the aspirated or drained abscess. The duration of antibiotic coverage can range from 1 week to 4 months, depending on the response of the patient. Once empirical antibiotic therapy commences, CT or ultrasonography should be done for diagnostic aspiration. If there is no intra-abdominal source of infection but at least 1 large abscess, percutaneous drainage and antibiotic therapy may suffice. In patients with many small abscesses without intra-abdominal pathology, antibiotic therapy alone is a reasonable treatment choice, with surgical drainage reserved for cases of antibiotic failure if the clinical setting

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dictates the need. If on the initial CT scan an intra-abdominal source is found, surgical drainage and surgical treatment of the source is recommended. Simple aspiration is useful as a diagnostic adjunct to antibiotic therapy in healthy young individuals and for draining many small abscesses. Most liver abscesses require continuous catheter drainage, with assessment by CT or ultrasonography once per week (or sooner if there is no response to therapy). In the past, surgical drainage was the only available treatment option for hepatic abscesses. Currently, the indications for surgery include cases of liver abscess with an identifiable abdominal pathology and cases in which percutaneous drainage fails or cannot be done. Recently, alternative approaches have been introduced for the treatment of pyogenic liver abscesses. Laparoscopic techniques have been used to drain hepatic abscesses and to identify and treat underlying abdominal pathology. This approach, in addition to antibiotic therapy, has been used for patients in whom percutaneous drainage has failed, thereby avoiding a laparotomy (9). Radiologic advances have allowed the drainage of pyogenic liver abscesses and the intracavitary instillation of antibiotics without the need for indwelling, percutaneously placed catheters (10). Endoscopic sphincterotomy with local antibiotic lavage by means of endoscopically placed nasobiliary catheters has been shown to be a safe and effective technique for completely resolving pyogenic abscesses of biliary origin, with only 1 of 19 patients requiring salvage surgical drainage (11).

Amebic Liver Abscess The treatment of choice for amebic liver abscesses is an amebicidal agent. Metronidazole 750 mg 3 times daily orally for 7 to 14 days can be effectively used to treat both the hepatic and intestinal phases of most cases of amebiasis. In some cases, however, metronidazole may have to be continued for 4 to 6 weeks. Patients unable to take metronidazole orally, can take it intravenously with similar results. Other agents used include emetine, dehydroemetine, and chloroquine; however, the toxicity of these drugs seldom makes them the primary agents of choice. Aspiration is rarely needed unless the diagnosis is suspect or a secondary bacterial infection is present. Surgical drainage has a role in suspected abscess rupture, adjacent structure perforation, and cases of erosion or poor response to medical therapy. Patients who fail to respond to antiamebic therapy may have a bacterial infection, and their treatment should be adjusted accordingly. In patients with perforated amebic abscesses, needle aspiration in combination with drug therapy is superior to drug therapy alone (12). The prognosis of hepatic amebic abscess is good: Death from uncomplicated amebic abscesses is less than 5%. In cases in which there is erosion into the pericardium or free intraperitoneal rupture, death increases to 30% to 50%.

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Splenic Abscesses Isolated splenic abscesses are rare and potentially lethal, and their diagnosis is often delayed. The incidence of splenic abscesses in autopsy series ranges from 0.14% to 0.70% (13). Immunosuppression by AIDS and for organ transplantation, more aggressive chemotherapy for a wider variety of cancers, and efforts to conserve the spleen after trauma have contributed to the recent increase in splenic abscesses and to the change in pattern and bacteriology of these lesions (14). Splenic abscesses can be seen de novo in patients in intensive care units (ICUs) and carry a high death rate (40%100%), especially after surgery or trauma (15).

Etiology The cause of splenic abscesses can be divided into the following 5 major categories (16): 1. Hematogenous spread from septic foci: probably the most common; distant sources of infection that affect the spleen include endocarditis, pyelonephritis, disseminated tuberculosis, Salmonella bacteremia in AIDS patients, immunosuppression in cancer patients, intravenous drug abuse, intra-abdominal sepsis, chest infections, osteomyelitis, infected vascular access sites, infected ventriculoperitoneal shunts, and tooth extractions. 2. Contiguous infection through direct spread from adjacent viscera: such as in the case of colonic or gastric perforations and pancreatic and subphrenic abscesses. 3. Secondary infection of a splenic infarction: such as those caused by emboli from the heart, lipid embolization in Weber-Christian disease, splenic artery embolization, and infarction caused by splenic vein thrombosis from sickle cell disease or hemoglobinopathies (e.g., thalassemia). 4. Splenic trauma: including procedural or iatrogenic injury. 5. Immunodeficiency: especially when fungi or unusual organisms are involved.

Clinical Manifestations The clinical presentation of splenic abscesses is nonspecific but includes abdominal pain in the left upper quadrant, pleuritic chest pain, fever, and leukocytosis (14). Most patients present with fever (69%-90%) and abdominal pain (56%-70%). Other findings that may suggest splenic abscesses are pain referred to the left shoulder (from diaphragmatic irritation), elevation of the left hemidiaphragm, and left pleural effusion. Splenomegaly is present in 31% to 40% of patients.

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Diagnosis A high degree of clinical suspicion is essential for the early diagnosis of splenic abscesses. Diagnosis usually is delayed, with the duration of symptoms averaging 16 to 22 days (17). Ultrasonography, CT, and MRI have been used successfully for diagnosing splenic abscesses. CT is superior to ultrasonography because it 1) can define the exact location of an abscess, 2) can demonstrate subcapsular or perisplenic pathology, 3) is unhindered by air in the left upper quadrant, and 4) has both a reported sensitivity and specificity of 96% (18). Leukocytosis has been reported in 60% to 100% of patients with splenic abscesses. Positive blood cultures have been found in 48% of patients, with only 24% having organisms similar to those obtained from their abscess pus. Thrombocytosis (mainly caused by splenic infarction) could occur in up to 17% of cases; however, it was present in 8 of 9 patients in an ICU setting. It is worth mentioning that unexplained thrombocytosis in a septic ICU patient with persistent left pleural effusion is suggestive of splenic abscess (15).

Treatment Once the diagnosis of a splenic abscess is made, treatment with broadspectrum antibiotics should be instituted, because 25% of splenic abscesses are polymicrobial with anaerobes (14). Antibiotic therapy should be targeted against streptococci and staphylococci, which are the most common organisms seen in splenic abscesses and reflect the most common causes of abscesses that result from endocarditis or intravenous drug abuse. Gram-negative rods such as Salmonella and E. coli account for 30% of cases of splenic abscess, whereas anaerobes account for 12%; both types of organism should be covered initially. Antibiotic therapy can then be tailored to the results of blood cultures, and surgical drainage can be done (Table 12-1). Fungal splenic abscesses (especially those caused by Can-dida) have been on the increase, principally among patients who receive corticosteroids and those who undergo chemotherapy for cancer; antifungal coverage alone may be adequate for treating these abscesses, particularly because most of those are caused by fungi and are small and multifocal. Antibiotic therapy alone, without drainage of a splenic abscess, carries a high death rate. Up to 90% of patients with unilocular, well-contained bacterial abscesses may be managed with CT-guided percutaneous indwelling catheter drainage in addition to antibiotics with splenectomy reserved for failures (18). Splenectomy remains the treatment of choice for many splenic abscesses and the gold standard for treating most of these lesions (19). Splenotomy with drainage is reserved for the most acutely ill patients, in whom extensive adhesions preclude the performance of a safe splenectomy.

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Table 12-1 Common Causes and Recommended Antimicrobial Therapies for Various Intra-abdominal Abscesses Condition

Liver abscess Pyogenic

Amebic Splenic abscess

Pancreatic abscess

Appendiceal abscess

Diverticular abscess

Common Etiologic Microorganisms

Antimicrobial Therapies*

Actinomyces spp. Bacteroides spp. Clostridium spp. Enterococcus spp. Escherichia coli Fusobacterium spp. Klebsiella pneumoniae Peptostreptococcus spp. Pseudomonas spp. Staphylococcus aureus Viridans-group Streptococcus

Single agents: Imipenem 500 mg IV q6h/meropenem 1 g IV q8h/ertapenem*. 1g IV daily/ tigecycline 100 mg IV initially then 50 mg IV q12h# or Beta-lactam or beta-lactamaseinhibitor combinations† Combination therapy: Ampicillin 1-2 g IV q6h + gentamicin‡ I.5 mg/kg IV q8h + metronidazole 500 mg IV q6-8h or Ceftazidime 2 g IV q12h or cefepime 2 g IV q12h + metronidazole 500 mg IV q6-8h For penicillin-allergic patients: Ciprofloxacin 400 mg IV q12h + metronidazole 500 mg IV q6-8h Metronidazole 750 mg PO tid for 7-14 d Entamoeba Single agents: histolytica Ceftriaxone 2 g IV q24h or Escherichia coli levofloxacin 500 mg IV q24h Salmonella spp. Combination therapy: Staphylococcus Nafcillin or oxacillin 2 g IV q4h + spp. gentamicin‡ I.5 mg/kg IV q8h Streptococcus spp. For penicillin-allergic patients: Vancomycin 1 g q12h* + gentamicin‡ I.5 mg/kg IV q8h or Aztreonam 2 g IV q8h** + clindamycin 600-900 mg IV q8h Bacteroides fragilis Single agents: Enterobacteriaceae As with pyogenic liver abscesses Enterococcus spp. Combination therapy: Escherichia coli Ceftazidime 2 g IV q12h + either Klebsiella pneumoniae metronidazole 500 mg IV q6h§ or Pseudomonas clindamycin 600-900 mg IV q8h aeruginosa For penicillin-allergic patients: Staphylococcus aureus As with pyogenic liver abscesses Bacteroides fragilis Single agents: Escherichia coli As with pyogenic liver abscesses Peptostreptococcus spp. Combination therapy: Pseudomonas As with pyogenic liver abscesses aeruginosa For penicillin-allergic patients: As with pyogenic liver abscesses Bacteroides fragilis Single agents: Escherichia coli As with pyogenic liver abscesses Continued

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Table 12-1 Continued Condition

Common Etiologic Microorganisms

Antimicrobial Therapies*

or Cefotetan 2 g q12h or cefoxitin 2 g q6h IV Combination therapy: Ampicillin 1-2 g IV q6h + gentamicin‡ 1 mg/kg IV q8h + either metronidazole 500 mg IV q6h§ or clindamycin 600-900 mg IV q8h For penicillin-allergic patients: As with pyogenic liver abscesses or Aztreonam 2 g IV q6h + metronidazole 500 mg IV q6h§ * Antibiotic therapy should be directed toward the final culture results. Unless otherwise specified, treatment should last for 5-14 days until the patient is afebrile and has a normal leukocyte count. The antibiotic dosages should be adjusted according to the patient’s renal and hepatic functions, with levels measured as necessary. # No pseudomonal coverage, no data available on viridans strep coverage. † These combinations include piperacillin-tazobactam 4.5 g q8h, ticarcillin—clavulanate 3.1 g q6h (has weak antienterococcal activity), and ampicillin-sulbactam 3 g IV q8h (has no antipseudomonal activity and increasing E. coli resistance reported). ** No reliable pseudomonal activity and no enterococcal activity. ‡ Dosing based on nonobese patients with normal renal function. Also, gentamicin 5-7 mg/kg/once-daily dosing has been used but not supported in critically ill patients. § Has poor antistaphylococcal activity. ¶ In some cases, a duration of up to 4-6 weeks may be necessary. ** This combination does not have good activity against gram-positive cocci such as Staphylococcus and Streptococcus species. Abbreviations: d = d day; h = hour; IV = intravenously; PO = orally; q = every; spp. = species; tid = three times a day.

Pancreatic Abscesses Pancreatic infection is usually a secondary process. The infection is usually bacterial and occurs in previously damaged pancreatic tissue. This damage is typically from acute pancreatitis (usually severe enough to cause necrosis) or trauma. Pancreatic abscess can be defined as a contained, intra-abdominal infection with purulent material close to the pancreas with or without pancreatic necrosis. Infected pancreatic necrosis is defined as a diffuse or focal area of nonviable parenchyma with associated bacterial infection (20). Infected necrosis is an important risk factor for illness and death (21).

Etiology Pancreatic abscesses occur as complications of pancreatitis and trauma. Additionally, endoscopic retrograde cholangiopancreatography is a cause

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Table 12-2 Etiologies of Acute Pancreatitis Biliary tract disease Alcohol Hyperlipidemia Hypercalcemia Familial Trauma

Ischemia Pancreatic duct obstruction Viral infection Scorpion venom Idiopathic Drugs

of pancreatitis and subsequent abscesses. Acute pancreatitis has many causes (Table 12-2). Most cases are related to the biliary tract or to alcohol consumption. Gallstones obstruct the ampulla of Vater, which diverts bile flow into the pancreatic duct, causing injury and subsequent pancreatitis. The exact mechanism of alcohol-induced pancreatitis is unknown. The presence of acute necrotizing pancreatitis increases the likelihood of pancreatic infection and/or abscess. Infection develops in 40% of cases of pancreatic necrosis, usually in the second or third week of the disease (22). Secondary pancreatic infections occur in 2% to 5% of cases of acute pancreatitis and represent serious complications (20). As a result, the pancreas becomes infected, either from the hematogenous spread of pathogens or from their transmural translocation from adjacent inflamed bowel. Organisms cultured from pancreatic abscesses are predominantly gramnegative and polymicrobial. They include E. coli, Klebsiella pneumonia, Enterococcus species, staphylococcus species, and pseudomonal species (23). Fungal pancreatic abscesses are mostly associated with ERCP, parenteral nutrition, and broad spectrum antibiotics. Most common isolates are Candida albicans and Candida glabrata.

Clinical Manifestations The clinical presentation of acute pancreatitis varies. The patient can present with a mild form of the disease or with hypovolemic shock, sepsis, and metabolic abnormalities (20). The pain typically begins in the midepigastrium and is constant. The pain itself is of varying intensity, and the patient may present with generalized peritonitis. The patient may report pain “boring into the back.” Nausea and vomiting may accompany the abdominal pain. Abdominal distention resulting from paralytic ileus may be present. If hemorrhagic pancreatitis is present, Grey Turner sign or Cullen sign (i.e., a bluish discoloration of the flank or umbilicus, respectively) may be present, indicating severe pancreatitis. Jaundice may be present in patients with gallstone-induced pancreatitis. The patient with secondary infection may recover initially from a bout of acute pancreatitis only to deteriorate suddenly, or he or she may simply fail to respond to the initial therapy.

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Diagnosis The diagnosis of acute pancreatitis is based on the clinical presentation of the patient, laboratory variables, and radiologic studies. An increased serum amylase is the laboratory parameter accepted most widely for assisting the diagnosis (24). A persistently increased amylase level beyond the first week usually reflects ongoing inflammation or may signal the development of complications such as a pseudocyst, phlegmon, or abscess (20). Persistent abdominal pain, fever, and leukocytosis also should alert the physician to the possibility of secondary infection. Identifying a pancreatic pseudocyst, phlegmon, or abscess can be made in 80% to 90% of cases through imaging studies with ultrasonography, CT, or radionuclide scanning; however, CT is diagnostically superior to ultrasonography. Plain radiography may reveal a left pleural effusion, elevated hemidiaphragm, or retrogastric or retroperitoneal air. Contrast studies might show displacement of the stomach or duodenum. It can be difficult to distinguish sterile pancreatic necrosis from secondarily infected pancreatic abscesses. A CT scan alone may be beneficial in this regard; but CT-guided aspiration, Gram staining, and culture may be necessary to make the distinction (24). Dynamic CT scanning can provide information about the viability of the pancreas through the uptake of intravenous contrast medium. MRI is not typically beneficial in aiding in the diagnosis of pancreatic abscess (25).

Treatment Prophylactic antibiotic treatment in severe pancreatitis may prevent complications such as an abscess. The choice of antibiotic is critical, because it must penetrate the pancreatic parenchyma. Drugs with poor pancreatic penetration include aminoglycosides, first-generation cephalosporins, cefoxitin, and ampicillin. Imipenem is usually the first choice, with ciprofloxacin or levofloxacin with metronidazole an alternative (21). In case of fungal infections, treatment could be either fluconazole 800 mg IV then 400 mg IV daily or amphotericin B lipid complex 5 mg/kg IV daily. New fungal agents such as echinocandins and voriconazole have been approved. Percutaneous drainage alone seems inadequate in most cases but can be considered as the initial treatment of culture-positive cysts (26). The indications for surgical drainage include demonstration of an infected pancreatic necrosis by bacterial cytology or dynamic CT scan or by a failure of a trial of percutaneous drainage. Several surgical options are available for the management of pancreatic cysts. Each has its proponents, and the surgeon should be familiar with all possible treatments. Reexploration is frequently needed in this group of patients. All necrotic material must be débrided. The pancreatic bed must be irrigated copiously. The pancreatic bed can be packed, and plans can be made

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for reoperation 48 hours later, with the absence or presence of healthy granulation used to determine a plan for subsequent laparotomies. Largebore drains are typically left in place. Another operative plan is to leave several large-bore drains in place after adequate tissue debridement. Subsequently, these drains can be used for continuous postoperative lavage in the ICU. Surgical debridement with closed-suction drainage is another option. With this method it is occasionally difficult to determine clinically when a repeat exploration is necessary. With the other methods described, reexploration is done at 48-hour intervals to assess the viability of the tissue. Recently, laparoscopic assisted drainage of pancreatic abscesses has been successful (27).

Appendiceal Abscess The natural history of appendicitis includes perforation in 16% of cases (28). When an appendix perforates, a periappendiceal abscess, a phlegmon, or diffuse peritonitis develops. A periappendiceal abscess is a pus-containing periappendiceal mass, which usually lies in the right lower quadrant. A periappendiceal phlegmon is an inflammatory mass that comprises the appendix, adjacent viscera, and the omentum but does not contain purulent material (29). Diffuse peritonitis signifies a surgical emergency. It is best to diagnose and treat appendicitis before perforation occurs to prevent the illness associated with the latter.

Etiology Appendiceal abscesses result from the rupture of an acutely inflamed appendix. From 2% to 6% of cases of acute appendicitis are complicated by periappendiceal masses and/or abscesses (29). Obstruction of the lumen by a fecalith is the most common cause of appendicitis. The obstruction causes distention of the appendiceal lumen, which in turn increases the intraluminal pressure (28). Mucosal secretion and multiplication of bacteria continue, adding to the increased pressure. The intraluminal pressure eventually exceeds venous pressure, whereas arterial inflow continues, resulting in vascular congestion (28). As the distention progresses, the arterial inflow is compromised, causing areas of infarction and necrosis. Ultimately this leads to perforation, usually on the antimesenteric side of the appendix. The bacteriology of appendiceal abscesses, as with most intra-abdominal abscesses, is polymicrobial. Anaerobes, aerobes, and facultative bacteria have been cultured from appendiceal abscesses. Bacteroides fragilis and E. coli are the most common organisms identified (30).

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Clinical Manifestations Abdominal pain is the most common report in appendicitis. The classic pain of appendicitis begins in the periumbilical region and, after a period of several hours, localizes to the right lower quadrant (28). This classic symptomatology is not always present. Anorexia almost always accompanies appendicitis, and vomiting occurs in most patients. If vomiting occurs before the onset of pain, the diagnosis of appendicitis should be questioned (28). The patient usually lies still, occasionally with the hips flexed to help relieve the peritoneal irritation. If the appendix lies anteriorly, right-lower quadrant pain is present in its characteristic fashion. Rebound and guarding are usually present, with maximal pain in the right lower quadrant. Leukocytosis is present. A low-grade fever is present, with the temperature rarely exceeding 38.5°C (28). Appendiceal rupture should be suspected in patients with a temperature more than 39°C and with leukocytosis exceeding 18,000/mm3 (28). Most appendiceal ruptures are contained, and generalized peritonitis is not present. If the rupture cannot be contained, generalized peritonitis occurs. In cases of appendiceal rupture, a mass may be palpable in the right lower quadrant. However, because of abdominal-wall guarding or obesity, the mass may not be palpable until the patient is anesthetized. Patients with an appendiceal mass and/or abscess tend to have longer periods of symptoms (usually lasting 5–7 days) before they present for treatment (29).

Diagnosis Plain radiography of the abdomen in appendicitis patients reveals a nonspecific bowel gas pattern and only rarely reveals a fecalith. Ultrasonography has been used to diagnose acute appendicitis and appendiceal masses and abscesses. The diameter of the appendix is measured together with graded compression. The diagnosis of appendicitis can be made if the appendix is noncompressible and 6 mm in diameter (31). The appendiceal mass can be seen more clearly on CT, which also allows one to assess the feasibility of percutaneous drainage. Contrast-enhanced CT is helpful in differentiating a phlegmon from an abscess.

Treatment Broad-spectrum antibiotics that are targeted at the polymicrobial nature of appendiceal abscesses should be instituted in patients with these lesions. An antibiotic regimen such as ampicillin/sulbactam or piperacillin/tazobactam or combination of an aminoglycoside with either clindamycin or metronidazole is effective (29) (see Table 12-1).

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Appendiceal abscesses can be treated in 2 ways: 1) immediate appendectomy with abscess drainage, or 2) initial nonoperative management with no oral intake, intravenous fluids, and intravenous antibiotics with percutaneous drainage. It has been shown that patients undergoing immediate appendectomy have a longer hospital stay, and a delayed elective operation may be safer (32). Most appendiceal masses resolve promptly with initial nonoperative treatment. If the mass and/or signs of infection persist, the causative abscess or phlegmon should be drained, preferably percutaneously. An interval appendectomy should be done 6 to 8 weeks later. An interval appendectomy is done to prevent recurrent episodes of appendicitis (29). The failure rate of nonoperative management is approximately 5% (33). Failure consisted of progression of disease to peritonitis or simply failure to improve. Most of those patients who had recurrent appendicitis had it within the first 9 weeks after discharge (33). Laparoscopic appendectomy is typically the treatment of choice for appendicitis (31). It permits a more complete examination of the abdomen and is especially useful for ruling out gynecologic diseases (31). Laparoscopically performed interval appendectomy has been proved to be safe (34). Patients 40 to 50 years of age or older who develop perforated appendicitis with a phlegmon or abscess and who initially were treated nonsurgically should have either a double-contrast enema or should undergo colonoscopy to rule out a malignant cecal tumor.

Diverticular Abscesses The terminology for diverticular disease and associated inflammation or abscesses may be confusing. Acute diverticulitis implies an acute inflammatory process that results from an inflamed diverticulum. The inflammation is limited to the involved bowel wall and surrounding structures (most commonly the attached mesentery), and there is no confined collection of pus. In contrast, a diverticular abscess is a collection of pus usually associated with a perforated diverticulum. This abscess may be relatively contained by either the bowel wall mesentery or other structures in close proximity (e.g., lateral or anterior abdominal wall, urinary bladder, loops of small intestine). The perforation may spread freely within the peritoneal cavity, leading to generalized peritonitis, which is a surgical emergency.

Etiology Diverticular abscesses arise from a diverticular perforation that may occur anywhere along the gastrointestinal tract. Diverticula are either congenital or acquired. Small bowel and cecum diverticula are congenital and may

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perforate, leading to many abscesses within a particular loop. The sigmoid colon is by far the most frequent point of origin of acquired diverticula, arising from a point of vascular egress within the hypertrophied muscular wall of the sigmoid colon. The following discussion focuses on abscesses associated with sigmoid diverticula (35).

Clinical Manifestations and Diagnosis Patients who present with a diverticular abscess usually have concomitant fever, leukocytosis, and abdominal pain. The temperature may reach 39°C or higher, and a marked left shift is usually noted in the complete blood count. Findings on physical examination are highly variable and range from a dull but persistent abdominal pain to signs of frank peritonitis. The pain may be localized to the suprapubic region in the midline if the abscess is confined to the mesentery. In this situation, the sigmoid colon is pushed medially and anteriorly. The pain may be restricted to the left lateral abdominal wall if the abscess or inflammation is located between the colon and the lateral abdominal wall. Bowel movements may reflect either constipation or diarrhea; but the passage of formed, regular stool is the exception. In some patients who present with acute diverticulitis, intensive antibiotic therapy may fail to resolve the inflammation and an abscess may develop. The clinical course of such patients is often characterized by unremitting fever, rising leukocytosis, and worsening abdominal pain. Scanning with CT has proved an invaluable radiographic method both for the diagnosis of diverticular abscess and as a guide to its treatment. Pus or abscess formation may be readily distinguished from the more common mesenteric inflammation. Importantly, CT permits the evaluation of other diseases, such as perforated cancer of the colon and appendicitis, which often mimics the clinical presentation of diverticulitis with associated abscess. In patients with diverticular abscesses, it is important to remember that, as with all intra-abdominal abscesses, occult hypoxemia may be present. Thus, routine monitoring of oxygenation becomes important. Additionally, the overall nutritional status of the patient should be assessed at the time of hospital admission.

Treatment Once diagnosed, a diverticular abscess is an indication for drainage. Diverticular abscesses do not resolve with antibiotic therapy alone. CT and CT-guided percutaneous drainage represent a huge step forward in the management of difficult, often elderly and frail, patients in whom many diverticular abscesses occur. A loculated abscess may be approached percutaneously, and effective drainage may be achieved. Usually, once defervescence and signs of systemic toxicity resolve, repeat CT is done at 5 to 7 days, along with a sinogram to ensure closure of the diverticulum and

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the absence of any persisting fistulous tract. A repeat CT scan is also done if the patient has not improved by 24 to 48 hours after drainage. This is used to assess any residual or ongoing abscesses. If at this point CT-guided drainage has been unsuccessful, surgical drainage by means of laparotomy should be instituted promptly. Broad-spectrum antibiotic coverage commences, with the regimen usually consisting of ampicillin and sulbactam, piperacillin and tazobactam or a combination of an aminoglycoside and an agent effective against anaerobes (e.g., clindamycin, metronidazole). Aminoglycosides should be administered with caution in the elderly, particularly those with underlying renal dysfunction. Alternatively, initial therapy may begin as monotherapy with a broad-spectrum cephalosporin (see Table 12-1). Once control of the abscess is achieved by nonoperative means, consideration should be given to elective colon resection with a primary anastomosis and a 1-stage operation (36).

Special Considerations Coverage of Enterococcus in intra-abdominal sepsis is controversial. Although coverage is not indicated in community-acquired intra-abdominal infections, coverage is recommended in complicated intra-abdominal infections in patients in septic shock, patients previously receiving prolonged treatment with cephalosporins, immunosuppressed patients with high risk for bacteremias, and patients with prosthetic heart valves and recurrent intra-abdominal infections (37). Isolation of fungi from intra-abdominal fluid after a viscous perforation is common because fungi are part of the normal intestinal flora. There is no consensus on prophylactic treatment of fungal isolates in all cases of intra-abdominal sepsis. Use of antifungal agents is recommended in patients with severe acute necrotizing pancreatitis, with recurrent gastrointestinal perforations or anastomotic leaks, with positive yeast blood cultures or yeast cultured from intra-abdominal abscesses (in the absence of other organisms), and who are profoundly immunocompromised (37,38). Antifungal therapy in the form of fluconazole or amphotericin B should always be continued for 2 to 3 weeks.

REFERENCES 1. D’Angelica M, Fong Y. The liver. In Townsend CM, et al, eds. Sabiston Textbook of Surgery. 17th ed. Philadelphia, Pa: Elsevier Saunders; 2004:1534-42. 2. Barnes PF, De Cock KM, Reynolds TN, Ralls PW. A comparison of amebic and pyogenic abscess of the liver. Medicine (Baltimore). 1987;66:472-83. 3. Branum GD,Tyson GS, Branum MA, Meyers WC. Hepatic abscess. Changes in etiology, diagnosis, and management. Ann Surg. 1990;212:655-62. 4. Johannsen EC, Madoff LC. Infections of the liver and biliary system. In Mandell GL, et al, eds. Principals and Practices of Infectious Diseases. 6th ed. Philadelphia, Pa: Churchill Livingstone; 2005:951-59.

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5. Perera MR, Kirk A, Noone P. Presentation, diagnosis and management of liver abscess. Lancet. 1980;2:629-32. 6. Thaler M, Pastakia B, Shawker TH, O’Leary T, Pizzo PA. Hepatic candidiasis in cancer patients: the evolving picture of the syndrome. Ann Intern Med. 1988;108:88-100. 7. Barbour GL, Juniper K Jr. A clinical comparison of amebic and pyogenic abscess of the liver in sixty-six patients. Am J Med. 1972;53:323-34. 8. Gerzof SG, Johnson WC, Robbins AH, Nabseth DC. Intrahepatic pyogenic abscesses: treatment by percutaneous drainage. Am J Surg. 1985;149:487-94. 9. Tay KH, Ravintharan T, Hoe MN, See AC, Chng HC. Laparoscopic drainage of liver abscesses. Br J Surg. 1998;85:330-2. 10. Miller FJ,Ahola DT, Bretzman PA, Fillmore DJ. Percutaneous management of hepatic abscess: a perspective by interventional radiologists. J Vasc Interv Radiol. 1997;8:241-7. 11. Dull JS, Topa L, Balgha V, Pap A. Non-surgical treatment of biliary liver abscesses: efficacy of endoscopic drainage and local antibiotic lavage with nasobiliary catheter. Gastrointest Endosc. 2000;51:55-9. 12. Meng XY, Wu JX. Perforated amebic abscess: Clinical analysis of 110 cases. South Med J. 1994;87:988-90. 13. Chun CH, Raff MJ, Contreras L, Varghese R, Waterman N, Daffner R, et al. Splenic abscess. Medicine (Baltimore). 1980;59:50-65. 14. Nelken N, Ignatius J, Skinner M, Christensen N. Changing clinical spectrum of splenic abscess. A multicenter study and review of the literature. Am J Surg. 1987;154:27-34. 15. Ho HS,Wisner DH. Splenic abscess in the intensive care unit. Arch Surg. 1993;128:842-6; discussion 846-8. 16. Madoff LC. Splenic abscess. In Mandell GL, et al, eds. Principals and Practices of Infectious Diseases. 6th ed. Philadelphia, Pa: Churchill Livingstone; 2005:967-8. 17. Phillips GS, Radosevich MD, Lipsett PA. Splenic abscess: another look at an old disease. Arch Surg. 1997;132:1331-5; discussion 1335-6. 18. Gleich S,Wolin DA, Herbsman H. A review of percutaneous drainage in splenic abscess. Surg Gynecol Obstet. 1988;167:211-6. 19. Sarr MG, Zuidema GD. Splenic abscess—presentation, diagnosis, and treatment. Surgery. 1982;92:480-5. 20. Yeo CJ, Cameron J. Acute pancreatitis. In Zuidema G, ed. Shackelford’s Surgery of the Alimentary Tract. 4th ed. Philadelphia, Pa: WB Saunders; 1996:18-37. 21. Hartwig W, Werner J, Uhl W, Büchler MW. Management of infection in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2002;9:423-8. 22. Stiles GM, Berne TV,Thommen VD, Molgaard CP, Boswell WD. Fine needle aspiration of pancreatic fluid collections. Am Surg. 1990;56:764-8. 23. Shi EC,Yeo BW, Ham JM. Pancreatic abscesses. Br J Surg. 1984;71:689-91. 24. Reber H. Pancreas. In Schwartz S, ed. Principles of Surgery. 7th ed. New York, NY: McGrawHill; 1999:1467-99. 25. Paushter DM, Modic MT, Borkowski GP, Weinstein MA, Zeman RK. Magnetic resonance. Principles and applications. Med Clin North Am. 1984;68:1393-421. 26. Baril NB, Ralls PW,Wren SM, Selby RR, Radin R, Parekh D, et al. Does an infected peripancreatic fluid collection or abscess mandate operation? Ann Surg. 2000;231:361-7. 27. Horvath KD, Kao LS, Wherry KL, Pellegrini CA, Sinanan MN. A technique for laparoscopicassisted percutaneous drainage of infected pancreatic necrosis and pancreatic abscess. Surg Endosc. 2001;15:1221-5. 28. Kozar R, Roslyn J. The appendix. In Schwartz S, ed. Principles of Surgery. 7th ed. New York, NY: McGraw-Hill; 1999:1383-94. 29. Nitecki S,Assalia A, Schein M. Contemporary management of the appendiceal mass. Br J Surg. 1993;80:18-20. 30. Thadepalli H, Mandal AK, Chuah SK, Lou MA. Bacteriology of the appendix and the ileum in health and in appendicitis. Am Surg. 1991;57:317-22. 31. Pegoli W. Acute appendicitis. In Cameron J. Current Surgical Therapy. 6th ed. St. Louis, Mo: Mosby; 1995:263-6. 32. Brown CV,Abrishami M, Muller M,Velmahos GC. Appendiceal abscess: immediate operation or percutaneous drainage? Am Surg. 2003;69:829-32. 33. Oliak D,Yamini D, Udani VM, Lewis RJ,Vargas H,Arnell T, et al. Nonoperative management of perforated appendicitis without periappendiceal mass. Am J Surg. 2000;179:177-81.

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34. Vargas HI,Averbook A, Stamos MJ. Appendiceal mass: conservative therapy followed by interval laparoscopic appendectomy. Am Surg. 1994;60:753-8. 35. Saini S, Kellum JM, O’Leary MP, O’Donnell TF,Tally FP, Carter B, et al. Improved localization and survival in patients with intraabdominal abscesses. Am J Surg. 1983;145:136-42. 36. Pruett TL, Rotstein OD, Crass J, Frick MP, Flohr A, Simmons RL. Percutaneous aspiration and drainage for suspected abdominal infection. Surgery. 1984;96:731-7. 37. Blot S, De Waele JJ. Critical issues in the clinical management of complicated intra-abdominal infections. Drugs. 2005;65:1612-20. 38. Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161-89.

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Part V

Genitourinary Infections

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Chapter 13

Urinary Tract Infections in Adults ALLEN R. RONALD, OC, MD

Key Learning Points 1. Acute bacterial cystitis episodes in women are very common, often related to sexual intercourse, best managed with a three day course of an anti-infective usually with minimal investigation, and prevented by intermittent or continuous prophylactic regimens. 2. Acute pyelonephritis is a relative medical emergency, should be diagnosed by urine culture, stratified by severity of illness and comorbidities, and imaging performed if indicated with effective, often parenteral, initial anti-infective treatment. 3. Asymptomatic bacteriuria regardless of pyuria, should in nonpregnant women and in men only be treated if an indication for treatment is present.

A

urinary tract infection (UTI) is the presence of microbes anywhere in the urinary tract, including the proximal urethra, bladder, prostate gland, ureters, and kidneys. UTIs are common in all populations, and their global annual incidence probably exceeds 250 million. The infection may be limited to asymptomatic superficial colonization of the epithelial lining of the urinary tract, or it may progress to invasive inflammatory injury to the renal parenchyma or suppuration of renal tissue, occasionally spreading through the renal capsule and creating a perinephric abscess. UTIs are categorized as uncomplicated if there is no known functional or anatomic abnormality of the urinary tract and no underlying host abnormalities. Approximately 80% of UTIs are uncomplicated. UTIs are termed complicated whenever any of the entities listed in Table 13-1 is present (1). Although many infections categorized as complicated can be readily cured, 245

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New Developments in the Diagnosis and Management of Urinary Tract Infections ●

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Trimethoprim-sulfonamide resistance continues to increase and in most areas of the world, including the United States, can no longer be used as empiric therapy for community-acquired urinary infection if the patient is moderately or seriously ill. Clonal Escherichia coli with invasive uropathogenic genes are spread widely in food and can be acquired from pets. Asymptomatic urinary infection in patients with diabetes mellitus and in patients with indwelling catheters should not be treated regardless of pyuria.

Table 13-1 Classification of Causes of Complicated Urinary Tract Infections Structural Abnormalities

Obstruction Vesicouretal reflux Neurogenic bladder Calculi Renal abscess(es) Fistula to intestine or other sites Urinary diversion procedures Infected cysts Urinary catheters Metabolic or Hormonal Abnormalities

Diabetes mellitus Pregnancy Renal impairment Impaired Host Response

Post-transplantation Neutropenia HIV/AIDS Unusual Pathogens Pseudomonas aeruginosa and other multiresistant organisms Calculi-associated bacteria Yeasts, fungi, mycobacteria AIDS = acquired immune deficiency syndrome; HIV = human immunodeficiency virus.

a proportion of complicated UTIs will be persistent, difficult-to-treat infections with frequent recurrences. As a result, the categorization of a UTI as complicated is important for patient management.

Epidemiology Approximately 150,000 individuals, or 1 per 1000 adults per year, are estimated to be admitted to hospitals with acute pyelonephritis in the United States (2,3). UTIs are the most common nosocomial-acquired infection,

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and their acquisition increases health care costs substantially. Although pyelonephritis is identified as the cause of death in only approximately 1000 individuals in the United States (3,4) septicemia, which arises from the urinary tract in at least 25% of instances, is responsible for more than 20,000 deaths each year (2). The epidemiology of urinary infection varies with age, gender, and underlying risk factors (5). During the first year of life, the cumulative prevalence of UTI in men is approximately 0.2%. These infections are frequently symptomatic, and require urologic investigation because of the possibility of underlying congenital anomalies. Urinary infections are subsequently rare in male children, with a cumulative incidence by the age of 10 years of less than 1%. The presence of a foreskin increases by at least 5-fold the probability of urinary infection during childhood (6). Among girls, the cumulative incidence of UTI during the first 10 years of age is 3%. UTIs in infancy and early childhood can be associated with symptomatic pyelonephritis, persisting renal infection with failure of renal growth, and extensive renal scarring. As a result, urinary infections in early childhood are investigated and managed more aggressively. Treatment is usually prescribed, and follow-up cultures should be done to ensure cure. However, asymptomatic bacteriuria in a normal urinary tract in girls older than age 6 years is usually benign, and aggressive investigation and management only warranted with recurrences. Acute cystitis is by far the most common clinical presentation of urinary infection in adults. Urinary infections are extremely common in sexually active women, with at least one third of women having had an episode of symptomatic UTI within 10 years of the initiation of sexual activity. In a prospective study of sexually active women in a health management organization, 50 of every 100 women, had acute cystitis each year (7). Extrapolating from these data would suggest that at least 25 million episodes of acute cystitis occur annually in the United States. Studies have shown that sexual intercourse and the use of spermicides, with or without a diaphragm, are predisposing factors for UTIs among sexually active women (8). Condoms coated with nonoxyl-9 also increase the risk of cystitis. Many other factors have been studied and seem not to be significant in predisposing to acute cystitis. These include voiding habits, bathing, intake of fluid, voiding after intercourse, the direction of wiping after defecation, douching habits, types of menstrual protection, or perineal hygiene (7). However, recent antecedent antimicrobial use, and in particular the use of beta-lactam antibiotics, alters normal vaginal flora and predisposes women to cystitis (9). Factors that predispose women to an initial episode of acute cystitis also predispose to recurring bouts. Approximately 5% of women are UTI-prone and experience many, closely spaced episodes of infection (7). Many of these women have a genetic trait and potentially invasive strains of Escherichia coli adhere more readily to their uroepithelial cells (10). No other functional

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abnormalities or defects in host response have been identified in these infection-prone women, and urologic investigation or treatment has no proven role in their management. A proportion of patients who present with acute cystitis have renal involvement. Table 13-2 identifies factors shown to increase the probability of upper tract infection in patients with symptoms confined to the bladder. Both acute and recurrent cystitis are common in postmenopausal women. The risk factors for such cystitis are not well understood, but at least 1 study suggests it may occasionally be caused by estrogen deficiency (11). Additionally, older women with recurring UTIs may often have increased residual urine or other functional abnormalities of the urinary tract. Acute pyelonephritis tends to occur among patients who are susceptible to acute cystitis. Pregnancy, diabetes, immunosuppression, and obstruction predispose both men and women to acute pyelonephritis. Among patients with diabetes, the incidence of acute hospitalization for pyelonephritis is almost 10 times that for controls without diabetes for both men and women (4). The epidemiology of complicated UTIs has not been well studied. In a survey of nosocomial UTI, the incidence was 4.3/1000 patient days, and 88% of these infections were catheter related (12). However, UTIs are common in a wide range of patients with abnormalities of the urinary tract. All patients with chronic indwelling catheters have bacteriuria, but most remain asymptomatic unless obstruction occurs. However, over decades of urinary drainage with a catheter, patients with cord injuries often experience complications caused by urinary stones or abscess formation, and a few progress to having end-stage renal disease. Complications are at least 3 times more common in chronically catheterized men than in chronically catheterized women. UTIs in pregnancy cause preterm labor and low birth weight (13). Also, almost half of patients with asymptomatic infections, if untreated, will develop pyelonephritis during pregnancy. Presumably, this is caused by physiologic and anatomic changes in the urinary tract during pregnancy. Screening for and treating asymptomatic bacteriuria in all pregnant patients during the first trimester will prevent approximately 80% of episodes of acute pyelonephritis during pregnancy, and this intervention has been shown in

Table 13-2 Factors that Predict Renal Involvement in Patients Presenting with Cystitis or Asymptomatic Bacteriuria Vesicouretal reflux Pregnancy Upper tract pathology (known or unknown) Diabetes Relapse (rapid recurrence with identical pathogen) Unusual or resistant pathogen Older age Nosocomially acquired infection

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prospective studies to decrease the overall incidence of prematurity by 10% to 20% (13). Asymptomatic UTIs are common, and their prevalence is increased among patients who are prone to symptomatic infections (5,14). The prevalence of asymptomatic bacteriuria has been studied in many populations, and relevant data are summarized in Table 13-3. Asymptomatic bacteriuria has been a controversial diagnosis. Is it a benign happening or is it a disease burden with links to other illness or consequences? Studies throughout the past decade have determined that, with the exception of its occurrence during pregnancy, asymptomatic UTI in the healthy adult urinary tract has limited significance for the patient’s ongoing health and rarely ever alters renal function or overall illness (15). As a result, asymptomatic UTI should not be routinely sought and treated. In particular, asymptomatic bacteriuria is extremely common among the elderly, and its treatment is usually futile and unnecessary (16). The known factors predisposing to asymptomatic infection are similar to those for symptomatic urinary infection and include diabetes, residual urine, urinary instrumentation, and in females sexual intercourse (5,15).

Etiology Most UTIs are caused by rapidly growing pathogens, with a predominance of E. coli, often of a restricted number of O:K:H serotypes. Table 13-4 compares the prevalence of organisms in community-acquired infections, most of which are uncomplicated, and in hospital-acquired infections, many of which are complicated. The E. coli strains that cause most communityacquired infections originate from colonic flora. E. coli strains that have uropathogenic genes can be acquired from sources in the environment including food and water and colonize the colon (17). Women with increased susceptibility to infections are more often colonized on the perineum with E. coli, which brings the potential pathogen into close proximity with the urethra (10). Bacterial multiplication in the urinary tract results in cytokine generation by mucosal cells, with the production of interleukins (ILs) IL-6 and IL-8 (18,19). IL-6 activates acute-phase reactants

Table 13-3 Prevalence of Asymptomatic Bacteriuria Population Screened

Males 1–12 years old Females 1–12 years old Females 20–40 years old (including pregnant women) Males 20–40 years old Elderly ambulatory patients (men and women) Elderly bedridden patients (men and women) Chronically catheterized patients (men and women)

0.1% 1% 3–6% 0.1% 5–15% 10–50% 100%

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Table 13-4 Microbiology of Urinary Infection Uncomplicated

Escherichia coli Klebsiella spp. Enterobacter spp. Proteus spp. Pseudomonas spp. Staphylococcus saprophyticus Staphylococcus epidermidis Enterococci Group B streptococci Staphylococcus aureus Candida spp.

80–85% 1–3% 1–3% 1–3% <1% 5–10% 1–3% 1–3% 1–3% <1% <1%

Complicated*

40–60% 5–10% 5–10% 5–10% 5–10% 1–2% 5–10% 5–10% 1–3% 1–3% 5–10%

* Many isolates of gram-negative rods in complicated urinary tract infections are multiresistant to urinary tract antimicrobial agents, and most have been acquired in an institutional setting (i.e., nosocomial).

and produces fever and other systemic symptoms (10). IL-8 is a chemoattractant for neutrophils (19). Organism characteristics associated with renal invasion among E. coli include production of hemolysin and aerobactin, resistance to the bactericidal activity of normal human sera, and the presence of a surface fimbrial protein that adheres to epithelial cell. These virulence factors are clustered in the genome on uropathogenicity islands (10). P-fimbriated E. coli of the pap+ genotype are more frequently associated with acute pyelonephritis (10). One multidrug-resistant clonal group with many virulence factors has seemed to cause outbreaks of acute pyelonephritis in the United States and Europe (20). Among sexually active women, Staphylococcus saprophyticus often is the second most common urinary pathogen. Its epidemiology is not well understood. Group B streptococci, Klebsiella spp., Proteus spp., and other gram-negative organisms occur, also in UTIs, but are less frequent among patients with community-acquired infections. Patients receiving antimicrobial therapy often acquire more resistant infections, usually caused by the alteration of their gastrointestinal flora that develops as a result of antimicrobial pressure (9). Among patients with complicated infections, various more resistant organisms occur. In the hospital setting, nosocomial infections are more common, and are often caused by difficult-to-treat pathogens such as Pseudomonas aeruginosa, other resistant gram-negative rods, and Staphylococcus epidermidis. Among older men, Enterococcus faecalis is the second most common pathogen, after E. coli. Institutionally acquired pathogens are often transmitted from other patients with nosocomial urinary infection. Candida albicans is commonly acquired within institutions, usually by patients with indwelling catheters and receiving antibacterial treatment regimens. Fastidious organisms including anaerobes, Ureaplasma urealyticum, and invasive fungal infection caused by organisms other than Candida are

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all occasional pathogens. Viruses are sometimes present in urine (viruria), and occasionally propagate in renal tissue, producing local or systemic symptoms. Outbreaks of hemorrhagic cystitis caused by adenovirus have been described (21). Polyoma virus can cause renal infection and lead to renal insufficiency in patients after renal transplants (22). Brucella spp. and M. tuberculosis should be considered in patients with persistent signs of infection and negative conventional urine cultures. However, these pathogens are unusual and, even in developing countries, are responsible for less than 1% of urinary infections.

Clinical Manifestations and Differential Diagnosis UTIs present clinically as cystitis with urgency, burning, frequency, and lower abdominal pain, or as pyelonephritis with fever, chills, flank pain, and symptoms of a systemic inflammatory response. Acute cystitis, particularly when the urethral symptoms are prominent, must be differentiated from sexually transmitted infections such as those caused by Chlamydia trachomatis, Neisseria gonorrhoeae, and herpes simplex, which can also present with urethral symptoms. Some women may have difficulty differentiating symptoms originating from the genital tract from those caused by urinary infection. In particular, the symptoms of urinary infection can be confused by patients with vulvovaginal moniliasis and other illnesses that manifest with predominantly vaginal symptoms. All women with a first diagnosis of urinary infection should have some laboratory investigation, usually including urinalysis and urine culture, and a sexual risk assessment. If the patient is at risk of a sexually acquired infection, further studies are indicated. Interstitial cystitis (IC) is a diagnosis that is poorly understood, difficult to confirm, and confused with recurring bacterial cystitis (23). This diagnosis is optimally made through a combination of features that include negative urine cultures (see section on Laboratory Testing), a lack of pyuria during symptomatic episodes, absence of a response to antibacterial treatment, and frequent recurrences. IC is at least 10 times as common in women as in men. On occasion, cystoscopy with dilatation of the bladder leads to the observation of petechiae on the bladder mucosa. However, the sensitivity and specificity of this cystoscopic diagnosis is still undetermined. At present, IC is a diagnosis of exclusion and should be made only with serial observations over a patient’s course. It is also uncommon in men. Additional investigation is required to establish diagnostic measurements and develop approaches for the care of these patients. Too often they are shunted from primary care physician to urologist and back with no adequate direction for long-term care. Acute pyelonephritis should be a specific diagnosis, because it is frequently misdiagnosed. Approximately one fifth of patients initially diagnosed with pyelonephritis are proven to have alternate diagnoses including

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Table 13-5 Complications of Acute Pyelonephritis Hypotension, septic shock, multiple organ failure, death Renal or perinephric abscesses Metastatic infections at other sites Papillary necrosis Acute renal failure Emphysematous pyelonephritis Renal gangrene Localized or generalized atrophy/permanent loss of function

acute pelvic inflammatory disease, ectopic pregnancy, diverticulitis, renal calculi, and other conditions that also deserve a specific diagnosis. As a result, patients with clinically presumed acute pyelonephritis should be followed carefully until the diagnosis is confirmed by laboratory results. In addition, further investigation may be indicated to exclude obstruction and suppurative processes. The complications of acute pyelonephritis are outlined in Table 13-5. Most complications occur because of infection in a host with an anatomic or functional abnormality of the urinary tract, but acute uncomplicated pyelonephritis occasionally leads to septic shock and organ failure. As a result, pyelonephritis must be regarded as a relative medical emergency and treated promptly and the patient observed until initial improvement is documented. Men may present with urethritis and/or cystitis caused by urinary infection as well as with prostatic symptoms. The clinical features and management of prostatitis and epididymitis are presented in Chapter 14.

Diagnosis Laboratory Testing Laboratory diagnosis of UTI is usually straightforward (24). Pyuria is present in more than 90% of patients with a UTI; and in its absence, the diagnosis should be reconsidered. The widely used leukocyte esterase test has a sensitivity of approximately 85% and a specificity of 90% for 10 or more leukocytes per high-power field. Microscopic hematuria is present in 20% to 40% of patients with acute cystitis. The observation is unusual in vaginitis. A urine Gram stain or direct bacterial visualization has a low sensitivity (60%-70%) in identifying cystitis in women caused by low bacterial numbers in one third of patients. Of particular importance is the observation that from 10% to 30% of patients with acute symptoms will have bacterial counts of less than 108 colony-forming units (CFUs)/L (105 CFU/mL) (25). Low count bacteriuria occurs in both men and women with both acute cys-

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titis and acute pyelonephritis. As a result, quantitative counts should not be used to exclude the diagnosis of UTI, particularly in patients with symptoms and pyuria. Conversely, asymptomatic bacteriuria is a diagnosis made by the laboratory, and requires at least 2 urine cultures with more than 108 CFU/L (105 CFU/mL) unless the specimen is obtained through a catheter. A positive microscopic examination of a properly collected, stained, and interpreted urine specimen is specific and may influence empiric treatment choices in patients with acute pyelonephritis (26). Urine culture requires proper collection and transport of the specimen to provide a definitive diagnosis. The specimen is usually cultured quantitatively on both blood agar and a selective medium. Although many so-called improved technologies have been evaluated for urine culture, none have proven to be less expensive or more definitive than the conventional urine culture technology. Men presenting with urethritis, epididymitis, or infection within the scrotal sac should have a urine culture; N. gonorrhoeae and C. trachomatis studies; and if possible, prostatic fluid cultures. Bacterial epididymo-orchitis is common in elderly men, particularly in the presence of an indwelling catheter. Occasionally, a needle aspirate of a suppurative process in the scrotal sac may lead directly to microbiologic diagnosis (see Chapter 14 for more details on the laboratory investigation of prostatitis). In both men and women with symptoms confined to the bladder, localization of infection to 1 or both kidneys has been an unrealized goal. Localization of infection urologically with ureteral catheterization is difficult, and involves risk. The bladder washout technique of Fairley is unpleasant and often gives confusing results. The antibody-coated bacteria test is insensitive and nonspecific. As a result, no procedure is currently recommended for most patients presenting without symptoms or with lower tract symptoms. However, relapse with the identical infecting pathogen within 2 weeks after a short (3-day) course of treatment in women usually means more established persistent infection (27). The microbiology of complicated urinary infections is less well characterized (23). Many pathogens are often present; and although 1 particular pathogen may initially predominate in culture often, suppression of 1 pathogen with a treatment regimen permits others to appear. Microbial numbers in complicated UTI and the correlates with abnormalities of the urinary sediment, including pyuria, are largely unstudied. Blood cultures should be obtained for patients with presumed acute renal infection and are positive in 15% to 30% of cases. A positive blood culture has not been shown to alter the outcome of therapy. Antimicrobial susceptibility testing of urine isolates should be done for patients with pyelonephritis and those with complicated infections. However, this is not warranted for patients with cystitis, unless there is a history of previous treatment failure. Follow-up urine cultures should be obtained only if patients have upper tract symptoms or complicated UTIs. Historically, too much emphasis has

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been given to culture follow-up of adults with normal urinary tracts. In the absence of symptoms, follow-up has not been shown to be useful.

Imaging Studies Imaging of the urinary tract has changed dramatically over the past 2 decades. Intravenous pyelography is less useful than computed tomography (CT) scanning (28). Sonography is particularly useful for rapid evaluation for obstruction or abscesses, but it is less sensitive than CT for recognizing calculi or renal abnormalities in acute pyelonephritis. Helical CT, if available, has become the procedure of choice for excluding obstruction, identifying suppurative processes, excluding other intraabdominal conditions that may mimic acute pyelonephritis, and diagnosing acute changes in patients with pyelonephritis (28). Helical CT has an accuracy of 97% in depicting ureteral calculi (28). It can also contribute to the diagnosis of renal tuberculosis and xanthogranulomatous pyelonephritis or other upper tract abnormalities that may present with symptoms that mimic recurrent urinary infection. Although helical CT requires a substantial initial investment of capital, the net marginal cost is less than excretory urography (intravenous pyelography [IVP]) and should, in most instances, replace this technology (28). Nuclear imaging is of less use (28). The radiotracer dimercaptosuccinic acid will be abnormal in patients with acute pyelonephritis, but seems to add nothing to a CT scan. A gallium- or indium-labeled leukocyte scan will usually be positive in patients with acute pyelonephritis, but these technologies are rarely necessary. Occasionally, in the search for fever of unknown origin, indium or gallium studies will localize infection to the kidney.

Treatment Drug choices and doses are summarized in Table 13-6.

Acute Cystitis The treatment of acute cystitis has been extensively studied in many randomly assigned controlled trials. On the basis of more than 20 studies of women with acute bacterial cystitis, trimethoprim-sulfamethoxazole (TMPSMX) has been the drug of choice for acute cystitis (29,30). Single-dose treatment with TMP-SMX eradicates bacteriuria in approximately 80% of women with acute cystitis; a 3-day regimen eradicates bacteriuria in significantly more women (more than 90%) and is equivalent to longer, 7- to 10day courses of therapy. Longer courses of therapy are associated with greater adverse effects and increase the propensity to TMP-SMX–resistant recurrences (29). Beta-lactam drugs have also been well studied in randomly assigned controlled trials of acute cystitis. Overall, they have a sig-

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Table 13-6 Drug Choice and Dose for Urinary Tract Infection Acute Bacterial Cystitis and Asymptomatic Bacteriuria Women

Trimethoprim/sulfamethoxazole Ciprofloxacin* Ofloxacin* Levofloxacin* Nitrofurantoin Cephalexin

100 mg/800 mg 500 mg 400 mg 500 mg 100 mg 500 mg

b.i.d. b.i.d. b.i.d. Daily q.i.d. q.i.d.

3 3 3 3 7 7

days days days days days days

160mg/800 mg 500 mg 400 mg 500 mg 500 mg

b.i.d. b.i.d. b.i.d. Daily q.i.d.

7 7 7 7 7

days days days days days

160 mg/800 mg 500 mg 400 mg 500 mg 500 mg

b.i.d. b.i.d. b.i.d. Daily q.i.d.

14 days 7 days† 7 days† 7 days† 14 days

Men

Trimethoprim/sulfamethoxazole Ciprofloxacin* Ofloxacin* Levofloxacin Cephalexin Acute Pyelonephritis (Men and Women)

Oral trimethoprim/sulfamethoxazole Ciprofloxacin* Ofloxacin* Levofloxacin Cephalexin

Intravenous Therapy/Hospitalization* (Usually for 2–4 Days Followed by an Oral Regimen for 14 Days

Gentamicin with ampicillin Ceftriaxone Imipenem Piperacillin/tazobactam Ciprofloxacin* Ofloxacin* Levofloxacin*

5 mg/kg 2g 1g 500 mg 3.375 g 400 mg 500 mg 500 mg

Daily q6h Daily q6h q8h q12h q12h Daily

2–4 2–4 2–4 2–4 2–4 2–4 2–4 2–4

days days days days days days days days

* Identified fluoroquinolone antimicrobial agents. Other members of this class may be equally effective. † A 7-day regimen of ciprofloxacin has been effective in curing most women with acute uncomplicated pyelonephritis. Similar studies in men or with other fluoroquinolones are not available.

nificantly lower eradication rate than TMP-SMX, particularly if prescribed for 3 days, and are associated with more adverse effects and recurrences with resistant pathogens (29,31). Fluoroquinolones have been compared in 3-day and 7- to 10-day regimens (31-33). All fluoroquinolone regimens eradicate infection in at least 90% of premenopausal women with acute bacterial cystitis. A 3-day course is probably the optimal duration of therapy for achieving the greatest efficacy with the fewest side effects. However, fluoroquinolones that have more prolonged urinary excretion may be as effective as single-dose agents. Nitrofurantoin has been used for 5 decades to treat acute cystitis, and almost all E. coli strains remain susceptible. Unfortunately, nitrofurantoin

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has been less well studied in controlled trials. A 7-day course of treatment is probably required to achieve a 90% success rate in acute cystitis (31,34). Fosfomycin is marketed for single-dose treatment of acute cystitis. It is a unique antimicrobial and has been used successfully in Europe. However, it has a success rate of only 85% to 90% in acute bacterial cystitis (35). TMP and sulfonamide resistance has emerged globally (36). Once community resistance to TMP-SMX among E. coli exceeds 10%, alternate agents usually should be selected. Although each of the fluoroquinolones is efficacious, ciprofloxacin is the most effective agent for gram-negative rods and probably should be the fluoroquinolone of initial choice on the basis of existing evidence. Fluoroquinolones should not be routinely prescribed for acute bacterial cystitis in children or pregnant or breast-feeding women. As a result, TMP-SMX, the nitrofurantoins, and some of the beta-lactams are the drugs of choice, in descending order, for patients with acute cystitis. Large, adequately designed therapeutic trials for etiologic organisms other than E. coli and postmenopausal women with acute cystitis still must be carried out to have better evidence for managing these infections.

Acute Pyelonephritis Patients with acute pyelonephritis are now being stratified according to their comorbidities and the severity of the presenting illness. Complications of acute pyelonephritis occur in 5% to 10% of patients, and are listed in Table 13-5. These complications are approximately 3 times as common in patients with diabetes. Studies have shown that patients with acute, presumably uncomplicated pyelonephritis, and even patients who are pregnant without severe symptoms, can be managed as outpatients with a 7- to 14-day course of oral antimicrobial therapy (37). The indications for hospitalization are listed in Table 13-7. TMP-SMX has been the empiric initial treatment of choice. However, as resistance has emerged, alternative agents have been selected (36). Talan and colleagues showed that the microbiological failure rate for Table 13-7 Indications for Hospitalization in Patients with Pyelonephritis Sepsis syndrome Uncertain diagnosis Structural abnormalities in urinary tract Diabetes Immunocompromised host Pregnancy* Multiresistant pathogens Failure of oral regimen Lack of home supports Concerns about compliance * Several studies have shown that 60% to 80% of pregnant patients can be treated safely for acute pyelonephritis as outpatients with oral antibiotics.

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TMP-SMX in acute pyelonephritis is approximately 50% if the infecting organism is resistant (38). In nonpregnant adults, the fluoroquinolones are an appropriate alternative choice. In the study already noted, Talan and coworkers found that ciprofloxacin prescribed for 1 week achieved a cure rate in excess of 90% in women with uncomplicated acute pyelonephritis (38). Although the beta-lactams are both parenterally and orally used for treatment of acute pyelonephritis, they have a lower eradication rate and should be reserved for populations in whom the fluoroquinolones are not optimal choices. Also, if the urine gram stain shows gram-positive cocci, amoxicillin or piperacillin with a beta-lactamase inhibitor should be included until the culture results are available. Patients who are very ill, have nosocomially acquired or complicated urinary infections (Table 13-1), or fail to respond to oral treatment require hospital admission for parenteral therapy (Table 13-7). An aminoglycoside with ampicillin, a third-generation cephalosporin, a fluoroquinolone, a beta-lactam–beta-lactamase inhibitor combination, or a carbapenem are all acceptable empiric regimens. Randomly assigned controlled trials have generally been inadequately sized to have the power to show superiority of one regimen over another, but there is considerable clinical experience with each of these regimens. For patients in whom Pseudomonas is a possible pathogen, imipenem, ceftazidime, ciprofloxacin, or piperacillin are preferred initial treatment choices. Most patients initially given parenteral therapy can be changed to oral therapy within 1 to 4 days. Two weeks is an optimal treatment regimen for more severe or complicated pyelonephritis in women, and longer courses have not been shown to be more effective. Men are often treated for 4 to 6 weeks with an oral regimen because of the possibility of concomitant prostatic infection. Patients with acute pyelonephritis usually respond to antibacterial therapy within 24 to 48 hours with resolution of fever and alleviated symptoms. If there is no response by 72 hours, further investigation is required to ensure that the initial diagnosis was correct, the organism is susceptible, and no obstructing or suppurative lesions are present. The common reasons for treatment failure in patients with acute pyelonephritis are outlined in Table 13-8.

Asymptomatic Bacteriuria Except for those done with pregnant women, few studies have identified optimal treatment regimens for asymptomatic patients with bacteriuria (14). Treatment should be initiated only after a repeat culture confirms the presence of bacteriuria and usually after a urinalysis to confirm the presence of pyuria. An indication for treatment should also be present (Table 13-9) (14). A 3-day regimen of TMP-SMX or, in nonpregnant patients, of a fluoroquinolone followed by a urine culture 2 weeks later will determine whether

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Table 13-8 Reasons for Failure to Respond in Patients with Acute Pyelonephritis Misdiagnosis (common) Pathogen resistant to prescribed antimicrobial (multiple pathogens may be present) Resistant pathogen emergent during therapy (unusual) Intercurrent infection or superinfection (particularly in a catheterized patient) Infection proximal to obstructed urinary tract Renal or perinephric abscess(es) Infected cyst Drug fever Metastatic infection elsewhere

Table 13-9 Indications for Treating Asymptomatic Bacteriuria* Pregnancy Infancy and childhood Diabetes† Infection with stone-forming pathogens, particularly Proteus mirabilis Prior to surgery at any site and in patients undergoing urethral manipulation Immunocompromise or neutropenia Following renal transplantation Following catheter removal with recently acquired infection * The diagnosis should be substantiated with significant quantitative cultures. † Further studies required.

treatment has eradicated the infection (Table 13-6). Approximately 70% of women are cured with a 3-day regimen. Patients in whom therapy fails should be further evaluated for a longer 2-week course of therapy, and a decision should be made about the necessity of investigation for underlying complications.

Complicated Urinary Infections The treatment regimens shown in Table 13-6 are largely empiric and untested in well-designed trials. Many patients who have complicated UTIs can be treated with ordinary courses of oral antibacterials with expectations of high cure rates, but a proportion of patients will have difficult-to-treat UTIs (1). Also, many patients with complicated UTIs have 2 or more underlying factors that predispose them to UTIs, which may be additive or synergistic. Complications can 1) increase the potential of an infection to be symptomatic or lead to serious outcomes, 2) increase the risk and incidence of a new infection occurring, and 3) increase the probability of treatment failure with an existing infection. These outcomes vary with the underlying reasons for complicated UTI and probably should be assessed independently as well as within the overall context of treatment indications and expected outcome.

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Urologic review is usually indicated in patients with complicated UTI. However, most surgical procedures for complicated UTI have not been validated by well-done, objective trials. The literature on complicated UTI is littered with unsatisfactory interventions that have often created their own iatrogenic problems. In almost all instances, obstruction should be relieved, calculi removed, and pus drained. However, in selected patients, these desired interventions may not be possible, and antimicrobial treatment can occasionally achieve adequate outcomes despite difficult scenarios. Infections in the lower male genital tract are addressed in Chapter 14. Infections in pregnant women have been discussed earlier. In the present section, the treatment of 7 specific categories of complicated UTI are presented.

Suppurative Renal Infections Suppurative infections are categorized as renal cortical abscesses, corticomedullary abscesses, and perinephric abscesses (39). Renal cortical abscesses are caused by hematogenous infection, usually with Staphylococcus aureus from a remote site. Corticomedullary abscesses are caused by classical urinary tract pathogens, and often occur in patients with complicated urinary infections in the presence of obstruction. The sequence seems to begin with a focal or sometimes multifocal acute bacterial pyelonephritis that proceeds to tissue liquefaction, often because of delayed or inappropriate treatment, obstruction, or concomitant xanthogranulomatous pyelonephritis. Perinephric abscesses often originate from a hematogenous site, and these are most commonly caused by either S. aureus or C. albicans. They also can develop from an ordinary episode of acute pyelonephritis or from extension of an intestinal perforation. The latter complication will usually create an abscess with many pathogens, including anaerobes. Suppurative renal diseases are too often diagnosed late or at postmortem. CT evaluation is the procedure of choice for early diagnosis and should be considered in all patients with persisting fever and possible renal abscesses. Treatment requires specific parenteral antimicrobial regimens directed at the presumed or proven pathogens, together with drainage procedures as indicated and vigorous management of often accompanying comorbidities either within the urinary tract or at other sites. Empiric treatment with antistaphylococcal, enterococcal, and gram-negative regimens should usually be initiated for all patients with abscesses until the cause is established. Often, percutaneous drainage is adequate, but surgical drainage may be required if fever persists and the patient does not rapidly recover. The fluoroquinolones and TMP-SMX are ordinarily excellent treatment choices for urinary tract pathogens, but they must be complemented with more specific antistaphylococcal and antianaerobic agents if these are deemed necessary.

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Infected Renal Cysts Both polycystic kidneys and solitary renal cysts can become infected, usually with aerobic gram-negative pathogens. These can be difficult to eradicate; and in multicystic kidneys, surgical drainage is often impossible and may be disastrous. Fortunately, long-term suppression and even cure can be achieved with the fluoroquinolones, which diffuse widely and are uninhibited by pus or a low pH within the cyst milieu. As a result, the fluoroquinolones, or occasionally TMP-SMX, can be prescribed for 6 to 12 weeks and, if necessary, for even longer periods to suppress and perhaps cure infection localized to 1 or more infected cysts (see Table 13-6 for dosages).

Urinary Tract Infections Associated with Renal Impairment UTIs are common complications of renal impairment, even though they are only rarely the sole cause of renal failure. Despite the observation that half of patients with renal failure at some time have a urinary infection, the optimal management of infections in these patients remains uncertain. In patients with bilaterally disparate renal function or with significant areas of impaired function within a single kidney, blood flow is preferentially increased to functioning renal tissue; and levels of an antimicrobial agent within the poorly perfused tissue may be inadequate to inhibit bacterial growth. Urinary levels of an antimicrobial agent in these patients may be sufficient to sterilize the urine despite persisting active infection in the kidney. In general, antibacterial agents that could further impair renal function, including the aminoglycosides, should be avoided. Also, therapeutic agents such as the tetracyclines and nitrofurantoin are contraindicated, because too little of these agents is filtered in areas of impaired renal function to effectively suppress bacterial multiplication. However, the quinolones, trimethoprim alone, and most beta-lactam agents are effective in the presence of renal impairment and are the therapeutic agents of choice for patients with impaired renal function. Drug dosages should be modified according to the level of renal impairment. Patients with impaired renal function and asymptomatic infection constitute a particularly problematic group. No careful studies of this population have been done, and in most patients the infection is probably not contributing to renal failure.

Urinary Tract Infections Associated with Diabetes Mellitus UTIs are 5 to 10 times more common among patients with diabetes mellitus than among controls (4,40). Approximately 20% of patients with diabetes have histologic evidence of pyelonephritis at postmortem. Most prospective studies suggest many reasons for the increased frequency, illness, and death from urinary infections among patients with diabetes. The

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complications of UTI in patients with diabetes include bacteremia, papillary necrosis, emphysematous cystitis and pyelonephritis, renal and perinephric abscesses, and ketoacidosis (41). No substantive studies have shown that treatment of asymptomatic infection in patients with diabetes will prevent these complications (42). As a result, the management of both asymptomatic bacteriuria and symptomatic infections in patients with diabetes is identical to that in other populations.

Urinary Tract Infections Caused by Catheterization All patients with long-term (>30 days) indwelling catheterization have infections, often with many pathogens that grow both in the urinary tract and on the catheter surface. Usually, 1 pathogen is predominant; but if it is suppressed with treatment, others may emerge. The complexity of infection in catheterized patients is not well understood, but more than 200,000 patients in the United States are chronically catheterized; and infections originating from their urinary tracts have substantial illness. Although most episodes of bacteriuria are asymptomatic, systemic symptoms including fever occur in 15% to 25% of patients per year of catheterization; and UTIs caused by catheterization account for approximately 15% of nosocomial bloodstream infections (43). It is estimated that approximately half of febrile episodes in chronically catheterized patients are caused by UTI. At postmortem, approximately one third of chronically catheterized patients have evidence of acute pyelonephritis. Other complications of chronic catheterization include renal stones, penile and scrotal abscesses, prostatic abscesses, and bladder cancer. Asymptomatic infection in chronically catheterized patients should not be treated (15,43). Treatment has no effect on the incidence of complications and leads to an increase in drug-resistant organisms (44). Some physicians consider Proteus mirabilis a particularly dangerous pathogen, because it frequently leads to encrustation of the catheter and bladder and to renal calculi. Unfortunately, eradication of P. mirabilis may be impossible in patients with indwelling catheters. The role of antimicrobial impregnated catheters in the prevention of urinary infection is controversial (45). Patients with symptoms caused by urinary invasion in the presence of a catheter require treatment. In most instances a broad-spectrum agent should be chosen and treatment should be limited, probably to 7 days, with the intention of suppressing the infection without attempting eradication (Table 13-6). Longer courses of therapy lead only to the selection of multiply resistant organisms that become increasingly difficult to treat and likely to spread to other catheterized patients. Candida spp. are common pathogens resulting from chronic catheterization and antibacterial use. In the absence of symptoms, Candida spp. should not be treated (46). In patients with symptoms, a short course of fluconazole constitutes optimal treatment and is superior to bladder irrigation with amphotericin B. However, in most instances candiduria should be

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allowed to persist, and it usually disappears without specific therapy once antibacterial regimens are stopped and the catheter is removed.

Urinary Tract Infections Associated with Renal Transplants UTI follows renal transplantation in approximately 50% of patients and is multifactorial, stemming in part from the initial use of a urinary catheter, surgical trauma, and immunosuppression (47). Urinary infection in the renal transplant patient can lead to pyelonephritis in the transplanted kidney or in native kidneys, and to reactivation of latent CMV infection in the allograft. As a result, early recognition and treatment of urinary infection, including yeast infection, is essential. TMP-SMX and fluoroquinolones are the treatments of choice for urinary infection post renal transplant and should be prescribed for 2 weeks.

Urinary Tract Infections Associated with Ileal Conduit Diversion A ureteroileal conduit diversion is required whenever malignancy, congenital anomalies, or other processes require removal of the bladder. These diversions are always infected with various pathogens, and 3 or more species are often present. No prophylactic regimens have been proven effective. Treatment leads only to increasingly resistant pathogens, and the patient ultimately becomes infected with pathogens that are difficult to treat. Obstruction, calculi, and other problems require frequent imaging and urologic investigations, and most patients have intermittent episodes of symptomatic invasive renal infection. These should be treated with a broad-spectrum empiric regimen for 7 to 10 days, with no attempt to eradicate the pathogen with prolonged treatment (Table 13-6). Unfortunately, management is problematic; and prospective controlled studies are required to determine what, if any, strategies will reduce the burden of disease caused by infection.

Prevention Many urinary infections can be prevented. Unfortunately, no vaccine has proven useful for preventing UTIs. However, several strategies have been shown in prospective studies to reduce the incidence and the disease burden of urinary infections. Among premenopausal women with recurring cystitis, antimicrobial prophylaxis, either used regularly or with intercourse, is effective. TMPSMX in a dose of 80 mg/400 mg 3 times a week, or a fluoroquinolone (i.e., ciprofloxacin) 250 mg 3 times weekly, reduces the number of recurrences by 10-fold (48). Nitrofurantoin taken daily is similarly effective (48). Because many infections follow intercourse, postcoital antibacterial treatment is another possible option. Usually, prophylaxis is prescribed for 1

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year, and patients are thereafter followed without prophylaxis to determine whether susceptibility to UTIs persists. Antimicrobial prophylaxis can be prescribed with similar efficacy for postmenopausal women. However, at least 1 controlled study has shown that many postmenopausal women are estrogen deficient, and that topical intravaginal estradiol markedly decreases the rate of infection by approximately 10-fold (11). Additional studies are required to determine whether restoration of vaginal lactobacilli in populations of patients whose vaginal microbial ecosystem is disturbed because of estrogen deficiency, antimicrobial use, or bacterial vaginosis can prevent recurrences of urinary infection. All women who experience recurrent infections should be cautioned with regard to the use of spermicides, including nonoxynol-9-impregnated condoms. Other interventions, including daily ingestion of 300 mL of cranberry juice, may be of value but better trials are required (49). Prevention of infection in catheterized patients is an effective initiative measure and should be a priority for all patients catheterized for 30 days or less. If proper measures are taken to maintain a closed drainage system, the risk of infection ranges from 3% to 10% per day. Most patients with shortterm catheter placement (<2 weeks) should be free of bacteriuria when the catheter is removed. Although some studies have suggested that systemic antibiotic therapy prevents infection in patients with short-term catheterization, its use will predictably lead to resistant infection, and most experts do not advise antibiotics for preventing bacteriuria during catheterization. If, however, bacteriuria is present after the catheter is removed, a short course of therapy is indicated even in the absence of symptoms, to prevent subsequent symptomatic infection from occurring (50). Condom catheter drainage can reduce some of the infectious complications of catheterization in men, but the incidence of infection remains increased with these appliances, and penile maceration is common. All patients undergoing urologic manipulation or surgery should have urine cultures done before the procedure, and any infection should be treated. Short-term or single-dose therapy with agents effective against gram-negative pathogens and enterococci should also be prescribed at the time of urologic surgical procedures.

Summary Urinary infections are common everyday events in medical practice. Many can be prevented. Most can be well treated outside the hospital with relatively inexpensive management programs. However, UTIs can on occasion be serious or even life-threatening infections. Appropriate investigation, specific therapy, and patient education usually can lead to a satisfactory outcome for what can otherwise be a frustrating, recurrent, and sometimes problematic illness. Many questions remain unanswered and far too little research is taking place in the world today on urinary infection (51).

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REFERENCES 1. Ronald AR, Harding GK. Complicated urinary tract infections. Infect Dis Clin North Am. 1997;11:583-92. 2. Peters KD, Kochanek K, Murphy SH. Deaths: Final data for 1996. Natl Vital Stat Rep. 1998;47:51-2. 3. Foxman B, Klemstine KL, Brown PD. Acute pyelonephritis in US hospitals in 1997: hospitalization and in-hospital mortality. Ann Epidemiol. 2003;13:144-50. 4. Nicolle LE, Friesen D, Harding GK, Roos LL. Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992; impact of diabetes, pregnancy, and aboriginal origin. Clin Infect Dis. 1996;22:1051-6. 5. Foxman B, Brown P. Epidemiology of urinary tract infections: transmission and risk factors, incidence, and costs. Infect Dis Clin North Am. 2003;17:227-41. 6. Wiswell TE, Hockey WE. Urinary tract infections and the uncircumcised state: An update. Clin Pediatr (Phila). 1993;32:130-4. 7. Hooton TM, Scholes D, Hughes JP,Winter C, Roberts PL, Stapleton AE, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med. 1996;335:468-74. 8. Hooton TM, Roberts PL, Stamm WE. Effects of recent sexual activity and use of a diaphragm on the vaginal microflora. Clin Infect Dis. 1994;19:274-8. 9. Smith HS, Hughes JP, Hooton TM, Roberts P, Scholes D, Stergachis A, et al. Antecedent antimicrobial use increases the risk of uncomplicated cystitis in young women. Clin Infect Dis. 1997;25:63-8. 10. Johnson JR. Microbial virulence determinants and the pathogenesis of urinary tract infection. Infect Dis Clin North Am. 2003;17:261-78, viii. 11. Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med. 1993;329:753-6. 12. Bronsema DA,Adams JR, Pallares R,Wenzel RP. Secular trends in rates and etiology of nosocomial urinary tract infections at a university hospital. J Urol. 1993;150:414-6. 13. Patterson TF, Andriole VT. Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era. Infect Dis Clin North Am. 1997;11:593-608. 14. Abrutyn E, Mossey J, Berlin JA, Boscia J, Levison M, Pitsakis P, et al. Does asymptomatic bacteriuria predict mortality and does antimicrobial treatment reduce mortality in elderly ambulatory women? Ann Intern Med. 1994;120:827-33. 15. Infectious Diseases Society of America. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40: 643-54. 16. Nicolle LE, Henderson E, Bjornson J, McIntyre M, Harding GK, MacDonell JA. The association of bacteriuria with resident characteristics and survival in elderly institutionalized men. Ann Intern Med. 1987;106:682-6. 17. Johnson JR, Kuskowski MA, Smith K, O’Bryan TT, Tatini S. Antimicrobial-resistant and extraintestinal pathogenic Escherichia cole in retail foods. J Infect Dis. 2005;191:1029-31. 18. Johnson JR, Manges AR, O’Bryan TT, Riley LW. A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet. 2002;359;2249-51. 19. Hedges S,Agace W, Svensson M, Sjögren AC, Ceska M, Svanborg C. Uroepithelial cells are part of a mucosal cytokine network. Infect Immun. 1994;62:2315-21. 20. Schilling JD,Mulvey MA,Vincent CD,Lorenz RG,Hultgren SJ. Bacterial invasion augments epithelial cytokine responses to Escherichia coli through a lipopolysaccharide-dependent mechanism. J Immunol. 2001;166:1148-55. 21. Numazaki Y, Kumasaka T,Yano N,Yamanaka M, Miyazawa T,Takai S, et al. Further study on acute hemorrhagic cystitis due to adenovirus type 11. N Engl J Med. 1973;289:344-7. 22. Wadei HM, Rule AD, Lewin M, Mahale AS, Khamash HA, Schwab TR, et al. Kidney transplant function and histological clearance of virus following diagnosis of polyomavirus-associated nephropathy (PVAN). Am J Transplant. 2006;6:1025-32. 23. Jones CA, Nyberg L. Epidemiology of interstitial cystitis. Urology. 1997;49:2-9. 24. Wilson ML, Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis. 2004;38:1150-8. 25. Stamm WE, Counts GW, Running KR, Fihn S,Turck M, Holmes KK. Diagnosis of coliform infection in acutely dysuric women. N Engl J Med. 1982;307:463-8. 26. Jenkins RD, Fenn JP, Matsen JM. Review of urine microscopy for bacteriuria. JAMA. 1986;225:3397-403.

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27. Ronald AR, Boutros P, Mourtada H. Bacteriuria localization and response to single-dose therapy in women. JAMA. 1976;235:1854-6. 28. Kawashima A, LeRoy AJ. Radiologic evaluation of patients with renal infections. Infect Dis Clin North Am. 2003;17:433-56. 29. Hooton TM,Winter C,Tiu F, Stamm WE. Randomized comparative trial and cost analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women. JAMA. 1995; 273:41-5. 30. Warren JW,Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA). Clin Infect Dis. 1999;29:745-58. 31. Hooten TM. The current management strategies for community-acquired urinary tract infection. Inf Dis Clin North Am. 2003;17:303-32. 32. Hooton TM, Johnson C, Winter C, Kuwamura L, Rogers ME, Roberts PL, et al. Single-dose and three-day regimens of ofloxacin versus trimethoprim-sulfamethoxazole for acute cystitis in women. Antimicrob Agents Chemother. 1991;35:1479-83. 33. Hooton TM, Scholes D, Gupta K, Stapleton AE, Roberts PL, Stamm WE. Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. JAMA. 2005;293:949-55. 34. Brumfitt W, Hamilton-Miller JM. Efficacy and safety profile of long-term nitrofurantoin in urinary infections: 18 years’ experience. J Antimicrob Chemother. 1998;42:363-71. 35. Stein GE. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection. Clin Ther. 1999;21:1864-72. 36. Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA. 1999;281:736-8. 37. Scholes D, Hooten TM, Roberts PL, et al. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med. 2005;142:120-7. 38. Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Iravani A, et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA. 2000;283:1583-90. 39. Dembry LM, Andriole VT. Renal and perirenal abscesses. Infect Dis Clin North Am. 1997;11:663-80. 40. Zhanel GG, Nicolle LE, Harding GK. Prevalence of asymptomatic bacteriuria and associated host factors in women with diabetes mellitus. The Manitoba Diabetic Urinary Infection Study Group. Clin Infect Dis. 1995;21:316-22. 41. Ronald A, Ludwig E. Urinary tract infections in adults with diabetes. Int J Antimicrob Agents. 2001;17:287-92. 42. Manitoba Diabetes Urinary Tract Infection Study Group. Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. N Engl J Med. 2002;347:1576-83. 43. Warren JW. Catheter-associated urinary tract infections. Infect Dis Clin North Am. 1997;11:609-22. 44. Wiener J, Quinn JP, Bradford PA, Goering RV, Nathan C, Bush K, et al. Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA. 1999;281:517-23. 45. Johnson JR, Kuskowski MA, Wilt TJ. Systematic review: antimicrobial urinary catheters to prevent catheter-associated urinary tract infection in hospitalized patients. Ann Intern Med. 2006;144:116-26. 46. Sobel JD, Kauffman CA, McKinsey D, Zervos M, Vazquez JA, Karchmer AW, et al. Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis. 2000;30:19-24. 47. Tolkoff-Rubin NE, Rubin RH. Urinary tract infection in the immunocompromised host. Lessons from kidney transplantation and the AIDS epidemic. Infect Dis Clin North Am. 1997;11:707-17. 48. Stapleton A, Stamm WE. Prevention of urinary tract infection. Infect Dis Clin North Am. 1997;11:719-33. 49. Jepson RG, Mihaljevia L, Craig J. Cranberries for preventing urinary tract infections. Cochrane Database Syst Rev. 2004;CD001321. 50. Harding GK, Nicolle LE, Ronald AR, Preiksaitis JK, Forward KR, Low DE, et al. How long should catheter-acquired urinary tract infection in women be treated? A randomized controlled study. Ann Intern Med. 1991;114:713-9. 51. Ronald AR, Nicolle LE, Stamm E, Krieger J,Warren J, Schaeffer A, et al. Urinary tract infection in adults: research priorities and strategies. Int J Antimicrob Agents. 2001;17:343-8.

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Chapter 14

Prostatitis and Epididymitis KEITH B. ARMITAGE, MD CATHERINE MARKIN COLECRAFT, MD

Key Learning Points 1. Chronic prostatitis remains a challenging clinical diagnosis, and the response to antimircrobial therapy uncertain. Confirmation of this diagnosis requires a systematic approach. Drugs vary in their ability to penetrate the non-inflammed prostate. 2. Acute prostatitis may present with dramatic signs and symptoms, and is usually an easy clinical diagnosis. 3. Chronic prostate pain may not be due to infection, and this is an area of ongoing research.

Prostatitis Prostatitis is one of the most frequently encountered urogenital conditions in primary care (1,2). Symptoms referable to prostatitis include low back pain, perigenital pain, irritative voiding, and voiding dysfunction (2-4). In the late 1970s, Stamey and coworkers advanced the understanding of prostatitis by dividing voided urine into three portions: a first void or urethral portion (VB1), a midstream void (VB2) or bladder portion, and postprostatic massage urine (VB3) or expressed prostatic secretion (3). This system allowed differentiation not only between urethral and prostatic infections in the presence of sterile midstream urine but also between bacterial and nonbacterial forms of prostatic infection (2-4). This process was named the localization technique and was described in the 1970s by Meares (4a). On the basis of this approach, prostatitis has been separated into 4 categories: 1) acute bacterial prostatitis (ABP), 2) chronic bacterial prostatitis (CBP), 3) 266

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New Developments in Prostatitis and Epididymitis • Evolving antimicrobial resistance requires physicians to reevaluate choices for

therapy of prostatitis and epididymitis. • Most ongoing research into prostatic diseases other than cancer is focused on the

etiology and therapy of chronic prostate pain. • Quinolones are no longer recommended by the CDC for treatment of gonococcal

infections; only cephalosporins are recommended.

Acute and chronic bacterial 10%

Abacterial 60%

Prostatodynia 30%

Figure 14-1 Frequency of differing forms of prostatitis.

chronic abacterial prostatitis (CAP), and 4) prostatodynia. Figure 14-1 illustrates the frequency of occurrence of the four types of prostatitis.

Etiology and Pathogenesis Despite progress made in the past 30 years in understanding the syndrome of prostatitis on the basis of localization technique and other methods, prostatitis is often difficult to diagnose accurately, and the etiologic agent is often difficult to identify. In 1980, Stamey (4b) stated that “little more is known about prostatitis than was reported by Hugh Young and associates in 1906.” In clinical practice, prostatitis is often treated on the basis of clinical signs and symptoms without the use of the localization technique. Although efficient, this approach may lead to over- or undertreatment owing to the inaccuracy of clinical diagnosis. Differentiating between the 4 classifications of prostatitis solely on the basis of clinical presentation or impression (with the possible exception of the acute bacterial form) is problematic. In cases of

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symptoms of recurrent or complicated prostatitis, it is crucial to use the localization technique described earlier to make an accurate diagnosis. The precise pathogenesis of prostatitis is unclear, which contributes to the confusion about its optimal management. In bacterial prostatitis, it has been hypothesized that infection may result from an ascending urethral infection, either by extension subsequent to vaginal (or rectal) inoculation of the urethral meatus during intercourse or by means of hematogenous or lymphatic spread of coliform microorganisms (1,5). Some have suggested that the reflux of urine into the prostatic ducts causes prostatic calculus formation, with the calculi then forming a nidus for bacterial infection (1,3,6). Others have described bacterial prostatitis as associated with a urinary tract infection (4,6). The implicated primary pathogens are enteric, aerobic, gram-negative rods that colonize the gastrointestinal tract and commonly infect the urinary tract, with Escherichia coli being the most frequently isolated organism. Enterococci, Pseudomonas, and other nonenteric gram-negative rods also are seen in acute and chronic prostatitis. Foreign bodies (e.g., indwelling Foley catheter, obstruction caused by benign prostatic hypertrophy) have been implicated as cofactors in the development of prostatitis (7). Genital pathogens such as Neisseria gonorrhoeae and Chlamydia trachomatis also have been implicated in prostatitis and are the most likely agents of this condition in men aged 35 years or younger (7,8). The cause may differ according to the category of prostatitis and the age of the patient. In older men, CAP, prostatodynia, and bacterial epididymoorchitis are among the most common presentations of prostatic disease; however, despite their frequency, the cause and pathogenesis of these diseases are not well characterized. In the case of CAP, molecular probe data suggest an infectious cause (8).

Clinical Manifestations As mentioned previously, patients with syndromes of prostatitis usually present with a range of symptomatology referable to the male urogenital tract and the perineum. This primarily consists of symptoms of irritative and dysfunctional voiding, such as urgency, hesitancy, dysuria, frequency, incomplete emptying of the bladder, fever, perigenital pain, ejaculatory discomfort, lowback pain, or low-abdominal pain. Constitutional signs and symptoms may or may not be present, depending on the type of prostatitis.

Diagnosis The diagnosis of prostatitis is often based on symptoms and prostatic tenderness on examination, but bacterial prostatitis can be differentiated from nonbacterial prostatitis only by urinary localization cultures or by the localization studies previously cited (1). The finding of bacterial pathogens in the urine after prostatic massage and in the presence of sterile urethral and midstream urine specimens is highly diagnostic of bacterial prostatitis (1).

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The prostatic localization technique demonstrates the contribution of urethral, prostatic, and bladder organisms to bacteriuria in specimens of voided urine and is the diagnostic gold standard for bacterial prostatitis. Additional studies for the diagnosis of prostatitis are available but typically are used only in cases that do not respond to treatment or in which prostatitis is recurrent or complicated. Plain radiography, ultrasonography, and intravenous urography can be used to rule out other conditions (e.g., osteitis pubis and urolithiasis, both of which mimic prostatitis) and, in the case of ultrasonography, to diagnose prostatitis (3). Both specific and nonspecific echogenic qualities have been described in prostatitis; however, nonbacterial prostatitis cannot be diagnosed with certainty by transrectal ultrasonography, and a normal ultrasound examination does not exclude its diagnosis (3). In contrast, the sonographic features of acute bacterial prostatitis are well documented and consist of an enlarged rounded prostate, usually with a symmetrical capsule; a decrease in echogenicity; and an increase in sound transmission within the gland parenchyma, which is believed to indicate edema (9). Other studies that may aid in the diagnosis of prostatitis include uroflowmetry, in which abnormalities are reported in only 30% of cases, and urine cytology, which lacks clinical data to support its value in the screening of patients with prostatitis. The value of the outcome of cytologic screening of patients with prostatitis depends exclusively on the experience of the investigator (3). The level of prostate specific antigen is often increased in the setting of acute and chronic prostatitis, and screening for prostate cancer should not be done when these conditions are suspected.

Treatment It is often difficult to differentiate between the various forms of prostatitis, which makes therapeutic decisions problematic. No specific therapy exists for nonbacterial and chronic prostatitis, and antimicrobial therapy is often ineffective. When using antimicrobial agents to treat prostatitis, it is important to consider the capacity of a particular drug to cross the prostate–blood barrier, and the performance of the drug in the relatively alkaline environment of the prostate. For an antimicrobial drug to enter the prostate, it must be lipid soluble and have a low protein-binding affinity, because drug-bound proteins do not pass freely into the prostatic fluid. The drug also should have a high dissociation constant at a high pH (i.e., pHa > 8.6) and optimal activity against gram-negative rods at a pH greater than 6.6 (4,6). Many of the available antimicrobial agents lack these penetration characteristics, most notably the beta-lactam drugs. Trimethoprim with or without sulfamethoxazole is an attractive option, because trimethoprim achieves high levels in the prostate and has good activity against primary pathogens. Trimethoprim alone is an attractive alternative to trimethoprim-sulfamethoxazole (TMP-SMX), because it is not commonly associated with hypersensitivity reactions and is inexpensive.

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The failure of antibiotics in treating some forms of prostatitis has led to the use of other treatment modalities. Several supportive and symptomatic modalities have been tried (6,10,11). Hyperthermia (e.g., hot sitz baths, transurethral microwave thermotherapy) has been used with limited success (10). Prostatic massage to break down loculi of infected prostatic secretions and/or fluid improves drainage but may have limited value in CBP. Anticholinergic agents effectively reduce urinary frequency and urgency but probably are best reserved for benign prostatic hypertrophy and bladderneck dyssynergia, because they may inhibit the flow of prostatic fluid (6). Nonsteroidal anti-inflammatory agents provide symptomatic relief for chronic prostatitis and prostatodynia, and the use of steroids has been tried during severe, acute symptomatic exacerbations of chronic prostatitis (6). All these measures afford only temporary relief, and few objective data are available to indicate that any of them alter the natural course of the disease. Primary care physicians can manage most cases of prostatitis, but urologic consultation should be considered for patients with recurrent or refractory symptoms. Surgical options have been proposed since the early 1970s for the management of chronic prostatitis that is unresponsive to medical management. In 1973, Warwick and coworkers (12) advocated open prostatectomy and posterior capsulectomy. Transurethral prostatectomy has been reported to alleviate symptoms of chronic prostatitis, even in the absence of outflow obstruction. However, this approach has lost favor because it does not provide lasting symptomatic relief; and it is now seldom recommended, particularly in view of the risk of impotence and incontinence associated with the procedure. Bladder-neck incision has been proposed for younger patients with refractory prostate pain. This approach has been reported to have less illness than transurethral prostatectomy (6). It is said to be curative in approximately one third of patients with proven chronic bacterial prostatitis. Retrograde transurethral balloon dilation has been introduced as an alternative treatment of patients with benign prostatic hypertrophy, CAP, or prostatodynia (6).

Acute Bacterial Prostatitis In contrast to the other forms of prostatitis, ABP is an easily recognized clinical entity that is dramatic in its presentation. The patient may present in the throes of an acute septic process, with irritative and obstructive voiding symptoms, including low-back and perineal pain. Fever of sudden onset, chills, rigors, myalgias (associated with dysuria, frequency, urgency, and hesitancy), a sensation of rectal fullness, and suprapubic discomfort often accompany the presentation. The signs and symptoms of ABP are both highly reliable and diagnostic. A complete genitourinary examination, including digital rectal examination, should be done judiciously on patients with suspected ABP to detect urethral discharge and evaluate scrotal content (to rule out concurrent urethritis and epididymitis). The digital rectal examination may pro-

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voke intense pain; conversely, a nontender prostate rules out ABP. It is important to note that prostatic massage is strongly contraindicated in ABP because of the very high risk of inducing a heavy bacterial load into the bloodstream and thus precipitating septicemia. Blood and urine cultures should always be a part of the routine workup in ABP. The severity of illness in ABP often leads to hospitalization and the initiation of parenteral antimicrobial therapy to cover major potential pathogens such as aerobic gram-negative rods. It is appropriate to complete the course of therapy with oral antibiotics once the patient has been stabilized. Many antimicrobial regimens are available for empirical therapy pending identification and recognition of the sensitivity patterns of the organism(s) obtained from culture specimens (Table 14-1). These options include the combination of a beta-lactam and an aminoglycoside, a fluoroquinolone, or TMP-SMX. Antibiotic therapy should be given for at least 2 weeks and even longer, depending on the severity of the presentation and the response to therapy (1,2,13,14). ABP usually responds well to antibiotic therapy despite the lack of optimal penetration characteristics for most of the antimicrobial agents used to treat it, as discussed previously, and their usually consequent failure to achieve therapeutic concentrations in prostatic fluid. Antimicrobial agents that are not normally effective in the prostate are effective in acute prostatitis because the acute inflammation in the disease renders the blood-prostate barrier more permeable, which is analogous to the situation of the blood-brain barrier during acute meningitis (4,13,14). Management of patients with ABP also should include supportive care with intravenous fluid resuscitation, bed rest, analgesia, and stool softeners. When urinary retention is a complicating factor, placing a suprapubic catheter is preferred to using a transurethral catheter to avoid blocking the drainage of infected prostatic secretions into the urethra (5). Aggressive treatment of ABP can prevent complications such as prostatic abscess, CBP, persistent asymptomatic bacteriuria, granulomatous prostatitis (i.e., the histologic stage of resolving ABP, which manifests on examination as an area of induration that is suspicious for malignancy), and prostatic infarction (1,2,6,14).

Chronic Bacterial Prostatitis Chronic bacterial prostatitis is a more subtle disease than ABP and is characterized by relatively asymptomatic periods that are punctuated by episodes of recurrent symptomatic bacteriuria. Patients often present with a long-standing history of irritative voiding symptoms with a persistence of urinary pathogens and the presence of inflammatory cells in the expressed prostatic secretion. In CBP, the diagnosis is more difficult, the response to therapy is less certain, and relapse is more common than with ABP. In contrast with ABP, lower urinary tract localization studies should be performed before antimicrobial therapy is begun for CBP. TMP-SMX or

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Table 14-1 Prostatitis Syndromes Clinical Manifestations

Acute bacterial prostatitis

Chronic bacterial prostatitis

Chronic abacterial prostatitis

Diagnosis

Common Bacterial Etiology

Management and Treatment

Dramatic and Hard, Enterobacteriaceae Pharmacologic: sudden onset; exquisitely (Escherichia coli initial irritative and tender, and most common) parenteral dysfunctional; warm antimicrobial voiding sympprostate on (e.g., toms; urinary digital ciprofloxacin, obstruction exam (Note: ofloxacin, (for 2–3 prostatic TMP-SMX, weeks); sysmassage is tetracycline, temic symptoms contraindipenicillin + (e.g., fever, cated); aminoglycochills, rigors) inflammaside) foltory cells in lowed by oral EPS/urine; antimicrobial positive for a total of culture and 3–6 weeks microbioSupportive: logic data analgesia, from EPS/ bedrest, urine antipyretic, stool softener, suprapubic catheterization (if obstruction present) Hallmark: Usually Enterobacteriaceae Oral fluororelapsing or normal (including quinolone for recurrent UTIs prostate Klebsiella, 4–6 weeks, and intervening examinaSerratia, oral TMPasymptomatic tion; inflam- Pseudomonas, SMX for 1–3 periods matory and Proteus months, oral Very variable; cells in species) TMP for 1–3 irritative; voiding EPS/urine; Enterococcus months, signs + symp positive species chronic toms; afebrile culture and suppressive or low grade microbiotherapy fever logic data from EPS/ urine Chronic irritative Normal Unknown; Counseling ± voiding sympprostate Chlamydia and antibiotics: toms; afebrile examinaUreaplasma are ?Doxycycline tion; inflam- suspected for 2 weeks matory or erythromycells in cin for 2 EPS/urine; weeks negative Continued

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Table 14-1 Continued Clinical Manifestations

Diagnosis

Common Bacterial Etiology

culture and microbiologic data from EPS/ urine Prostatodynia Chronic low-back, Normal Unknown; perineal, and prostate noninfectious suprapubic examinapain; psychologtion; usually ical disturbances no inflammatory cells in EPS/urine; negative culture and microbiologic data from EPS/urine

Management and Treatment

Counseling; alphaadrenergic– blocking agent

EPS = expressed prostatic secretion; TMP-SMX = trimethoprim–sulfamethoxazole; UTIs = urinary tract infections.

trimethoprim alone are cost-effective antibiotics for treating CBP; the cure rate with these drugs is approximately 30% to 40% (1). The quinolones are also efficacious but more expensive. Clinical trials with the fluoroquinolones norfloxacin and ciprofloxacin have achieved cure rates of 60% to 92% (1). These trials were criticized for having only short-term followup, which may have underestimated the number of relapses. In an attempt to assess the long-term efficacy of these drugs, Weidner and coworkers (14a) reported cure rates with ciprofloxacin and norfloxacin of 53% and 64%, respectively, after 6 to 12 months of follow-up (1). Chronic, low-dose, suppressive therapy may be tried in an attempt to control the symptoms of patients with many relapses of ABP. Antimicrobial recommendations for chronic suppressive therapy include trimethoprim, nitrofurantoin, minocycline, and the fluoroquinolones, all of which have to some degree the characteristics favorable for penetration into and entrapment within the prostate. All of the fluoroquinolones have low protein-binding affinities, small molecular sizes, high lipid solubility, and basic properties (1).

Chronic Abacterial Prostatitis Chronic abacterial prostatitis is a common form of prostatitis; however, despite its frequency, it is attended by a lack of scientific data (3,6). Patients with CAP are usually between the ages of 20 and 35 years. CAP may represent a noninfectious disease entity that results from the urethral reflux of urine into the prostatic ducts, causing a chemical prostatitis. Alternatively, an unidentified infectious agent may cause CAP, and there are molecular

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probe data to suggest this (8). The role of C. trachomatis (and other bacteria implicated in nongonococcal urethritis) in the pathogenesis of CAP has been a topic of debate since the early 1970s (2). Chronic abacterial prostatitis has no pathognomonic or characteristic histopathologic features; the only marker of the disease is a modest increase in chronic inflammatory cells. The symptoms resemble those of other prostatitis syndromes except for fluctuation with remission followed by recrudescence in 3- to 6-week cycles (6). Because of the cyclic nature of the condition, the efficacy of antimicrobial therapy is difficult to assess. In the literature, the approach to the role of antimicrobial drugs in CAP has changed over the years. In 1978, Meares (4a) and Stamey (4b) opposed the use of antimicrobial therapy because no infectious agent could consistently be isolated, and empiric use of various antibiotics was ineffective. In 1985, Simmons and Thin (14b) advocated the use of minocycline, which not only has the desirable penetration characteristics for permeability into prostatic tissue but also seemed to be clinically efficacious in treating CAP. In the 1980s and early 1990s, there was a revival of enthusiasm for antimicrobial therapy in CAP, perhaps reflecting the belief in the potential role of pathogens such as C. trachomatis and Ureaplasma urealyticum in causing the disease (6). A 1991 review of the available data indicated that some patients with CAP did improve with antimicrobial therapy, and the authors highlighted TMP-SMX as the antibiotic of choice for prolonged therapy (6). Doxycycline and erythromycin also have been recommended for treating CAP (Table 14-1) (6). Psychological factors can be an important aspect of the management of CAP and other forms of chronic prostatitis. Many patients benefit from a candid discussion of the enigmatic nature of the disease. Reassurance that in most cases it is not a sexually transmitted disease (STD), that it is not hereditary, and that it does not cause infertility may help prepare the patient to cope with what can be a chronic illness. Honesty about the current therapeutic limitations for CAP should be emphasized to the patient (6).

Prostatodynia The term prostatodynia literally means pain in the prostate. Clinically, the term is used to refer to a prostate pain syndrome for which no cause can be established and for which there is no objective evidence of it being caused by infection or inflammation. Patients with prostatodynia constitute approximately one third of patients who present with chronic prostatitis syndromes. Despite the lack of evidence of inflammation, patients present with many of the symptoms associated with prostatitis, including perineal, low-back, and suprapubic pain. Generally, irritative voiding symptoms such as dysuria and urinary frequency are absent. The prostate is normal and without tenderness on physical examination. A normal examination and the lack of inflammatory cells distinguishes prostatodynia from CAP, in which leucocytes and lipidladen macrophages are characteristically found. Localization cultures are also

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negative in prostatodynia. Possible mechanisms of prostatodynia include neuromuscular abnormalities such as detrusor sphincter dyssynergia or overactivity of the pelvic sympathetic nerves at the level of the external urethral sphincter (1,2,6). These suggested mechanisms are based on observations of attenuated urinary flow rates with incomplete relaxation of the bladder neck and narrowing of the urethra proximal to the external urethral sphincter (2). Therapeutic agents of potential benefit include alpha-blockers such as phenoxybenzamine and prazosin, which reduce spasm and intraurethral pressure. This effect should prevent intraprostatic urinary reflux that could result in chemical prostatitis. Psychological issues also should be addressed in these patients and nonpharmacologic therapies considered (14c,14d). Table 14-1 provides a summary of the salient features of the four prostatitis syndromes.

Epididymitis Epididymitis is a common clinical syndrome in primary care, accounting for 600,000 visits to physicians per year (5). From 1990 to 1991, epididymitis was estimated to be responsible for approximately 20% of urologic inpatient admissions (15,16). In developing nations, it has been cited as a common cause of infertility because concurrent orchitis is frequent in this setting (presumably because of lack of, inadequate, or delayed treatment resulting in testicular involvement) (17). Infertility is an uncommon complication of unilateral orchitis but occurs in up to 50% of cases of bilateral orchitis. When treatment is lacking or delayed, other major sequelae of acute epididymitis and epididymo-orchitis include testicular atrophy (approximately 67% of patients), testicular abscess, and infarction or necrosis (approximately 5%) (14-17).

Etiology Inflammation of the epididymis can result from trauma or other noninfectious insults but is most often caused by infection. Urine has been postulated as the precipitating irritant in some cases of epididymitis, and drugs have been implicated on rare occasions. Epididymitis caused by amiodarone has been well described, and clinicians who care for patients that received this drug must be aware of this adverse reaction to prevent subjecting the patient to unneeded work-up and antimicrobial therapy. Epididymitis caused by amiodarone is a benign and self-limited sterile epididymitis that requires no treatment other than cessation of the amiodarone (15,18). When an infectious cause is identified in acute epididymitis, the etiologic organisms usually fall into 1 of 2 categories: genital or sexually acquired pathogens (e.g., gonococcus, Chlamydia, Ureaplasma) or urinary tract pathogens (aerobic gram-negative rods, enteric coliforms such as E. coli, Klebsiella, Proteus, Pseudomonas). The likelihood of isolating 1

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type over another from a particular patient is related to age, sexual activity, and the presence of anatomical or functional genitourinary pathology (19). Sexually transmitted causes of epididymitis are rare in the prepubertal child, and the isolation of an STD organism should alert the clinician to the probability of sexual abuse. The most likely causes of urinary tract infection in this age group are coliform organisms or Pseudomonas. STDs are the most common cause of epididymitis in heterosexual men younger than 35 years of age (20), possibly via an ascending infection from the urethra. However, epididymitis as a complication of urethritis occurs only rarely (estimated frequency 1%-2%) (21). Urinary pathogens are an infrequent cause of epididymitis in anatomically intact, heterosexual, young adult men. Conversely, in sexually active homosexual men of similar age, the most common etiologic agents are enteric pathogens acquired during anogenital intercourse and then introduced into the urogenital tract. In older men and in men with structural or functional defects (e.g., benign prostatic hypertrophy or bladder-neck obstruction), urinary tract pathogens are the likely culprits.

Clinical Manifestations Epididymitis typically presents with unilateral testicular pain, swelling, erythema, and tenderness of an acute or subacute onset. Inflammation of the epididymis in severe cases often extends to the testicle itself or the scrotum. Patients present with an acute scrotum, the differential diagnosis of which is listed in Table 14-2. These scrotal signs and symptoms may pre-sent in the absence of urogenital symptomatology, such as urethral discharge and/or dysuria. Constitutional symptoms such as fever or chills may or may not be associated with the scrotal signs and symptoms, depending on the severity of illness. Less frequently, the patient may present only with vague lower abdominal and inguinal reports of sudden onset. Testicular torsion, epididymitis, and epididymo-orchitis have a similar presentation, and differentiation between the conditions on clinical grounds alone is often difficult.

Diagnosis Clinically, the diagnosis of epididymitis can be made easily, usually confirmed by an extremely tender epididymis. As mentioned previously, diagnostic confusion can arise when epididymitis is accompanied by significant orchitis, in which case other acute testicular conditions must be considered. In epiTable 14-2 Differential Diagnosis of the Acute Scrotum Testicular torsion Epididymo-orchitis Torsion of appendix testis Hydrocele

Inguinal hernia Traumatic hematoma Henoch–Schönlein purpura Idiopathic scrotal edema

Modified from Petrack EM, Hafeez W. Testicular torsion versus epididymitis: a diagnostic challenge. Pediatr Emerg Care. 1992;8:347–50.

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didymitis without orchitis, the need for radiographic studies is unusual and probably should be limited to situations in which the etiologic diagnosis cannot be ascertained. Radiodiagnostic tools (e.g., ultrasonography, intravenous pyelography) often yield indecisive results with regard to epididymitis, making them unreliable. Their role should be to rule out other noninfectious or noninflammatory causes of a tender, swollen scrotum. In situations in which structural abnormalities of the lower urinary tract are a concern (e.g., in infants or elderly patients), studies such as intravenous pyelography may help provide objective data. When orchitis is present and cannot be differentiated from torsion by clinical examination, radiographic diagnostic tools that are potentially useful include radionuclide scanning (99m-technetium) and Doppler ultrasonography. Both tests are sensitive in revealing decreased blood flow through the spermatic cord (an observation indicative of testicular torsion) (22). In epididymitis, radionuclide scanning demonstrates increased perfusion around the testicle. Doppler ultrasonography demonstrates brisk blood flow. Ultrasonography easily reveals structural testicular abnormalities and intraor extratesticular lesions; however, differentiating between an infection and a tumor is more difficult with this technique (22-24). Torsion is a surgical emergency and, if strongly suspected clinically, should prompt an immediate consult with a urologist. Optimal recovery of gonadal viability is achieved with operative intervention within 6 hours of torsion onset. Within this time frame, the salvage rate is 80%. After a period of 10 to 12 hours, the salvage rate precipitously decreases to less than 20% (24). In cases of recurrent disease or in other settings in which establishing an exact etiologic diagnosis may be important, evaluation should be directed at both genital and urinary sources of infection. A common clinical practice when evaluating genitourinary diseases is to obtain a midstream urine specimen from a patient before examination. In the setting of the epididymitis, this practice results in the loss of potentially diagnostic urethral data. A urethral swab before voiding or at least a first-void urine specimen (i.e., the first 7-8 mL of urine) reveals evidence of urethritis in most instances if it is present (Table 14-3). In addition to a complete genitourinary examination, both urethral and urinary specimens should be microscopically examined.

Table 14-3 Diagnostic Criteria for Urethritis ≥4 PMNLs per oil-immersion field (of urethral specimen per sediment of 10–15 mL of first-catch urine specimen) (14) OR >5 PMNLs per high-power field (
1000) on microscopic evaluation of urethral smear (25) OR ≥15 PMNLs per field (
400) on microscopic evaluation of resuspended sediment of a centrifuged 10–15 mL first-catch urine specimen (23) OR Mucopurulent or purulent urethral discharge (26)

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Treatment When a diagnosis of epididymitis is considered, prompt initiation of antimicrobial therapy is indicated. Delaying the initiation of treatment risks progression to epididymo-orchitis with potential loss of gonadal function. When orchitis does occur, it must be treated promptly and aggressively to prevent or minimize the risk of this and other complications discussed previously. Severe disease usually merits the use of parenteral therapy; otherwise, an oral agent such as TMP-SMX or a fluoroquinolone is often adequate. However, if gonococcus is suspected, a fluoroquinolone alone should be used. Epididymitis usually responds readily to therapy with antimicrobial agents, with the choice of drug based on the age of the patient. Antimicrobial agents with activity against enteric pathogens are prescribed for older men, and treatment directed against pathogens associated with STD is used in sexually active younger men. If there is any indication of a concomitant urethritis, either microscopically or clinically, treatment should be directed against the STD genital pathogens N. gonorrhoeae and C. trachomatis (Figure 14-2, Table 14-4)

Urethritis

Gonococcal

Neisseria gonorrhoeae and/or Chlamydia trachomatis present in 30%–50% of cases

Treat for both gonorrhea and chlamydia

Nongonococcal

Acute/Subacute

Chronic (i.e., persistent and recurrent symptoms after)

Treat for chlamydia

Postgonococcal (i.e., following treatment of)

Treat as for nongonococcal urethritis

Reevaluate index patient and sexual partners; rule out urethral pathology; re-treat with alternative regimen, then observe if no etiologic diagnosis is obtained; disease is usually self-limited

Figure 14-2 Algorithm for the management of urethritis.

C. trachomatis* Ureaplasma urealyticum ?Mycoplasma hominis ?M. genitalium Trichomonas Herpes simplex virus Yeast (Candida albicans)

Nongonococcal

* Most commonly isolated.

Neisseria gonorrhoeae ± Chlamydia trachomatis (15%–25% of heterosexual men, 5% of homosexual men)

Gonococcal

Pathogens

Peaks at 2–3 weeks

<1 week

Incubation Period

Table 14-4 Distinguishing Features of Urethritis Syndromes

2–3 times more prevalent; scant, mucoid, whitish discharge

Florid, purulent urethral discharge (usually)

Epidemiology and Distinguishing Aspects

Treat for both gonorrhea For N. gonorrhoeae (all and chlamydia; evaluate as a single dose): and treat sexual partners Ceftriaxone 125 mg IM for both; counsel or Cefixime 400 mg PO patients about total or Cefotaxime 500 mg compliance (including IM sexual abstinence Plus until treatment is For C. trachomatis: completed) Doxycycline 100 mg PO bid for 7 days or Azithromycin 1 g PO as a single dose Thorough reevaluation, Doxycycline 100 mg PO including urethroscopy bid for 7 days or to rule out urethral Azithromycin 1 g PO pathology; alternate single dose or regimen; tincture of Erythromycin 500 mg PO time; no further qid for 7 days or antibiotic therapy Ofloxacin 300 mg PO q12h for 7 days or Trovafloxacin 200 mg PO qd for 5 days

Principles of Management Suggested Antibiotic (Treatment and Prevention) Regimens

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Table 14-5 Suggested Regimens for Epididymo-orchitis Types of Epididymitis

Associated Features

Sexually transmitted

Age <35 years

Non–sexually transmitted

Age >35 years

Pathogens

Recommended Regimens

Gonococci, Chlamydia Ceftriaxone 250mg IM in a (heterosexual) single dose + doxycycline 100 mg PO bid for 10 days Enteric organisms Ofloxacin 300mg PO bid (homosexual) for 10–14 days (200 mg IV bid for 10–14 days) Enteric organisms, Ofloxacin 300 mg PO bid urinary pathogens for 10–14 days (200 mg IV bid for 10–14 days) or Ciprofloxacin 500 mg PO bid for 10–14 days (400 mg IV bid for 10–14 days)

Adapted from Centers for Disease Control and Prevention. 1998 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep. 1998;47(RR-1):49–55,86–87; and Gilbert DN, Moellering RC Jr, Sande MA. The Sanford Guide to Antimicrobial Therapy, 31st ed. 2001:5,26.

(15). If a urethral discharge is absent or if microscopy reveals lack of polymorphonuclear leukocytes and the urine specimen reveals inflammation and bacteria, treatment should be like that given for a complicated urinary tract infection. Table 14-5 lists some suggested regimens, and Figure 14-3 is an algorithm for the treatment of epididymitis. Symptomatic treatment of the patient with epididymitis is often indicated and remains an integral part of management of the disease in severe cases. Management may include bed rest, analgesics, scrotal elevation to allow maximal lymphatic drainage, avoidance of constricting clothing, and local application of ice packs (14,15). In the preantibiotic era, surgery was often used to treat epididymitis, which produced immediate analgesia, prompt resolution of fever, reduced incidence of sterility, increased testicular salvage rate, decreased recurrence rate, and a shorter recovery time. With the advent of antibiotics, the degree of illness associated with epididymitis decreased substantially, as did the status of surgery as the treatment of choice. Today there are both absolute and relative indications for surgery in treating epididymitis (17), which are listed in Table 14-6.

Summary Prostatitis and epididymitis represent heterogeneous conditions that are commonly encountered in the primary care setting. With the exception of its acute form, prostatitis can be difficult to diagnose and treat; hence, it is important to evaluate patients with prostatitis for both infectious and

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Acute epididymitis

Pubescent to elderly

Infant to pubescent

Sexual activity?

Yes

Initial treatment to cover urinary pathogens; rule out torsion if clinically suspected; used radiography to screen for anatomical anomaly

No Yes

Homosexual activity?

See Figure 13.2

Urethritis? No

Yes

No

Urethral symptoms/signs?

Yes

Broad-spectrum antibiotics to cover genital and urinary pathogens and enteric coliforms

No

Urethral symptoms/signs?

Yes

Treat urinary pathogens and enteric coliforms

Sterile pyuria

Bacteriuria

No

Treat genital pathogens

Treat for urinary pathogenesis

Figure 14-3 Algorithm for the management of epididymitis.

Table 14-6 Indications for Surgical Intervention for Epididymitis Absolute Indications Abscess formation Testicular ischemia

Testicular torsion Solitary testicle Scrotal fixation (indicates severe inflammation and potential suppuration)

Relative Indications Failure to respond clinically to medical therapy within 48 hours Situations in which rapid convalescence is of primary concern (e.g., in an elderly patient); prolonged bedrest is contraindicated

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noninfectious causes. In contrast, the clinical presentation of epididymitis is usually clear cut, and management options for this condition are well defined.

REFERENCES 1. Schaeffer AJ. Diagnosis and treatment of prostatic infections. Urology. 1990; 36(Suppl):S13-S7. 2. Chronic Prostatitis Collaborative Research Network Group. Demographic and clinical characteristics of men with chronic prostatitis: the national institutes of health chronic prostatitis cohort study. J Urol. 2002;168:593-8. 3. de la Rosette JJ, Debruyne FM. Diagnostics and treatment of prostatitis: an actualized overview. Rev Med Suisse Romande. 1992;112:757-63. 4. Cunha BA, Marx JD, Gingrich D. Managing prostatitis in the elderly. Geriatrics. 1991;46:50-63. 4a. Meares EM Jr. Prostatitis syndromes: new perspectives about old woes. J Urol. 1980;123:141-7. 4b. Stamey TA. Pathogenesis and Treatment of Urinary Tract Infections. Baltimore, Md: Williams & Wilkins; 1980:1-342. 5. Krieger JN. Prostatitis, epididymitis, and orchitis. In: Mandell, Douglas, Bennett, eds. Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Livingstone; 2000:1243-50. 6. McNaughton Collins M, MacDonald R, Wilt TJ. Diagnosis and treatment of chronic abacterial prostatitis: a systematic review. Ann Intern Med. 2000;133:367-81. 7. Eisenstein BI. In: Mandell, Douglas, Bennett, eds. Principles and Practice of Infectious Diseases. 4th ed. 1995:1970-1. 8. David RD, DeBlieux PM, Press R. Rational antibiotic treatment of outpatient genitourinary infections in a changing environment. Am J Med. 2005;118 Suppl 7A:7S-13S. 9. Doble A, Carter SS. Ultrasonographic findings in prostatitis. Urol Clin North Am. 1989; 16:763-72. 10. Servadio C, Leib Z, Lev A. Diseases of prostate treated by local microwave hyperthermia. Urology. 1987;30:97-9. 11. Choi NG, Soh SH, Yoon TH, Song MH. Clinical experience with transurethral microwave thermotherapy for chronic nonbacterial prostatitis and prostatodynia. J Endourol. 1994;8:61-4. 12. Turner-Warwick R,Whiteside CG,Worth PH, Milroy EJ, Bates CP. A urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and trans-trigonal posterior prostatectomy. Br J Urol. 1973;45:44-59. 13. Liu H, Mulholland SG. Appropriate antibiotic treatment of genitourinary infections in hospitalized patients. Am J Med. 2005;118 Suppl 7A:14S-20S. 14. Atala A. What’s new in urology. J Am Coll Surg. 2004;199:446-61. 14a. Weidner W, Schiefer HG, Dalhoff A. Treatment of chronic bacterial prostatitis with ciprofloxacin. Results of a one-year follow-up study. Am J Med. 1987;82:280-3. 14b. Simmons PD,Thin RN. Minocycline in chronic abacterial prostatitis: a double-blind prospective trial. Br J Urol. 1985;57:43-5. 14c. Berger RE. Predictors of quality of life and pain in chronic prostatitis/chronic pelvic pain syndrome: findings from the National Institutes of Health Chronic Prostatitis Cohort Study. J Urol. 2005;174:1842-3. 14d. Summaries for patients. Treating men with chronic prostatitis/chronic pelvic pain syndrome. Ann Intern Med. 2004;141:I8. 15. Berger RE. Acute epididymitis: etiology and therapy. Semin Urol. 1991;9:28-31. 16. Kaver I, Matzkin H, Braf ZF. Epididymo-orchitis: a retrospective study of 121 patients. J Fam Pract. 1990;30:548-52. 17. Vordermark JS, Deshon GE, Jones TA. Role of surgery in management of acute bacterial epididymitis. Urology. 1990;35:283-7. 18. Sadek I, Biron P, Kus T. Amiodarone-induced epididymitis: report of a new case and literature review of 12 cases. Can J Cardiol. 1993;9:833-6. 19. Oriel JD. Male genital Chlamydia trachomatis infections. J Infect Dis. 1992;25(Suppl 1): 35-7. 20. Petrack EM, Hafeez W. Testicular torsion versus epididymitis: a diagnostic challenge. Pediatr Emerg Care. 1992;8:347-50. 21. Lucas LM, Smith DL. Nongonococcal urethritis: diagnosis and management. J Gen Intern Med. 1987;2:199-203. 22. Petrack EM, Hafeez W. Testicular torsion versus epididymitis: a diagnostic challenge. Pediatr Emerg Care. 1992;8:347-50.

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23. Hsu CF,Wang CC, Chu CC, Chou TY, Diau GY, Chu ML. Epididymo-orchitis in an infant resulting from Escherichia coli urinary tract infection. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1996;37:48-51. 24. Rosenson AS, Ali A, Fordham EW, Chaviano A. A false-positive scan for testicular torsion and false-negative scan for epididymitis. Clin Nucl Med. 1990;15:863-4. 25. Drugs for sexually transmitted infections. Med Lett Drugs Ther. 1999;41:85-90. 26. Centers for Disease Control and Prevention. 2002 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep. 2002;51(RR6-1):1-84.

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Chapter 15

Common Sexually Transmitted Diseases RICHARD BEIGI, MD, MSC BARBARA M. GRIPSHOVER, MD

Key Learning Points 1. Patients should be counseled that regular use of condoms has been demonstrated to reduce the acquisition and transmission of all STDs and their use should be recommended. 2. Screening for Gonorrhea and Chlamydia in both men and women should use the highly sensitive Nucleic Acid Amplification Tests (NAATs) when possible 3. Genital herpes infections are extremely common and the majority of those infected are unaware of their status. 4. Syphilis remains the 2nd most common genital ulcer disease in the United States, disproportionately affecting the African American population. 5. Penicillin is the drug of choice for all stages of syphilis infection. 6. Chancroid remains a highly prevalent cause of genital ulcer disease in underdeveloped countries but is rare in the United States.

S

exually transmitted diseases (STDs) are among the oldest and most prevalent infectious diseases of humans. The Hebrew Testament of the Bible and writings of ancient China contain references to gonorrhea. Today, one fourth of all adults in some parts of sub-Saharan Africa are infected with HIV. Genital ulcerative diseases (GUDs), cervicitis, and urethritis all facilitate the transmission of HIV infection, and the treatment of these STDs can decrease the rate of new HIV infection. The major STD syndromes and their most common causes are listed in Table 15-1. Because many of these conditions are covered elsewhere in this 284

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New Developments in the Diagnosis and Treatment of Sexually Transmitted Diseases • New type-specific serological tests for herpes infections are now available, but

the exact indications for their use are still a subject of debate and investigation. • Quinolone-resistant Neisseria gonorrhoeae (QRNG) has emerged as a prevalent

and important cause of genital infection in many parts of the world. • Reports highlight the emergence of azithromycin-resistant Treponema pallidum

and confirm penicillin as the primary treatment method. • An effective quadrivalent human papillomavirus (HPV) vaccine exists and targets

young women before sexual debut and young sexually-active women (See chapter 18 on Papillomavirus and Cervical Cancer).

text, this chapter discusses only the most common pathogens that cause urethritis in men and cervicitis in women (Neisseria gonorrhoeae and Chlamydia trachomatis) and the common causes of GUD in developed countries (1). A few unifying principles apply to the treatment of any patient with an STD (Table 15-2). The first is that patients with one STD are at risk for other STDs and should be screened for gonorrhea, chlamydia, syphilis, and HIV. Women should have a Pap smear to exclude lesions caused by cervical infection with human papillomavirus. All sexual partners of patients with a diagnosed STD must be treated, and the patient must be reminded to refrain from sexual inter-

Table 15-1 Common Sexually Transmitted Disease Syndromes Syndrome

Symptoms

Pathogens

Urethritis

Urethral discharge, dysuria

Cervicitis

Often asymptomatic, vaginal discharge, dysuria

Genital ulcer disease

Single or multiple ulcers in genital area

Warts (condyloma) Molluscum contagiosum

Asymptomatic raised plaques Asymptomatic papules with central umbilication Fever, malaise, anorexia, jaundice Fever, lymphadenopathy, pharyngitis, rash

Neisseria gonorrhoeae Chlamydia trachomatis Uraplasma urealyticum Trichomonas vaginalis (rare) Neisseria gonorrhoeae Chlamydia trachomatis Unknown (>80%) Herpes simplex Treponema pallidum Hemophilus ducreyi Human papilloma virus Pox virus

Hepatitis Primary human immunodeficiency virus (HIV) infection

Hepatitis A virus Hepatitis B virus HIV

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Table 15-2 General Principles of Management of Patients with a Sexually Transmitted Disease 1. Screen for other sexually transmitted diseases including gonorrhea culture, Chlamydia detection, serologic test for syphilis, and antibody to human immunodeficiency virus. 2. All sexual partners of patient must be evaluated and treated. 3. Advise temporary abstinence from sexual intercourse until patient and all other affected persons have completed therapy. 4. Advise use of condoms to prevent further infection. 5. Consider hepatitis B vaccine for patient and all sexual contacts, and hepatitis A vaccine as well if patient is a homosexual male.

course until he or she and his or her partner(s) have completed a course of therapy to prevent reinfection. Finally, patients should be reminded that regular use of condoms will prevent the acquisition and transmission of STDs.

Gonorrhea in Adults Gonorrhea is a common bacterial illness that is transmitted sexually and perinatally. It primarily affects mucous membranes of the lower genital tract and, less frequently, those of the rectum, oropharynx, and the conjunctivae (2).

Etiology Gonorrhea is caused by N. gonorrhoeae, a gram-negative diplococcus that has complex growth requirements, growing best at 35°C to 37°C and with 5% carbon dioxide added. Many gonococci have a conjugative plasmid that enables them to acquire non–self-plasmids, which may be a mechanism for the acquisition of antimicrobial resistance.

Clinical Manifestations Asymptomatic Infection The prevalence of asymptomatic urethral N. gonorrhoeae infection in military recruits or otherwise unselected men ranges from 1% to 2%; if contacts of patients with gonorrhea are cultured, the prevalence can be as high as 50%. In women, the prevalence of asymptomatic N. gonorrhoeae infection ranges from 19% to more than 50% (3,4). Genital Infection in Men Urethritis is the most common clinical manifestation of gonorrhea in men. A purulent discharge and dysuria are frequent. As shown in Table 15-3, one cannot differentiate gonococcal from nongonococcal urethritis on the basis

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Table 15-3 Gonococcal and Nongonococcal Urethritis: Clinical Picture Characteristic

Mean incubation period, days Symptoms Discharge and dysuria Discharge or dysuria Signs No discharge Purulent discharge Mucoid discharge

Gonococcal

Nongonococcal

5

10

48–71% 29%

38% 62%

0% 91% 9%

19% 23% 58%

of clinical findings. Between 15% and 30% of male patients with gonorrhea have coexistent C. trachomatis urethritis. Less than 1% of cases are complicated by epididymitis (5,6).

Genital Infection in Women Women with symptomatic gonorrhea can present with a vaginal discharge, dysuria, or intermenstrual bleeding (4). Close to 50% of patients with positive endocervical cultures for N. gonorrhoeae (the endocervix is the site most often affected in women) have positive urethral cultures (the urethra is the site most frequently involved by gonorrhea in hysterectomized patients). Coinfection with C. trachomatis is twice as common in women with gonorrhea as it is in men with gonorrhea (6). Less frequently, women can present with infection of Skene or Bartholin glands. Pelvic inflammatory disease, a potentially severe complication of gonococcal infection, is discussed in Chapter 16 (7,8). Pharyngeal and Rectal Infections and Gonococcal Conjunctivitis Pharyngeal infection with N. gonorrhoeae occurs most commonly in women and men who have sex with men (MSM) and is symptomatic in less than 5% of patients (5). Microbiologic cure rates of pharyngeal gonorrhea are consistently lower than for gonococcal infections at other anatomic sites (9). Although frequently asymptomatic, patients with rectal gonococcal infection can present with pain, tenesmus, a purulent discharge, or rectal bleeding (5). Gonorrhea is the most common cause of proctitis in MSM (30%), with C. trachomatis (19%) and herpes simplex virus (16%) being frequent pathogens as well. Similar to genital infection, coinfection with gonorrhea and chlamydia is common in proctitis (24%) (10). Adult gonococcal conjunctivitis results from manual or direct contamination of the conjunctiva with infected genital secretions. If inadequately treated, it can progress to sight-threatening ulcerative keratitis. Patients present with severe conjunctival inflammation and a copious purulent discharge, which is unilateral in 60% of cases. Although 60% of adult

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patients with gonococcal conjunctivitis have urogenital cultures positive for N. gonorrhoeae, most are unaware of eye contamination with genital secretions. The diagnosis of gonococcal conjunctivitis is easily made by Gram staining the conjunctival secretions. The visual outcome of the disease is related to the severity of disease at the time adequate therapy begins (11).

Disseminated Gonococcal Infection Disseminated gonococcal infection (DGI) is an uncommon complication of infection with N. gonorrhoeae (<1% of infected patients) that results from a complex interaction between bacterial (e.g., resistance to complement-mediated killing, presence of Por IA, and AHU− auxotype) and host (e.g., complement deficiency, perimenstrual period) factors (12-14). Patients with DGI usually present after a few days of malaise, fever, and asymmetric polyarthralgia or monoarthralgia. The frequency of urogenital symptoms varies, and only a minority of patients present with cutaneous reports. On examination, most patients are found to have polyarthritis (involving the knees, elbows, or distal joints), and only a quarter have monoarthritis (most commonly of the knee or ankle). Purulent joint effusions seldom result in permanent articular damage. Tenosynovitis and skin lesions that consist of papules or pustules on the torso or limbs are commonly present. The diagnosis of DGI is usually made on the basis of clinical features and positive cultures from a mucosal site or normally sterile body fluid (e.g., blood, synovial fluid). The laboratory and microbiologic findings in DGI are shown in Table 15-4. Other Infections Perihepatitis (15,16) and endocarditis (17) are uncommon complications of infection with N. gonorrhoeae. The discussions of these two conditions are beyond the scope of this chapter.

Diagnosis A Gram stain of urethral secretions and a direct-detection method for N. gonorrhoeae and C. trachomatis should be done for all patients who present with

Table 15-4 Laboratory Findings in Disseminated Gonococcal Infection Peripheral white blood cell (WBC) count Synovial fluid WBC count* Culture (% positive) Urogenital site Synovial fluid Blood Skin

10–12
109/L 20–50
109/L 80–90% 40–50% 20–40% <5%

* The rate of synovial culture positivity directly correlates with synovial WBC count.

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urethritis (urethral discharge, dysuria, or both). If facilities for Gram staining are unavailable, direct detection methods for both N. gonorrhoeae and C. trachomatis should be used, and the patient should be treated for both infections (18). Evaluation for cervicitis in women should include a direct detection test for both N. gonorrhoeae and C. trachomatis; Gram stain is not helpful in the evaluation of cervicitis because of lower sensitivity and specificity.

Direct Visualization The Gram-stained smear has the advantages of low cost and rapidity but requires technical skill and does not provide information about the antibiotic sensitivity of the stained organism. The Gram stain is a good, quick, and inexpensive method for making a positive diagnosis of gonorrhea in symptomatic men, but the absence of typical gram-negative intracellular diplococci from the stained smear cannot be used to exclude the diagnosis. The Gram stain is not helpful in the evaluation for cervical, rectal, or pharyngeal gonorrheal infection. Direct Detection of N. gonorrhoeae Cell Components NUCLEIC ACID PROBE TESTS Two nucleic acid hybridization tests are Food and Drug Administration (FDA)-cleared to detect N. gonorrhoeae (and C. trachomatis). These tests use nucleic acid probes complementary to specific unamplified nucleic acid sequences in the patient specimen. Because they detect unamplified sequences, they are less sensitive than the nucleic acid amplification tests (NAATs) discussed next. They can be useful when proper culture conditions are unavailable because they can detect nonviable organisms, and they can be stored up to 7 days unrefrigerated before testing (19,20). NUCLEIC ACID AMPLIFICATION TESTS NAATs (polymerase chain reaction [PCR] tests, ligase chain reaction [LCR] tests) are designed to amplify nucleic acid sequences specific for the organism being detected. They do not require viable organisms, have increased sensitivity caused by their ability to detect as little as a single copy of the target DNA or RNA, and can be used on urine specimens as well. NAATs of either urethral or cervical swab specimens (from men and women, respectively) seem to be more sensitive than does the culture of these sites (20-23). CULTURE Culture has a sensitivity of 50% to 95% for N. gonorrhoeae, depending on the site tested and the criterion used as a standard. The advantages of culture are a high specificity and the availability of information about antibiotic sensitivity. In addition, culture is the test of choice to detect rectal and pharyngeal gonorrhea. The disadvantages of culture are the inevitable delay before it provides results and its requirement for organisms to remain viable (e.g., carbon dioxide, moisture, nutrients). A comparison of the different diagnostic methods for gonorrhea is shown in Table 15-5.

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Table 15-5 Sensitivity and Specificity of Different Diagnostic Methods for Genital Specimens for Gonorrhea Obtained from Symptomatic Individuals Relative to Culture Test

Site

Sensitivity (%)

Specificity (%)

Gram stain

Male urethra Endocervix Male urethra Endocervix Male urine Female urine

95–100 40–60 92 86 89–98 (72–95)* 50–95 (50–84)

95–100 95–100 96 96 99–100 99–100

Nucleic acid probe Nucleic acid amplification test

* Values in parentheses indicate the percent of culture-positive samples obtained by urethral and endocervical swab.

Treatment Single-dose treatment should always be used for uncomplicated gonococcal infections (24-28). Additionally, treatment of C. trachomatis should always be given to patients being treated for any infection caused by N. gonorrhoeae (unless a highly sensitive test for C. trachomatis has been done at the same time and is negative). The reasons for this recommendation are the high coinfection rate of the two organisms, the consistently low return rate for treatment of patients not treated during their initial visit, and the decreased complication rate and cost effectiveness of this measure (8,29). Ceftriaxone is the only commonly used antimicrobial agent for gonorrhea that is partly effective for treating incubating syphilis; however, because incubating syphilis is rare among patients being treated for gonorrhea, it should not be a major consideration in the choice of an antimicrobial agent for this population (30). Although many antimicrobial agents are effective as single-dose therapy for uncomplicated gonococcal infections, Table 15-6 shows the agents that offer the best balance of efficacy and safety. N. gonorrhoeae is eliminated from the male urethra within 24 hours after treatment with either ceftriaxone, cefixime, or ciprofloxacin (31). Tests of cure are not recommended for asymptomatic patients because of the following three reasons: 1. The modern treatment of urogenital gonorrhea is highly efficacious. 2. Most treatment failures are symptomatic. 3. A culture of the anatomic sites at which failure is most likely to occur (the pharynx and rectum) is relatively insensitive (30,32). Nevertheless, all sexual contacts of a patient with gonorrhea should be treated if their last sexual contact with the patient took place within the 60 days preceding the patient’s treatment. QRNG has emerged as a clinically relevant problem worldwide. First described in Asia in the 1980s, these strains have spread worldwide and are

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Table 15-6 Recommended Treatment of Gonococcal Infections in Adults Uncomplicated urogenital infection

Uncomplicated pharyngeal infection Disseminated gonococcal infection

Conjunctivitis To any of the preceding, if chlamydia coinfection has not been ruled out, add

Ceftriaxone 125 mg IM; or Cefixime 400 mg PO; or Ciprofloxacin 500 mg PO* † Ofloxacin 400 mg PO* †; or Levofloxacin 250 mg PO* †; or Spectinomycin 2 g IM‡ Ceftriaxone 125 mg IM; or Ciprofloxacin 500 mg PO* † Ceftriaxone 1 g IV QD; or Ceftizoxime 1 g IV q 8 h; or Cefotaxime 1 g IV q 8 h; or Ciprofloxacin 400 mg IV q 12 h* †; or Ofloxacin 400 mg IV q 12 h* †; or Levofloxacin 250 mg IV QD* †; or Spectinomycin 2 g IM q 12 h‡ until defervescence. Then complete at least 7 days of therapy with either: Cefixime 400 mg PO BID; or Ciprofloxacin 500 mg PO BID* †; or Ofloxacin 400 mg PO BID* †; or Levofloxacin 500 mg PO once QD* † Ceftriaxone 1 g IM once and irrigation of the affected eye(s) with saline once Azithromycin 1 g PO once; or Doxycycline 100 mg PO BID for 7 days+

* Quinolone-resistant Neisseria gonorrhoeae (QRNG) is prevalent in Asia, Australia, the Pacific Islands, England, Wales, Hawaii, and California, and also in men who have sex with men in the United States. Quinolones should not be used to treat gonorrheal infections in these settings (33,34). † Contraindicated in pregnancy. ‡ At the time of editing, spectinomycin was not available in the US. Abbreviations: BID, twice daily; h, hour; IM, intramuscularly; IV, intravenously; PO, orally; q, every; QD, daily

prevalent throughout Asia, Australia, the Pacific Islands, England, and Wales. In these countries quinolones are no longer recommended to treat gonorrhea (33). In the United States, QRNG is prevalent in Hawaii and California and are detected at an increased incidence among MSM. The Centers for Disease Control (CDC) does not recommend quinolones for treatment of gonorrhea in these populations at this time, and with continued transmission of these strains to wider populations in the United States, it is likely in the near future quinolones will not be recommended to treat gonorrhea (34).

Prevention Condoms are an effective means for decreasing the transmission of N. gonorrhoeae (35) and other STDs. Their use should always be recommended to

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patients who present with an STD. Screening to detect and treat asymptomatic gonorrheal infections is another possible method of prevention of transmission. As mentioned earlier, the prevalence of asymptomatic gonococcal infection in men is less than 3%. Testing of first-catch urine specimens for leukocyte esterase in male populations that are at high risk for such infection (e.g., adolescent male detainees, minorities attending an emergency room) has positive and negative predictive variables of 13% to 30% and 99% to 100%, respectively (36,37). Unfortunately, only 20% to 60% of patients with positive screening cultures for N. gonorrhoeae return for treatment (36,38). As a measure for decreasing the transmission of gonorrhea, it is not yet clear if it is cost effective to treat every asymptomatic man who has a positive leukocyte esterase screen. All pregnant women and any woman who presents to an STD clinic should be screened for gonorrhea; young unmarried women also should be considered candidates for screening (39,40).

Chlamydial Infections in Adults Chlamydial infections are the most common bacterial STDs in the United States (41-43). They are caused by C. trachomatis, a species of bacteria that grows intracellularly. Infection with C. trachomatis manifests as nongonococcal urethritis in men and as mucopurulent cervicitis in women. Chlamydial infections and their complications are estimated to result in 2.7 billion dollars of health care costs in the United States each year (44).

Etiology C. trachomatis is an obligate intracellular bacterium with a biphasic life cycle (41,42). The infectious elementary-body (EB) form of the organism is taken into squamocolumnar cells of the endocervix, urethra, rectum, and conjunctiva by endocytosis. Once inside the cell, the EB reorganizes to become the metabolically active reticulate body (RB), which replicates by binary fission within the intracellular inclusion (43). As the RB matures to the infectious EB form, the inclusion ruptures, killing the host cell and releasing EBs in a free state to infect other cells. Previous infection with C. trachomatis does not provide immunity (42). Sexually active adolescents have the highest prevalence of chlamydial infection, with approximately 10% of screened asymptomatic adolescents testing positively in several series (45). Because chlamydial infections are often asymptomatic, the duration of untreated disease is longer than that of treated disease, facilitating its transmission into broader demographic groups than is the case with gonorrhea. As many as 20% to 30% of men with gonococcal urethritis are coinfected with C. trachomatis (6,41), and the incidence of coinfection with the two organisms is even greater among women.

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Clinical Manifestations Asymptomatic Infection Nearly 25% of chlamydial urethral infections in men are asymptomatic (41), whereas approximately 60% to 70% of chlamydial endocervical infections in women are asymptomatic. Genital Infection in Men Urethritis is the most common manifestation of C. trachomatis infection in men, and such disease represents from 30% to 50% of all cases of nongonococcal urethritis (41,46-48). The discharge is classically less copious and less purulent than that of gonococcal urethritis (49); it is often noted only in the morning and in association with mild dysuria. However, the spectrum of symptoms of chlamydial urethritis overlaps that of gonococcal urethritis (see Table 15-3). Only a Gram stain that reveals intracellular gram-negative diplococci can establish a clinical diagnosis of gonococcal urethritis reliably and, as mentioned earlier, does not exclude concurrent chlamydial infection. C. trachomatis is the most frequent cause of epididymitis in men younger than 35 years of age (42). Chlamydial urethritis is also the most common trigger of the reactive arthritis of Reiter syndrome. Approximately 1% of men with nongonococcal urethritis develop acute aseptic arthritis. The arthritis associated with chlamydial infection improves with treatment of this infection. Genital Infection in Women Although most chlamydial infections in women are asymptomatic, manifestations of the infection in other cases include vaginal discharge (from endocervical infection), intermenstrual bleeding, and dysuria (42,50,51). Examination with a speculum can reveal a mucopurulent discharge in the cervical os; however, this is neither sensitive nor specific for infectious cervicitis. As much as 20% of women with genital chlamydial infections can have only a urethral infection. Ascending infection that leads to endometritis and salpingitis can also occur with chlamydial infection (as with gonorrhea), and its effects range from acute severe abdominal pain to asymptomatic salpingitis. Evidence of chlamydial infection is found in approximately 20% of cases of acute pelvic inflammatory disease (42). Sequelae of chlamydial salpingitis include tubal infertility, pelvic pain, and ectopic pregnancy. Many studies have shown an association between serologic evidence of previous chlamydial disease and tubal infertility; however, most of the women affected were not aware of having had chlamydial infections (52). This is thought to be caused by asymptomatic upper genital tract infection with C. trachomatis and potentially other common genital tract bacteria. Inclusion Conjunctivitis In adults, chlamydial eye infection presents with hyperemia, mucoid discharge, and the sensation of a foreign body in the eye (42). If untreated,

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chlamydial inclusion conjunctivitis can persist for months but rarely causes conjunctival scarring. More than 50% of chlamydial eye infections in adults are associated with concurrent genital infections (42).

Diagnosis The choice of tests for diagnosing genital chlamydial infections is not simple (22,46,53-55). NAATs are the most sensitive and very specific, however also the most costly. Table 15-7 summarizes some characteristics of the currently available assays for diagnosing genital chlamydial infections

Detection of C. trachomatis Cell Components DIRECT FLUORESCENT ANTIBODY TEST The direct fluorescent antibody test (DFA) uses specific fluorescinated monoclonal antibodies to proteins of C. trachomatis to detect EBs of the organism. It is a rapid and relatively specific test; its disadvantages are that it is tedious, is subject to the expertise of the observer, and requires a fluorescence microscope (22). ENZYME IMMUNOASSAY FOR CHLAMYDIAL ANTIGENS The enzyme immunoassay is an acceptable method for diagnosing genital C. trachomatis infections from urethral and endocervical swabs in both male and female patients. Its specificity makes it useful for screening low prevalence populations (22). NUCLEIC ACID PROBE ASSAYS The nucleic acid probe assays for chlamydial infection use either a DNA probe that hybridizes with rRNA of C. trachomatis, or a RNA probe that hybridizes with chlamydial DNA. These tests are specific, and samples can be batch-processed and stored up to a week before processing. The same sample can be used to test for N. gonorrhoeae as well. In one direct comparison study, the DNA probe was significantly more sensitive in detecting chlamydial infection than several different enzyme immunosorbent assay (EIA) (56). Table 15-7 Characteristics of Tests to Diagnose Chlamydia trachomatis Genital Infections in Adults Test

Site

Culture

Cervical Urethral (male) Cervical Urethral (male) Cervical Urethral (male) Cervical Cervical Urine (female) Urine (mae)

Direct fluorescence antibody (DFA) Enzyme immunoassay (EIA) Nucleic acid probe Nucleic acid amplification test (NAAT)

Sensitivity (percentage)

Specificity (percentage)

55–81 65–75 74 74 61–72 79 72–75 84–91 79–83 85

100 100 97 99 99 97 99 99 99 99

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NUCLEIC ACID AMPLIFICATION TESTS As described earlier for detection of N. gonorrhoeae, NAATs use various nucleic acid amplification techniques to detect specific DNA or RNA sequences of C. trachomatis in the clinical sample (5662). NAATs are more sensitive than culture and detect 20% more chlamydial infections than a non-NAAT probe and retain good specificity (57). Another important advantage of NAATs is that the sensitivity for infection when applied to urine is close to the sensitivity of the NAAT method as applied to urethral and cervical swabs and is much higher than that of swabs tested for chlamydia by other means. As a result, NAATs are the only tests recommended for diagnosis of chlamydial infection in urine specimens from men and women (22). ISOLATION TESTS C. trachomatis must be grown in cell culture, and isolation is rarely used for diagnosis except in medicolegal instances when its high specificity is needed.

Treatment The mainstay of treatment of uncomplicated chlamydial urethritis and cervicitis has been doxycycline (or erythromycin in pregnancy) given for a week (Table 15-8) (1). A great advance in simplifying treatment of people at risk (e.g., adolescents who are so disproportionately affected by chlamydial infections) has been the recognition of the fact that a single 1-gram dose of azithromycin eradicates chlamydial infection (50,63). Unfortunately, azithromycin is a significantly more expensive antibiotic than doxycycline or erythromycin; however, in one analysis, the decrease in late complications of chlamydial cervicitis in people treated with azithromycin versus doxycycline (with some instances of failure estimated to result from noncompliance) made azithromycin more cost effective to the medical system (64). Ofloxacin has activity against C. trachomatis but, like doxycycline or erythromycin, requires a week of therapy. However, one situation in which this costly drug might be helpful is in epididymitis, because of its coverage of both C. trachomatis and enteric pathogens.

Prevention As with all STDs, the use of condoms and the treatment of sexual partners of infected people can decrease the rate of transmission of chlamydial

Table 15-8 Treatment for Chlamydial Cervicitis and Urethritis Doxycycline 100 mg orally twice a day for 7 days, or Azithromycin 1000 mg orally once, or Ofloxacin 300 mg orally twice a day for 7 days Levofloxacin 500 mg orally for 7 days For pregnant patients: Erythromycin 500 mg four times a day for 7 days, or Amoxicillin 500 mg orally three times a day for 7 days, or Azithromycin 1 g orally taken once

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infections. In a managed care population in Seattle, screening of women at high risk for chlamydial infection (i.e., unmarried, younger than 24 years of age, and having had more than two sexual partners in the past 12 months) for chlamydial cervicitis decreased the incidence of pelvic inflammatory disease (65). Additionally, treating pregnant women can decrease premature labor, premature rupture of membranes, and birth rates of infants who are small for their gestational age (66).

Genital Herpes Infection Etiology and Epidemiology Genital herpes, a sexually transmitted viral infection, is the most common cause of GUD in the United States. In 80% to 90% of cases, genital herpes is caused by infection with herpes simplex virus type 2 (HSV-2), with the remaining 10% to 20% of cases caused by herpes simplex virus type 1 (HSV-1), which more commonly causes orolabial disease (67). There seems to be an increase in HSV-1 genital infections in recent years, although genital infection is still predominantly caused by HSV-2 (1). Both types of HSV are DNA viruses, and, like all members of the herpes virus family, HSV establishes a lifelong, latent infection in its human host. Latent HSV resides in sensory nerve ganglia and, in genital herpes, resides particularly in the sacral nerve ganglion. Seroepidemiologic studies in the United States have indicated that up to 21.7% of U.S. citizens between the ages of 13 and 74 years are infected with HSV-2—an increase of 32.3% in the prevalence of infection from the late 1970s to the late 1980s (68). Many studies have shown that most people infected with HSV-2 are unaware of being infected (69-74), which indicates that asymptomatic viral shedding is the major method of transmission of such infection. In prospective studies of couples discordant for anti–HSV-2 antibody (72,73), the transmission of infection was detected in 10% of couples per year. Transmission was higher when the male partner was the infected source partner and also when the previously uninfected partner was seronegative for HSV-1 and HSV-2. A study of patients at private obstetric offices in California found that 10% of pregnant women were at risk for contracting HSV-2 from their spouses despite a mean duration of exposure of 6.1 years (70).

Clinical Manifestations Asymptomatic Infection As mentioned previously, most HSV-2 infections are asymptomatic. These can be first recognized by transmission to another person who develops symptomatic disease.

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First-Episode Genital Herpes Patients with a first episode of genital herpes and without serologic evidence of previous HSV infection have a more severe course of disease than do those with previous HSV infection (67). Clinically recognized, new HSV infections among those with serologic evidence of previous HSV infection are termed nonprimary, first episode outbreaks. The incubation period after sexual exposure is usually 3 to 7 days. Primary infection often begins with systemic symptoms, including headache, fever, and myalgia for the first few days of the illness. Pain and itching in the genital area are the first local symptoms noted, followed by the development of painful vesicles on the vulva and labia in women and on the penile shaft and glans in men. Usually the vesicles have ulcerated by the time the patient seeks medical care. Pain peaks approximately 1 week into the illness, then gradually resolves as lesions heal. New lesions develop in most patients well into the first week of clinical illness, and typically all lesions resolve by 3 weeks after the start of the illness. Bilateral, tender, nonfluctuant inguinal adenopathy develops in the second week and is one of the last symptoms to resolve. Cervicitis occurs in almost 90% of primary genital HSV infections in women; urethritis occurs in 80%. Complications of primary genital HSV include meningitis, which occurs in one third of women and in 13% of men approximately 1 week into the illness, and autonomic dysfunction (including urinary retention), which is rare. It is worthy of emphasis that most newly infected individuals with HSV-2 manifest no symptoms, and thus often go undiagnosed. Recurrent Infection Constitutional symptoms infrequently accompany recurrent episodes of genital HSV, and the duration of lesions in such episodes is much shorter than in cases of primary disease, with healing typically occurring after 7 to 10 days. Almost half of episodes of recurrent HSV infection are preceded by a prodrome of tingling paresthesias, sometimes radiating to the buttocks or hips. Recurrences are 20% more common in men than in women and are more common in people who have a severe primary episode of genital infection (75). Treatment of the primary episode does not decrease the rate of recurrence (76). Recurrence of genital HSV-1 infection is less likely than that of genital HSV-2 infection (77).

Diagnosis The diagnosis of genital HSV infection is often clinically apparent when patients present with classically clustered vesicles or ulcers; however, confirmatory tests are available and especially important for patients with atypical lesions. Because the diagnosis of genital herpes can cause significant psychological trauma, confirmatory tests in the office are helpful in eliminating any uncertainty. Culturing the base of a fresh vesicle gives the highest yield of virus.

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Culture Herpes simplex virus grows readily in cell culture, with a cytopathic effect noted within 48 to 72 hours (78,79). Titers of virus are highest in clinical specimens from early vesicles and wet ulcers; virus also can be cultured from the cervix (88% of primary infections) and rectum (the most common site of asymptomatic shedding of virus in women, and from which shedding is not correlated with anal intercourse). Culture is the gold-standard test for HSV infection, but the yield decreases in older lesions. HERPES SIMPLEX VIRUS ANTIGEN DETECTION Monoclonal antibodies are available to detect HSV antigens, and they can distinguish types 1 and 2 from each other (78). Fluorescence-labeled antibodies can be used to detect HSV antigens in cells scraped from the base of an ulcer and dried on a slide. This method is less sensitive than culture but constitutes a rapid test specific for HSV. POLYMERASE CHAIN REACTION FOR HERPES SIMPLEX VIRUS DNA The PCR for detecting HSV infection is based on DNA amplification of the virus from a vesicle or ulcer. Although this has been shown to be more sensitive than culture for detecting HSV (80), its role in routine clinical practice has yet to be established. SEROLOGIC TESTS HSV-1 and HSV-2 share most of their immunogenic sequences resulting in many cross-reacting antibodies. However one structural protein, glycoprotein G (gG-1 in HSV-1 and gG-2 in HSV-2) does elicit a type-specific antibody response. Several tests are now commercially available that detect these type-specific antibodies and can reliably distinguish HSV-2 infection from HSV-1 infection. These include the HerpeSelect enzyme-linked immunoabsorbent assay (ELISA) and immunoblot assays by Focus, which are laboratory based tests, and a point-of-care diagnostic test done on a fingerstick blood sample marketed by Diagnology as POCkitHSV 2. These should not be confused with the many non-glycoprotein G HSV serologic tests that cannot distinguish HSV-1 and HSV-2 (81,82). The type-specific HSV serologic tests are both sensitive (93%-99%) and specific (94%-98%), and turn positive by 12 weeks after primary infection. These tests are clinically helpful in detecting HSV in patients presenting with recurrent genital ulcerations when other tests (such as culture) are nondiagnostic (83). Also, these tests can be of benefit in counseling a couple where one partner is known to be HSV infected, given the high prevalence of asymptomatic HSV infection. This could be helpful for a pregnant asymptomatic partner of a person with HSV infection, for if she is seronegative the couple could take measures to avoid her acquisition of primary HSV infection at the end of her pregnancy (and the risk of subsequent neonatal HSV infection) (84).

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Treatment First-Episode Genital Herpes In the early 1980s, acyclovir therapy was first shown to decrease the duration of viral shedding, pain, development of new lesions, and time to complete healing of lesions in first-episode genital herpes (85,86). Although topical acyclovir can reduce the duration of viral shedding, it is clearly inferior to systemic therapy (86). Treatment does not prevent further recurrences. The newer antiviral agents famciclovir and valacyclovir are also active against HSV (87,88). They have better bioavailability and a longer half-life than does acyclovir, thereby permitting less frequent dosing. For initial episodes of genital HSV, valacyclovir 1000 mg given twice daily was just as efficacious as acyclovir 200 mg given five times daily (Table 15-9). Episodic Recurrent Therapy Studies with acyclovir, famciclovir, and valacyclovir show that treatment initiated at the first symptom of recurrence of genital HSV infection can decrease the duration of pain, viral shedding, and lesions by approximately 1 day (86-88). Unless the recurrence is exceptionally painful, treating episodic recurrences is not usually indicated in otherwise normal hosts. Suppressing Recurrent Genital Herpes Simplex Virus Patients who have more than six recurrences in a year can benefit from continuous suppressive therapy for symptomatic recurrent genital HSV. Acyclovir has the longest track record for suppressive therapy, being safe and effective for patients who require treatment for as long as 6 years (89,90). Famciclovir and valacyclovir are also effective in suppressing recurrences of genital HSV. Patients in whom suppressive therapy is started should have it stopped on a

Table 15-9 Treatment for Genital Herpes Simplex Virus Infection First episode genital herpes Acyclovir Famciclovir Valacyclovir Episodic recurrent therapy Acyclovir Famiciclovir Valacyclovir Continuous suppressive therapy Acyclovir Famiciclovir Valacyclovir

400 mg three times a day for 7–10 days 200 mg five times a day for 7–10 days 250 mg twice a day for 5 days 1000 mg twice a day for 7–10 days 400 200 125 500

mg mg mg mg

three times a day for 5 days five times a day for 5 days twice a day for 5 days twice a day for 3 days

400 mg twice a day 250 mg twice a day for 7–10 days for first episode 500 mg once a day (if <9 recurrences in a year) 1000 mg once a day (if >9 recurrences in a year)

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yearly basis to see whether continued therapy is needed, because the frequency of recurrence does decrease with time. Suppressive therapy also decreases asymptomatic shedding of HSV-2, but not completely (90).

Prevention Patients with genital HSV infections should be advised to refrain from intercourse when they have lesions. To avoid transmission of infection by asymptomatic shedding of the virus, infected patients should use condoms at all times. Suppressive therapy with valacyclovir decreases the rate of transmission of HSV to a susceptible partner (from 3.6 % to 1.9% over 8 months), but does not reduce the risk to negligible (91). Therefore suppressive therapy is most useful for preventing frequent symptomatic HSV recurrences.

Syphilis Syphilis is an STD caused by infection with the bacterial spirochete Treponema pallidum (92,93). Traditionally, syphilis has been divided into three stages: primary syphilis (a GUD), secondary syphilis (caused by dissemination of T. pallidum from the primary site of infection and characterized by a generalized rash and lymphadenopathy), and tertiary syphilis (the result of long-standing untreated end-organ disease).

Etiology and Epidemiology T. pallidum is a thin, unicellular, coiled bacterium that can be recognized under a darkfield microscope by its characteristic corkscrew motility with flexion about the center of the organism (92,93). Because T. pallidum cannot be cultured in vitro, the test for viable organisms requires injection of a specimen into rabbit testes. The rabbits are then monitored for the development of orchitis and serologic evidence of infection (94). Although its incidence has been decreasing recently in the United States, syphilis remains the second most common GUD. Its incidence is higher among African Americans than among other racial groups. Epidemics have been associated with crack cocaine use and the exchange of sex for drugs (95), and recently identification of sexual partners over the Internet by MSM (96). People with early syphilis are infectious to their sexual partners (92). All partners who have had sex within 3 months of diagnosis with a patient who has primary syphilis and anyone who has had sex within 6 months of diagnosis with a patient who has secondary syphilis should be considered at risk for contracting the disease and should be referred for treatment (1).

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Clinical Manifestations For a more exhaustive discussion of the clinical manifestations of syphilis, see references 92, 93, and 95.

Primary Syphilis Approximately 3 weeks (range 10-90 days) after exposure to T. pallidum, an ulcer develops at the site of organism inoculation (92,93,95). This chancre is typically painless with indurated edges and can be found on the penis, vagina, lip, mouth, or anus. Firm, nontender, bilateral inguinal adenopathy is often present. The chancre heals spontaneously in 3 to 6 weeks. Secondary Syphilis Symptoms of secondary syphilis develop from 4 to 10 weeks after the appearance of the chancre of primary syphilis. The most common of these symptoms is a rash that is usually accompanied by constitutional symptoms, including malaise, low-grade fever, arthralgias, and generalized lymphadenopathy. The rash is typically nonpruritic and maculopapular, originating on the trunk and proximal extremities but then spreading to include the palms of the hands and soles of the feet. However, the rash also can be pustular, nodular, or eczematous. Other skin manifestations of secondary syphilis include patchy alopecia (5%); condyloma lata (10%-20% of cases), which are heaped gray plaques in moist skin folds that teem with spirochetes; and pharyngeal mucous patches (6%-30%), which are gray erosions surrounded by an erythematous border. None of these lesions is painful. Involvement of the central nervous system in secondary syphilis can be manifested as aseptic meningitis (with headache, photophobia, and neck stiffness), cranial neuropathy (especially that which involves the VIII nerve), and eye involvement (especially in the form of anterior uveitis). Rare complications include hepatitis, glomerulonephritis, arthritis, and periostitis. Latent Syphilis As with the chancre of primary syphilis, the manifestations of untreated secondary syphilis resolve, and the patient enters a prolonged period of asymptomatic infection. For treatment purposes, latent syphilis is infection that is present for more than 1 year or nonprimary and nonsecondary disease that occurs with an infection of unknown duration. The diagnosis of latent syphilis is a serologic diagnosis, because the patient is by definition asymptomatic. Tertiary Syphilis Late complications of syphilis are rare in today’s antibiotic era. One third of individuals with untreated syphilis develop late complications on an average of 10 to 20 years after infection. Gummata (chronic necrotizing

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inflammatory lesions found predominantly in skin, subcutaneous tissue, and bone) are the most common manifestation of tertiary syphilis, occurring in 15% of untreated patients. Syphilitic aortitis, which results from endarteritis obliterans in the vasa vasorum of the aorta, causes aneurysmal dilatation of the ascending aorta and is clinically apparent in 10% of individuals with long-standing syphilis. The late neurological sequelae of untreated syphilis include tabes dorsalis (in which demyelination of the posterior columns and dorsal roots results in shooting pains and ataxia), generalized paresis, and loss of parenchymal nerve cells (which results in dementia, hyperactive reflexes, pupillary abnormalities [accommodation without reactivity], and slurred speech).

Neurosyphilis The nervous system can be involved at all stages of infection by T. pallidum (97). In fact, the organism can be found in the cerebrospinal fluid (CSF) of 29% of patients with primary syphilis (98). As mentioned previously, meningitis is an early manifestation of neurosyphilis, occurring in the first year or two after infection, commonly with secondary syphilis. Meningovascular syphilis occurs from 4 to 7 years after infection and is caused by endarteritis obliterans in the small vessels of the meninges, brain, and spinal cord; it presents with strokes and seizures. Tabes dorsalis and generalized paresis occur decades after infection. Syphilis and HIV infection Several reports suggest that syphilis progresses more rapidly in people who are coinfected with HIV. A higher incidence of chancre is found in HIVinfected individuals with secondary syphilis (43% vs. 15% in HIV-negative people). HIV-infected individuals who are treated appropriately for early syphilis have still developed neurosyphilis (94). Meningovascular syphilis also occurs earlier in HIV-infected individuals (99,100). These findings have led to the recommendation for a CSF examination to exclude asymptomatic neurosyphilis in all HIV-infected individuals who have latent syphilis (1). Given the potential differences in natural history and response to therapy seen in HIV-infected individuals, consultation with an expert is advised for any nonstereotypic clinical or serologic response to stage-appropriate therapy.

Diagnosis Detection of Treponema pallidum in Clinical Specimens Mucosal lesions of primary and secondary syphilis (e.g., chancres, mucous patches, condyloma lata) can be scraped and examined under a darkfield microscope to detect treponemes moving in their characteristic spiral manner (92). The sensitivity and specificity of this test both depend in part on the skill of the microscopist. Fluorescent antibodies are available for

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detecting treponemal antigens (direct fluorescent antibody [DFA] test) in slide preparations of scrapings from lesions and have the advantage of binding with antigens in dried specimens so that the latter can be sent to a central laboratory. The PCR technique for amplifying treponemal DNA in a lesion has a sensitivity similar to that of darkfield microscopy and DFA testing (101,102).

Serologic Tests Two classes of serologic tests have been the mainstay of diagnosis for syphilitic infections and are used to monitor the response to treatment (92, 95,103,104). Nontreponemal tests detect antibodies to the lipid antigens of T. pallidum, and treponemal tests detect antibodies directed at treponemal antigens (92,95,103,104). Nontreponemal serologic tests (e.g., rapid plasma reagin [RPR] test, Venereal Disease Reference Laboratory [VDRL] test) are technically easier to do than are the treponemal tests (e.g., fluorescent treponemal antibody-absorption test, microhemagglutination assay for T. pallidum). Moreover, the antibody titer in the RPR and VDRL tests changes in response to therapy. However, all positive results of nontreponemal serologic tests must be confirmed as true positives by verifying them with a treponemal test. Table 15-10 shows the common causes of false-positive results to VDRL tests. The treponemal tests first become positive during primary syphilis and, once positive, usually remain so for the life of the patient despite appropriate therapy. By 1 week after occurrence of the chancre in primary syphilis, the results of the VDRL or RPR test should be positive, and 100% of results of these two tests are positive during secondary syphilis. The titers are highest in secondary syphilis and decrease in time even without therapy, so that approximately 25% of cases of latent syphilis culminate as seronegative with the VDRL and RPR tests. In response to therapy, the titers with the two tests should decline by fourfold at 6 months for primary

Table 15-10 Common Causes of False-Positive Non-Treponemal Tests Infectious Bacterial: Viral:

Endocarditis, pneumococcal pneumonia, tuberculosis, chancroid, scarlet fever, leptospirosis, mycoplasma, rickettsial disease Varicella, hepatitis, measles, infectious mononucleosis, human immunodeficiency virus infection, mumps

Noninfectious Pregnancy Chronic liver disease Intravenous drug use Advancing age Connective tissue disease (especially systemic lupus erythematosis) Cancer Multiple blood transfusions

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and secondary disease; latent disease takes longer to respond, and titers should be fourfold lower by 12 months (103,105).

Treatment Penicillin remains the drug of choice for treating syphilis at all stages (Table 15-11) (1). Doxycycline is an alternative for penicillin-allergic patients; however, there is no alternative to penicillin therapy for pregnant women and people with neurosyphilis, and desensitization must be done. Although a single 2-gram dose of azithromycin is as efficacious as a single dose of penicillin for early syphilis, (106), routine use of azithromycin cannot be recommended because of reports of azithromycin-resistant T. pallidum in the United States, Canada, and Ireland (107). As already noted, serologic testing should be repeated at 6 and 12 months of treatment to assess the adequacy of response; titers should decrease by fourfold within 12 months after treatment is begun. People who should have a CSF examination before being treated for latent syphilis include those with neurological or ophthalmic symptoms; evidence of active tertiary syphilis (e.g., aortitis, gumma); failure of previous treatment (with increasing VDRL test titers or a high titer [>1:32] that does not decrease); and HIV infection (1).

Prevention All sexual partners of syphilis patients and any contacts of these individuals must be identified so that they can be treated with an effective antimicrobial Table 15-11 Treatment of Syphilis* Primary

Secondary or Early Latent

Late latent or unknown duration and late syphilis

Neurosyphilis

Benzathine penicillin G 2.4 million units intramuscularly once For penicillin allergic patients: Doxycycline 100 mg orally twice a day for 2 weeks, or tetracycline 500 mg orally four times a day for 2 weeks Benzathine penicillin G 2.4 million units intramuscularly once For penicillin allergic patients: Doxycycline 100 mg orally twice a day for 2 weeks, or tetracycline 500 mg orally four times a day for 2 weeks Benzathine penicillin G 2.4 million units intramuscularly each week for 3 weeks For penicillin allergic patients: Doxycycline 100 mg orally twice a day for 4 weeks, or tetracycline 500 mg orally four times a day for 4 weeks. Aqueous penicillin G 18–24 million units a day, given as 3–4 million units IV every 4 hours for 10–14 days, or procaine penicillin 2.4 million units intramuscularly each day with probenecid 500 mg orally four times a day, both for 10–14 days

* Pregnant women and persons with neurosyphilis must be treated with a penicillin-containing regimen, and therefore need desensitization if they are penicillin-allergic.

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regimen. Individual eradication of syphilis, whether symptomatic or asymptomatic, is important. Education should be given to patients and their contacts about abstinence and the use of condoms. Patients and others at risk for syphilis should be made aware that the presence of genital ulcers increases the risk of acquiring HIV infection.

Chancroid Chancroid is a sexually transmitted GUD caused by Haemophilus ducreyi, a fastidious, pleomorphic gram-negative coccobacillus that requires carbon dioxide, hemin, and nicotinamide adenine dinucleotide for growth in culture. Chancroid is the most common GUD in underdeveloped countries but is infrequent in North America and occurs most commonly in outbreaks (108,109). Chancroid has been proven to increase the transmission of HIV.

Clinical Manifestations The classic description of chancroid is a tender, purulent ulcer (or ulcers) that invades beneath or undermines the border of normal tissue (80,110, 111). This lesion usually appears after a median incubation period of 5 to 7 days. Common locations of chancroid lesions, in order of frequency, are the preputial orifice, coronal sulcus, and the frenulum of the penis (in men) or the fourchette, vestibule, and labia minoris of the vagina (in women). It is now known that the classic presentation of chancroid is uncommon (112114); however, lymphadenopathy is common in chancroid, is unilateral in half of cases, and evolves into a fluctuant abscess or bubo in many cases. The clinical diagnosis of GUD suffers from inaccuracy. There is broad overlap in clinical features among HSV, chancroid, and syphilis, and the likelihood that a certain constellation of signs reflects a given entity depends heavily on the relative prevalence of each of the GUD entities in the location in which the finding is made. Thus, single clinical features that are highly specific for a particular GUD are not sufficiently sensitive for its diagnosis (e.g., ulcer induration was found to be 95% specific for syphilis in one study but was only 47% sensitive). Furthermore, as many as 25% of patients have mixed infections (primary syphilis and chancroid are the most common ulcerative infections [114]); thus, diagnostic tests are needed to ascertain the cause of most cases of GUD. Because the male-to-female ratio for chancroid ranges from 3:1 to 25:1, it has been suggested that women can be asymptomatic carriers of H. ducreyi. However, a study done with molecular amplification techniques found that only 2% to 4% of female prostitutes in Africa carried H. ducreyi asymptomatically (115). Men with chancroid frequently give a history of a recent exposure to female prostitutes. Asymptomatic female partners can provide an alternative explanation for this finding.

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Diagnosis The minimal procedures needed to make an etiologic diagnosis in patients who present with GUD include a darkfield microscopic examination and serologic testing for syphilis and cultures for chancroid and HSV infection (113,116). If these tests are unavailable and the patient’s lesions are not typical for herpes, therapy for chancroid, syphilis, and herpes (if indicated) should be prescribed. The following are the performance characteristics of diagnostic tests for chancroid.

Direct Visualization and Culture Gram staining of ulcer secretions to identify the school-of-fish appearance of H. ducreyi, which causes the disease, is insensitive for the diagnosis of chancroid (40%-60%). The sensitivity of culture of this fastidious organism in patients with clinically diagnosed chancroid ranges from 30% to 90% (117). Detection of Microbial Components A multiplex PCR has been developed for detecting T. pallidum, H. ducreyi, and HSV (118,119). It seems to be much more sensitive and only slightly less specific than culture-based methods for the diagnosis of GUD. Nevertheless, the method fails to detect GUD in 20% of patients, and its applicability to routine clinical practice remains to be determined.

Treatment As mentioned previously, the clinical presentation of GUD often prevents an etiologic diagnosis in presenting patients, and many centers do not do the minimal tests needed to establish such a diagnosis. Fortunately, syphilis is relatively uncommon in North America (120), and most cases of chancroid occur in specific geographic areas (84% of the 386 cases of chancroid reported in 1996 occurred in New York State, Louisiana, Texas, and Illinois [120]). Thus, if a patient presents with vesicular lesions or with a constellation of symptoms and signs highly suggestive of HSV infection (the most common cause of GUD in North America), then a diagnosis of such infection is likely. The patient should be treated for HSV infection if indicated, and a serologic test for syphilis should be done. If the diagnosis is uncertain, then the patient should be treated for syphilis (and for chancroid if the patient resides in a community in which H. ducreyi is a significant cause of GUD), and a serologic test for syphilis should be done. Many antibiotics are effective for treating chancroid (1,121). Recommended options for antibiotic treatment are shown in Table 15-12. Ulcers are usually culture negative after the third day of treatment, and patients have to be reevaluated after 5 to 7 days of therapy. Objective signs of improvement are decreased purulence at the ulcer base and epithelialization of the ulcer (121). Most ulcers heal within 10 days, but some can take as long as 28 days.

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Table 15-12 Recommended Regimens for the Treatment of Chancroid Azithromycin 1 g orally once, or Ceftriaxone 250 mg intramuscularly once, or Ciprofloxacin 500 mg orally twice a day for 3 days, or Erythromycin 500 mg orally four times a day for 7 days

Healing can be slower in uncircumcised patients or in patients coinfected with HIV. If no signs of improvement are seen after 7 days of treatment, the clinician must consider either an incorrect diagnosis or coinfection with another STD as possible explanations for treatment failure. The fluctuant adenopathy of chancroid can take longer than ulcers to resolve, and its failure to resolve by 7 days after the beginning of treatment should not be considered treatment failure. Drainage of chancroid lesions is often needed, and there is evidence that incision and drainage of these lesions can entail less retreatment than does needle aspiration (122).

Prevention As with other STDs, the prevention of chancroid involves identifying and treating the sexual contacts of patients. Condoms and careful partner selection can reduce the transmission of H. ducreyi. It is important to stress once again that genital ulcers increase the chance of acquiring HIV disease.

REFERENCES 1. Centers for Disease Control and Prevention. 2002 Guidelines for treatment of sexually transmitted diseases. MMWR Morbid Mortal Wkly Rep. 2002;51:1-80. 2. Handsfield HH, Sparling PF. Neisseria gonorrhoeae. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Elsevier Churchill Livingstone; 2005:2514-29. 3. Handsfield HH, Lipman TO, Harnisch JP,Tronca E, Holmes KK. Asymptomatic gonorrhea in men. Diagnosis, natural course, prevalence and significance. N Engl J Med. 1974;290:117-23. 4. McCormack WM, Stumacher RJ, Johnson K, Donner A. Clinical spectrum of gonococcal infection in women. Lancet. 1977;1:1182-5. 5. Sherrard J, Barlow D. Gonorrhoea in men: clinical and diagnostic aspects. Genitourin Med. 1996;72:422-6. 6. Project RESPECT Study Group. Chlamydia trachomatis among patients infected with and treated for Neisseria gonorrhoeae in sexually transmitted disease clinics in the United States. Ann Intern Med. 2003;139:178-85. 7. Platt R, Rice PA, McCormack WM. Risk of acquiring gonorrhea and prevalence of abnormal adnexal findings among women recently exposed to gonorrhea. JAMA. 1983;250:3205-9. 8. Stamm WE, Guinan ME, Johnson C, Starcher T, Holmes KK, McCormack WM. Effect of treatment regimens for Neisseria gonorrhoeae on simultaneous infection with Chlamydia trachomatis. N Engl J Med. 1984;310:545-9. 9. Moran JS. Treating uncomplicated Neisseria gonorrhoeae infections: Is the anatomic site of infection important? Sex Transm Dis. 1995;224:39-46. 10. Klausner JD, Kohn R, Kent C. Etiology of clinical proctitis among men who have sex with men. Clin Infect Dis. 2004;38:300-2. 11. Wan WL, Farkas GC, May WN, Robin JB. The clinical characteristics and course of adult gonococcal conjunctivitis. Am J Ophthalmol. 1986;102:575-83.

Tan ch15.qxd 10/12/07 10:20 AM Page 308

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12. Ross JD. Systemic gonococcal infection. Genitourin Med. 1996;72:404-7. 13. Wise CM, Morris CR, Wasilauskas BL, Salzer WL. Gonococcal arthritis in an era of increasing penicillin resistance. Presentations and outcomes in 41 recent cases (1985-1991). Arch Intern Med. 1994;154:2690-5. 14. Morello JA, Bohnhoff M. Serovars and serum resistance of Neisseria gonorrhoeae from disseminated and uncomplicated infections. J Infect Dis. 1989;160:1012-7. 15. Curtis AH. A cause of adhesions in the right upper quadrant. JAMA. 1930;94:1221-2. 16. Fitz-Hugh T. Acute gonococcal perihepatitis of the right upper quadrant in women. JAMA. 1934;102:2094-6. 17. Jackman JD Jr., Glamann DB. Gonococcal endocarditis: twenty-five year experience. Am J Med Sci. 1991;301:221-30. 18. Jephcott AE. Microbiological diagnosis of gonorrhoea. Genitourin Med. 1997;73:245-52. 19. Schwebke JR,Zajackowski ME. Comparison of DNA probe (Gen-Probe) with culture for the detection of Neisseria gonorrhoeae in an urban STD programme. Genitourin Med. 1996;72:108-10. 20. Johnson RE, Newhall WJ, Papp JR, et al. Screening tests to detect Chlamydia trachomatis and Neisseria gonorrhoeae infections—2002. MMWR Recomm Rep. 2002 Oct 18;51 (RR-15):1-38. 21. Stary A, Ching SF, Teodorowicz L, Lee H. Comparison of ligase chain reaction and culture for detection of Neisseria gonorrhoeae in genital and extragenital specimens. J Clin Microbiol. 1997;35:239-42. 22. Koumans EH, Johnson RE, Knapp JS, St Louis ME. Laboratory testing for Neisseria gonorrhoeae by recently introduced nonculture tests: a performance review with clinical and public health considerations. Clin Infect Dis. 1998;27:1171-80. 23. Ching S, Lee H, Hook EW 3rd, Jacobs MR, Zenilman J. Ligase chain reaction for detection of Neisseria gonorrhoeae in urogenital swabs. J Clin Microbiol. 1995;33:3111-4. 24. Moran SJ, Levine WC. Drugs of choice for the treatment of uncomplicated gonococcal infections. Clin Infect Dis. 1995;2(suppl 1):S47-65. 25. Bignell C. Antibiotic treatment of gonorrhoea—clinical evidence for choice. Genitourin Med. 1996;72:315-20. 26. Ison CA. Antimicrobial agents and gonorrhoea: therapeutic choice, resistance and susceptibility testing. Genitourin Med. 1996;72:253-7. 27. Lind I. Antimicrobial resistance in Neisseria gonorrhoeae. Clin Infect Dis. 1997;24 Suppl 1:S93-7. 28. Centers for Disease Control and Prevention. 2002 guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep. 2002;51(RR-6):36-42. 29. Washington AE, Browner WS, Korenbrot CC. Cost-effectiveness of combined treatment for endocervical gonorrhea. Considering co-infection with Chlamydia trachomatis. JAMA. 1987;257:2056-60. 30. Peterman TA, Zaidi AA, Lieb S,Wroten JE. Incubating syphilis in patients treated for gonorrhea: a comparison of treatment regimens. J Infect Dis. 1994;170:689-92. 31. Haizlip J, Isbey SF, Hamilton HA, Jerse AE, Leone PA, Davis RH, et al. Time required for elimination of Neisseria gonorrhoeae from the urogenital tract in men with symptomatic urethritis: comparison of oral and intramuscular single-dose therapy. Sex Transm Dis. 1995;22:145-8. 32. Carne CA. Epidemiological treatment and tests of cure in gonococcal infection: evidence for value. Genitourin Med. 1997;73:12-5. 33. Martin IM, Ison CA, Aanensen DM, Fenton KA, Spratt BG. Changing epidemiologic profile of quinolone-resistant Neisseria gonorrhoeae in London. J Infect Dis. 2005;192:1191-5. 34. Centers for Disease Control and Prevention. Increase in fluoroquinolone-resistant Neisseria gonorrhoeae among men who have sex with men—United States, 2003, and revised recommendations for gonorrhea treatment, 2004. Morb Mort Wkly Rep 2004;53(16):335-38. 35. Sánchez J, Gotuzzo E, Escamilla J, Carrillo C, Moreyra L, Stamm W, et al. Sexually transmitted infections in female sex workers: reduced by condom use but not by a limited periodic examination program. Sex Transm Dis. 1998;25:82-9. 36. McNagny SE, Parker RM, Zenilman JM, Lewis JS. Urinary leukocyte esterase test: a screening method for the detection of asymptomatic chlamydial and gonococcal infections in men. J Infect Dis. 1992;165:573-6. 37. O’Brien SF, Bell TA, Farrow JA. Use of a leukocyte esterase dipstick to detect Chlamydia trachomatis and Neisseria gonorrhoeae urethritis in asymptomatic adolescent male detainees. Am J Public Health. 1988;78:1583-4. 38. Schwebke JR, Sadler R, Sutton JM, Hook EW 3rd. Positive screening tests for gonorrhea and chlamydial infection fail to lead consistently to treatment of patients attending a sexually transmitted disease clinic. Sex Transm Dis. 1997;24:181-4.

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39. Rice RJ, Roberts PL, Handsfield HH, Holmes KK. Sociodemographic distribution of gonorrhea incidence: implications for prevention and behavioral research. Am J Public Health. 1991;81:1252-8. 40. Mertz KJ, Levine WC, Mosure DJ, Berman SM, Dorian KJ, Hadgu A. Screening women for gonorrhea: demographic screening criteria for general clinical use. Am J Public Health. 1997;87:1535-8. 41. Schachter J. Chlamydial infections (first of three parts). N Engl J Med. 1978;298:428-35.] 42. Stamm WE, Jones RB, Batteiger BE. Chlamydia trachomatis (trachoma, perinatal infections, lymphogranuloma venereum, and other genital infections). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practices of Infectious Diseases. 6th ed. Philadelphia: Elsevier ChurchillLivingstone; 2005:2239-55. 43. Martin DH. Chlamydial infections. Med Clin North Am. 1990;74:1367-87. 44. Washington AE, Katz P. Cost of and payment source for pelvic inflammatory disease. Trends and projections, 1983 through 2000. JAMA. 1991;266:2565-9. 45. Weinstock H, Dean D, Bolan G. Chlamydia trachomatis infections. Infect Dis Clin North Am. 1994;8:797-819. 46. Stamm WE. Diagnosis of Chlamydia trachomatis genitourinary infections. Ann Intern Med. 1988;108:710-7. 47. Stamm WE, Koutsky LA, Benedetti JK, Jourden JL, Brunham RC, Holmes KK. Chlamydia trachomatis urethral infections in men. Prevalence, risk factors, and clinical manifestations. Ann Intern Med. 1984;100:47-51. 48. Holmes KK, Handsfield HH, Wang SP, Wentworth BB, Turck M, Anderson JB, et al. Etiology of nongonococcal urethritis. N Engl J Med. 1975;292:1199-205. 49. McCutchan JA. Epidemiology of venereal urethritis: comparison of gonorrhea and nongonococcal urethritis. Rev Infect Dis. 1984;6:669-88. 50. Martin DH, Mroczkowski TF, Dalu ZA, McCarty J, Jones RB, Hopkins SJ, et al. A controlled trial of a single dose of azithromycin for the treatment of chlamydial urethritis and cervicitis. The Azithromycin for Chlamydial Infections Study Group. N Engl J Med. 1992;327:921-5. 51. Brunham RC, Paavonen J, Stevens CE, Kiviat N, Kuo CC, Critchlow CW, et al. Mucopurulent cervicitis—the ignored counterpart in women of urethritis in men. N Engl J Med. 1984;311: 1-6. 52. Cates W Jr., Wasserheit JN. Genital chlamydial infections: epidemiology and reproductive sequelae. Am J Obstet Gynecol. 1991;164:1771-81. 53. Robinson AJ, Ridgway GL. Modern diagnosis and management of genital Chlamydia trachomatis infection. Br J Hosp Med. 1996;55:388-93. 54. Taylor-Robinson D, Thomas BJ. Laboratory techniques for the diagnosis of chlamydial infections. Genitourin Med. 1991;67:256-66. 55. Schachter J. DFA, EIA, PCR, LCR and other technologies: what tests should be used for diagnosis of chlamydia infections? Immunol Invest. 1997;26:157-61. 56. Newhall WJ, Johnson RE, DeLisle S, Fine D, Hadgu A, Matsuda B, et al. Head-to-head evaluation of five chlamydia tests relative to a quality-assured culture standard. J Clin Microbiol. 1999;37:681-5. 57. Black CM, Marrazzo J, Johnson RE, Hook EW 3rd, Jones RB, Green TA, et al. Head-to-head multicenter comparison of DNA probe and nucleic acid amplification tests for Chlamydia trachomatis infection in women performed with an improved reference standard. J Clin Microbiol. 2002;40:3757-63. 58. Shafer MA, Schachter J, Moncada J, Keogh J, Pantell R, Gourlay L, et al. Evaluation of urine-based screening strategies to detect Chlamydia trachomatis among sexually active asymptomatic young males. JAMA. 1993;270:2065-70. 59. Chernesky MA, Lee H, Schachter J, Burczak JD, Stamm WE, McCormack WM, et al. Diagnosis of Chlamydia trachomatis urethral infection in symptomatic and asymptomatic men by testing first-void urine in a ligase chain reaction assay. J Infect Dis. 1994; 170:1308-11. 60. Sellors JW, Mahony JB, Jang D, Pickard L, Goldsmith CH, Gafni A, et al. Comparison of cervical, urethral, and urine specimens for the detection of Chlamydia trachomatis in women. J Infect Dis. 1991;164:205-8. 61. Lee HH, Chernesky MA, Schachter J, Burczak JD, Andrews WW, Muldoon S, et al. Diagnosis of Chlamydia trachomatis genitourinary infection in women by ligase chain reaction assay of urine. Lancet. 1995;345:213-6. 62. Gaydos CA, Crotchfelt KA, Howell MR, Kralian S, Hauptman P, Quinn TC. Molecular amplification assays to detect chlamydial infections in urine specimens from high school female

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Expert Guide to Infectious Diseases students and to monitor the persistence of chlamydial DNA after therapy. J Infect Dis. 1998;177:417-24. Stamm WE, Hicks CB, Martin DH, Leone P, Hook EW 3rd, Cooper RH, et al. Azithromycin for empirical treatment of the nongonococcal urethritis syndrome in men. A randomized doubleblind study. JAMA. 1995;274:545-9. Magid D, Douglas JM Jr., Schwartz JS. Doxycycline compared with azithromycin for treating women with genital Chlamydia trachomatis infections: an incremental cost-effectiveness analysis. Ann Intern Med. 1996;124:389-99. Scholes D, Stergachis A, Heidrich FE, Andrilla H, Holmes KK, Stamm WE. Prevention of pelvic inflammatory disease by screening for cervical chlamydial infection. N Engl J Med. 1996;334:1362-6. Cohen I, Veille JC, Calkins BM. Improved pregnancy outcome following successful treatment of chlamydial infection. JAMA. 1990;263:3160-3. Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med. 1983;98:958-72. Johnson RE, Nahmics AJ, Magder LS. A seroepidemiology survey of the prevalence of herpes simplex virus type 2 infection in the United States. N Engl J Med. 1989;321:8-12. Frenkel LM, Garratty EM, Shen JP,Wheeler N, Clark O, Bryson YJ. Clinical reactivation of herpes simplex virus type 2 infection in seropositive pregnant women with no history of genital herpes. Ann Intern Med. 1993;118:414-8. Kulhanjian JA, Soroush V,Au DS, Bronzan RN,Yasukawa LL,Weylman LE, et al. Identification of women at unsuspected risk of primary infection with herpes simplex virus type 2 during pregnancy. N Engl J Med. 1992;326:916-20. Koutsky LA, Stevens CE, Holmes KK,Ashley RL, Kiviat NB, Critchlow CW, et al. Underdiagnosis of genital herpes by current clinical and viral-isolation procedures. N Engl J Med. 1992;326: 1533-9. Mertz GJ, Benedetti J, Ashley R, Selke SA, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med. 1992;116:197-202. Bryson Y, Dillon M, Bernstein DI, Radolf J, Zakowski P, Garratty E. Risk of acquisition of genital herpes simplex virus type 2 in sex partners of persons with genital herpes: a prospective couple study. J Infect Dis. 1993;167:942-6. Mertz GJ. Epidemiology of genital herpes infections. Infect Dis Clin North Am. 1993;7:825-39. Sacks SL. Frequency and duration of patient-observed recurrent genital herpes simplex virus infection: characterization of the nonlesional prodrome. J Infect Dis. 1984;150: 873-7. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic firstepisode infection. Ann Intern Med. 1994;121:857-64. Koelle DM, Benedetti J, Langenberg A, Corey L. Asymptomatic reactivation of herpes simplex virus in women after the first episode of genital herpes. Ann Intern Med. 1992;116:433-7. Corey, L. Herpes simplex virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Elsevier Churchill-Livingstone; 2005: 1762-80. Nahass GT, Goldstein BA, Zhu WY, Serfling U, Penneys NS, Leonardi CL. Comparison of Tzanck smear, viral culture, and DNA diagnostic methods in detection of herpes simplex and varicella-zoster infection. JAMA. 1992;268:2541-4. DiCarlo RP, Armentor BS, Martin DH. Chancroid epidemiology in New Orleans men. J Infect Dis. 1995;172:446-52. Wald A, Ashley-Morrow R. Serological testing for herpes simplex virus (HSV)-1 and HSV-2 infection. Clin Infect Dis. 2002;35:S173-82. Cowan FM. Testing for type-specific antibody to herpes simplex virus—implications for clinical practice. J Antimicrob Chemother. 2000;45 Suppl T3:9-13. Song B, Dwyer DE, Mindel A. HSV type specific serology in sexual health clinics: use, benefits, and who gets tested. Sex Transm Infect. 2004;80:113-7. Guerry SL, Bauer HM, Klausner JD, Branagan B, Kerndt PR, Allen BG, et al. Recommendations for the selective use of herpes simplex virus type 2 serological tests. Clin Infect Dis. 2005;40: 38-45. Mertz GJ, Critchlow CW, Benedetti J, Reichman RC, Dolin R, Connor J, et al. Double-blind placebo-controlled trial of oral acyclovir in first-episode genital herpes simplex virus infection. JAMA. 1984;252:1147-51. Whitley RJ, Gnann JW Jr. Acyclovir: a decade later. N Engl J Med. 1992;327:782-9.

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87. Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med. 1996;156:1729-35. 88. Sacks SL,Aoki FY, Diaz-Mitoma F, Sellors J, Shafran SD. Patient-initiated, twice-daily oral famciclovir for early recurrent genital herpes. A randomized, double-blind multicenter trial. Canadian Famciclovir Study Group. JAMA. 1996;276:44-9. 89. Goldberg LH, Kaufman R, Kurtz TO, Conant MA, Eron LJ, Batenhorst RL, et al. Long-term suppression of recurrent genital herpes with acyclovir. A 5-year benchmark. Acyclovir Study Group. Arch Dermatol. 1993;129:582-7. 90. Wald A, Zeh J, Barnum G, Davis LG, Corey L. Suppression of subclinical shedding of herpes simplex virus type 2 with acyclovir. Ann Intern Med. 1996;124:8-15. 91. Valacyclovir HSV Transmission Study Group. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med. 2004;350:11-20. 92. Tramont EC. Treponema pallidum (syphilis). In: Mandel GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Elsevier ChurchillLivingstone; 2005:2768-85. 93. Hutchinson CM, Hook EW 3rd. Syphilis in adults. Med Clin North Am. 1990;74:1389-416. 94. Gordon SM, Eaton ME, George R, Larsen S, Lukehart SA, Kuypers J, et al. The response of symptomatic neurosyphilis to high-dose intravenous penicillin G in patients with human immunodeficiency virus infection. N Engl J Med. 1994;331:1469-73. 95. Hook EW 3rd, Marra CM. Acquired syphilis in adults. N Engl J Med. 1992;326:1060-9. 96. Centers for Disease Control and Prevention. Internet use and early syphilis infection among men who have sex with men—San Francisco, California, 1999-2003. MMWR Morb Mortal Wkly Rep. 2003;52(50):1229-32. 97. Simon RP. Neurosyphilis. Arch Neurol. 1985;42:606-13. 98. Lukehart SA, Hook EW 3rd, Baker-Zander SA, Collier AC, Critchlow CW, Handsfield HH. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med. 1988;109:855-62. 99. Katz DA, Berger JR, Duncan RC. Neurosyphilis. A comparative study of the effects of infection with human immunodeficiency virus. Arch Neurol. 1993;50:243-9. 100. Johns DR,Tierney M, Felsenstein D. Alteration in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med. 1987;316:1569-72. 101. Orle KA, Gates CA, Martin DH, Body BA,Weiss JB. Simultaneous PCR detection of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers. J Clin Microbiol. 1996;34:49-54. 102. Jethwa HS, Schmitz JL, Dallabetta G, Behets F, Hoffman I, Hamilton H, et al. Comparison of molecular and microscopic techniques for detection of Treponema pallidum in genital ulcers. J Clin Microbiol. 1995;33:180-3. 103. Romanowski B, Sutherland R, Fick GH, Mooney D, Love EJ. Serologic response to treatment of infectious syphilis. Ann Intern Med. 1991;114:1005-9. 104. Hart G. Syphilis tests in diagnostic and therapeutic decision making. Ann Intern Med. 1986;104:368-76. 105. Brown ST, Zaidi A, Larsen SA, Reynolds GH. Serological response to syphilis treatment. A new analysis of old data. JAMA. 1985;253:1296-9. 106. Riedner G, Rusizoka M, Todd J, Maboko L, Hoelscher M, Mmbando D, et al. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med. 2005;353:1236-44. 107. Lukehart SA, Godornes C, Molini BJ, Sonnett P, Hopkins S, Mulcahy F, et al. Macrolide resistance in Treponema pallidum in the United States and Ireland. N Engl J Med. 2004;351:154-8. 108. Murphy TF. Haemophilus infections. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Elsevier Churchill-Livingstone; 2005: 2666-9. 109. Schmid GP, Sanders LL Jr., Blount JH, Alexander ER. Chancroid in the United States. Reestablishment of an old disease. JAMA. 1987;258:3265-8. 110. Hammond GW, Slutchuk M, Scatliff J, Sherman E,Wilt JC, Ronald AR. Epidemiologic, clinical, laboratory, and therapeutic features of an urban outbreak of chancroid in North America. Rev Infect Dis. 1980;2:867-79. 111. Strakosch EA, Kendell HW, Craig RM, Schwemlein GX. Clinical and laboratory investigation of 370 cases of chancroid. J Invest Dermatol. 1945;6:95-107.

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112. Dangor Y, Ballard RC, da L Exposto F, Fehler G, Miller SD, Koornhof HJ. Accuracy of clinical diagnosis of genital ulcer disease. Sex Transm Dis. 1990;17:184-9. 113. DiCarlo RP, Martin DH. The clinical diagnosis of genital ulcer disease in men. Clin Infect Dis. 1997;25:292-8. 114. Dillon SM, Cummings M, Rajagopalan S, McCormack WC. Prospective analysis of genital ulcer disease in Brooklyn, New York. Clin Infect Dis. 1997;24:945-50. 115. Hawkes S, West B, Wilson S, Whittle H, Mabey D. Asymptomatic carriage of Haemophilus ducreyi confirmed by the polymerase chain reaction. Genitourin Med. 1995;71:224-7. 116. Beck-Sague CM, Cordts JR, Brown K, Larsen SA, Black CM, Knapp JS, et al. Laboratory diagnosis of sexually transmitted diseases in facilities within the United States. Results of a national survey. Sex Transm Dis. 1996;23:342-9. 117. Jones CC, Rosen T. Cultural diagnosis of chancroid. Arch Dermatol. 1991;127:1823-7. 118. Orle KA, Gates CA, Martin DH, Body BA,Weiss JB. Simultaneous PCR detection of Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus types 1 and 2 from genital ulcers. J Clin Microbiol. 1996;34:49-54. 119. Morse SA,Trees DL, Htun Y, Radebe F, Orle KA, Dangor Y, et al. Comparison of clinical diagnosis and standard laboratory and molecular methods for the diagnosis of genital ulcer disease in Lesotho: association with human immunodeficiency virus infection. J Infect Dis. 1997;175: 583-9. 120. Centers for Disease Control and Prevention. Summary of notifiable diseases, United States, 1997. MMWR Morb Mortal Wkly Rep. 1997;46:1-6. 121. Dangor Y, Ballard RC, Miller SD, Koornhof HJ. Treatment of chancroid. Antimicrob Agents Chemother. 1990;34:1308-11. 122. Ernst AA, Marvez-Valls E, Martin DH. Incision and drainage versus aspiration of fluctuant buboes in the emergency department during an epidemic of chancroid. Sex Transm Dis. 1995;22:217-20.

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Chapter 16

Pelvic Inflammatory Disease ROBERT F. FLORA, MD, MBA HEATHER RUPE, DO JAMES FANNING, DO

Key Learning Points 1. The minimum criteria for treatment of PID are uterine/adnexal tenderness, cervical motion tenderness, and no other identifiable causes. 2. All sexual partners of a PID patient within the last 60 days should be evaluated and treated. 3. The need for hospitalization is based on the discretion of the healthcare provider. Treatment regimens have been redefined as parenteral or oral instead of inpatient or outpatient.

P

elvic inflammatory disease (PID) is caused by an infection that ascends from the vagina or cervix into the upper genital tract. One or more sites of the upper genital tract can be involved including the endometrium (endometritis), fallopian tubes (salpingitis), ovary (oophoritis), myometrium (myometritis), serosa and broad ligament (parametritis), and pelvic peritoneum (peritonitis). Because of the inflammatory process, adherence of intra-abdominal pelvic organs and collection of pus can lead to the development of a tuboovarian complex or abscess. Involvement of the serosa of the appendix or liver can lead to a periappendicitis or perihepatitis, respectively. Clinically, the terms salpingitis and PID are used synonymously. Salpingitis refers to an inflammatory process occurring in the fallopian tube. However, Jacobson and Westrom (1) showed only two-thirds of women with the clinical diagnosis of PID had laparoscopic evidence of a tubal infection. Aside from the acute problems caused by PID, other sequelae such as ectopic pregnancies, infertility, and chronic pelvic pain can result. 313

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Box 16-1 New Developments in the Management of Pelvic Inflammatory Disease ●

● ●

Levofloxacin has been added to PID treatment regimens for oral (A), alternative parenteral, and dual treatment for sexual partners. Ciprofloxacin has been deleted from the alternative parenteral regimen. HIV patients are more likely to have tubo-ovarian abscesses than non-HIV patients. However, both respond equally to parenteral and oral treatment. It is unclear whether more aggressive management is needed.

Abbreviation: PID = pelvic inflammatory disease.

In the past, chronic PID was used to describe patients with these sequelae, but the term has largely been abandoned.

Epidemiology Unlike some sexually transmitted diseases (STDs), reporting PID is not mandatory. Also, it is estimated that 60 % of PID is subclinical. (2) Thus, accurate estimates of its prevalence are difficult to determine. Rein and coworkers (3) used 3 years of insurance claims information and national survey data to estimate the direct and indirect medical cost of PID in the United States. They estimated that 1.76 million visits for acute PID and its sequelae were made annually from 1993 to 1995. Acute PID accounted for 1.2 million of these visits as inpatient, outpatient, or STD clinic visits. Among the sequelae related to cases of PID, chronic pelvic pain accounted for 300,000 visits, ectopic pregnancies for 145,000 visits, and infertility for 78,000 cases. In 1998, the annual total direct cost attributable to PID was estimated between $1.62 and $1.88 billion (3). This estimate is much lower than the 1994 Institute of Medicine estimate of $3.12 billion (4) or the 2000 projection by Washington and Katz (5) of $9 billion. The difference may be because of several factors, including a decrease in the cases of PID and gonorrhea, better and more widespread screening for Chlamydia, switching from inpatient to outpatient management, and better data sources (3, 6). From 1980 to 1998, there was a decrease in hospitalizations for ectopic pregnancies and PID. Additionally, initial visits to physician offices by women 15 to 44 years of age decreased from more than 400,000 visits per year to approximately 250,000 (7). Regardless of this decrease, PID and its sequelae still have a profound effect on health care and its related costs.

Etiology The infectious process in PID is polymicrobial and caused by many different organisms (8). The spread of these organisms occurs through their

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progress from the vagina and endocervix through the cervical canal and into the upper genital tract. Four factors that contribute to this spread include uterine instrumentation, hormonal changes during menses, retrograde menstruation, and virulence factors associated with specific organisms (9). Spread can also occur by hematogenous route in a small percentage of patients; hence, tubal ligation is not necessarily preventative (10). Determination of the microbial cause is difficult to study because of many factors, including difficulty of culturing the upper tract genital except through a surgical approach, contamination by vaginal flora, different laboratory methods, and the difficulty in making a clinical diagnosis of PID. In their long-term study, Jossens and colleagues concluded that 65% of their cases of PID had either Neisseria gonorrhea or Chlamydia trachomatis identified (STD-related PID). In 30% of their cases, only anaerobic or facultative bacteria were isolated (non–STD-related PID). However, these anaerobic and facultative bacteria were also frequently recovered when an STD organism was identified (11). These other organisms included Prevotella, Bacteroides, Peptostreptococcus and Peptococcus, Gardnerella vaginalis, Streptococcus, Escherichia coli, Haemophilus influenzae, cytomegalovirus, and others. Mycoplasma hominis, Ureaplasma urealyticum, and Trichomonas vaginalis have also been isolated in the fallopian tubes. Bacterial vaginosis is also thought to shift the vaginal flora to an anaerobic state and increase the risk of PID (2,9,12). The sexually transmitted diseases N. gonorrhoeae and C. trachomatis account for most cases of PID. These start as a cervicitis, which can ascend and lead to PID. Approximately 70% are asymptomatic infections. Without treatment, 20% to 40% of asymptomatic cases will develop PID. The number of cases of Chlamydia has been increasing every year. In 1998, the rate was 382.2 per 100,000. This rate increase is felt to be because of better screening practices. Screening programs can reduce the incidence of PID by 60% (7,13). Since the late 1970s, infections with N. gonorrhoeae have been steadily decreasing. However, an increase was noted between 1997 and 1998 from 119 cases per 100,000 to 131.5. If untreated, 10% to 40% of these cases will develop PID. Approximately half of the gonococcal infections are asymptomatic (7,14).

Risk Factors Several demographic and social risk factors have been associated with the development of PID including young age, lower socioeconomic status, and single or divorced status. No correlation has been reported between urban versus rural residence. Risk factors associated with acquisition of an STD are also associated with progression to PID including sexual partner characteristics, infectivity rates, duration of infection, and sociocultural environment. Contraceptive use of barrier methods and oral contraceptives

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decrease the risk of PID. However, the use of oral contraceptives was associated with the increased diagnosis of chlamydia cervicitis. The intrauterine device (IUD) was associated with an increase of non-STD pelvic inflammatory disease. Health care–seeking behavior decreased the risk of PID when prompt evaluation, compliance with treatment, and treatment of partner occurred. Smoking and menses are also associated with an increased risk. Substance abuse has been associated with the increased risk of acquiring an STD but not of developing PID (9,15). Jossens and colleagues studied factors that are more likely to be associated with an STDrelated pelvic inflammatory infection versus a non-STD infection. Patients with PID were more likely to have an STD-related PID infection if they were African-American, used no contraception, had a previous history of an STD with gonorrhea, had a previous PID infection with gonorrhea, presented with a history of pain less than 3 days, or had 2 or more sexual partners in the last 30 days or 3 or more partners in the past 60 days. Factors increasing the likelihood of a PID infection being non-STD related included current IUD use, history of IUD use, and pelvic surgery in the past 30 days. Multivariate analysis was done to adjust for confounding and showed the risk of African-American race to be associated with STD associated pelvic inflammatory disease and current IUD use associated with non-STD pelvic inflammatory disease. Douching was not shown to increase the likelihood of PID (16).

Diagnosis The diagnosis of PID is difficult. The presentation of PID is severe in approximately 4%, mild to moderate in 36%, and subclinical in 60% (2). Laparoscopy is considered the gold standard for diagnosis. However, Molander and colleagues showed only a 78% accuracy of laparoscopic diagnosis compared with pathologic diagnosis (17). Because of costs and availability issues of laparoscopy, most diagnosis is done clinically. However, in a large study of 813 women with the clinical diagnosis of PID, only 532 (65%) had confirmation at laparoscopy. Other conditions such as appendicitis, endometriosis, and ectopic pregnancy were found. This was recently supported by Molander and colleagues where only 61% of their patients with suspected clinical PID were confirmed. However, they laparoscopically managed the confirmed PID patients with irrigation, lysis of adhesions, and drainage and irrigation of pyosalpinx and tuboovarian complexes (1,18). The Centers for Disease Control and Prevention (CDC) 2002 Guidelines state that no single factor or combination of history, physical, or laboratory factors have adequate sensitivity and specificity to make the diagnosis of acute PID (19). Table 16-1 lists tests or procedures that may assist in the diagnosis and management of acute PID. A leukocyte count is an unreliable indicator because half of the women with PID may have no leukocy-

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Table 16 -1 Possible Evaluative Tools in the Diagnosis and Management of PID (19) ● ● ● ● ● ● ● ● ● ● ●

Pregnancy test White blood count Erythrocyte sedimentation rate C-reactive protein Gram stain if cervical discharge present Cervical screening test or cultures for gonorrhea and chlamydia Wet prep to evaluate for bacterial vaginosis Endometrial biopsy Ultrasound MRI Laparoscopy

Abbreviations: MRI = magnetic resonance imaging; PID = pelvic inflammatory disease.

tosis. An erythrocyte sedimentation rate (ESR) has a moderately high sensitivity but a low specificity for PID. Acute phase reactants such as C reactive protein are only slightly more sensitive than an ESR. A pregnancy test should be obtained to rule out an ectopic pregnancy. A Gram stain of cervical discharge and cervical cultures for gonococcus and chlamydia are helpful and should be obtained. But these results can return with a false result even though an upper tract infection with the organism exists and is documented. Ideally, sexual partners of the patients should also be cultured. An endometrial biopsy can confirm the presence of endometritis. Ultrasonography helps identify a tuboovarian complex, hydrosalpinx or pyosalpinx, and free peritoneal fluid. Magnetic resonance imaging (MRI) and transvaginal power Doppler sonography are currently not cost effective, but may have utility in the future (20) Because of the difficulty in diagnosis and the severity of sequelae that may result, a low threshold for diagnosis and treatment is recommended. Minimum criteria for empiric treatment should include (19) adnexal tenderness, cervical motion tenderness, and no other identifiable causes. Additional criteria that support the diagnosis include the following: ● ● ● ● ● ●

Oral temperature more than 101°F (>38.3°C) Abnormal cervical or vaginal discharge Leucocytes seen on saline microscopy of vaginal secretions Elevated erythrocyte sedimentation rate Elevated C-reactive protein Laboratory documentation of cervical infection with N. gonorrhea or C. trachomatis

Definitive criteria can include the following: ●

Endometritis on an endometrial biopsy

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●

●

Thickened fluid filled tubes with or without free pelvic fluid or tuboovarian complex confirmed by transvaginal sonography or MRI Laparoscopic abnormalities consistent with PID

Treatment Ideally, treatment of lower genital tract infections from gonorrhea, chlamydia, or bacterial vaginosis will prevent most PID. However, no good overall screening program exists in the United States. Also, because many lower tract infections are asymptomatic, cases of acute PID will occur. Thus, once an acute upper tract process occurs, the treatment of PID should be directed toward the treatment of a polymicrobial infection. Coverage should include N. gonorrhoeae and C. trachomatis, anaerobic bacteria, facultative bacteria, and streptococci. Figure 16-1 shows an algorithm for care of a patient with PID. As previously mentioned, the threshold for treatment should be low. Treatment should be started as soon as possible to decrease the incidence of long-term sequelae. Treatment can be either outpatient or inpatient. A steady decreasing trend has been seen in the hospitalization of women 15 to 44 years of age from 1981 to 1997 (7). Approximately 20% to 25% of patients with acute PID are hospitalized (21). Many factors come into play when deciding on outpatient versus inpatient management. However, the CDC 2002 guidelines have listed criteria for hospitalization with parenteral therapy (19). In parenteral therapy, at least 24 hours of clinical improvement should occur before considering switching to oral therapy. In tuboovarian abscess or complexes (TOA), at least 24 hours of inpatient observation is recommended before considering home parenteral antimicrobial treatment. These criteria include the following: ● ● ● ● ● ●

Surgical emergencies such as appendicitis cannot be excluded Pregnancy Failure of clinical response to oral therapy Unable to follow or tolerate oral therapy Severe illness, nausea and vomiting, high fever TOA

Outpatient Oral Treatments Outpatient oral treatments are shown in Table 16-2. If no response is noted after 72 hours, parenteral therapy should be instituted. Doxycycline plus amoxicillin or clavulanic acid was proven effective in a clinical trial; however, some found gastrointestinal side effects could limit compliance (19). Other alternative oral therapies are available but not enough data were available for the CDC 2002 guidelines to include them in the recommendations.

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Figure 16-1. Algorithm for treatment of patient with PID. (Republished with permission from Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-5):45-51.)

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Table 16 -2 Oral Regimen for Pelvic Inflammatory Disease Treatment Regimen A

Ofloxacin 400 mg PO bid for 14 d or Levofloxacin 500 mg PO once daily for 14 d with or without Metronidazole 500 mg PO bid for 14 d Regimen B

Ceftriaxone 250 mg IM once or Cefoxitin 2 g IM plus probenecid 1 g PO in a single dose or Other parenteral 3rd-generation cephalosporin (e.g., ceftizoxime or cefotaxime) plus Doxycycline 100 mg PO bid for 14 d with or without Metronidazole 500 mg PO bid for 14 d Republished with permission from Centers for Disease Control and Prevention. Guidelines for Treatment of Sexually Transmitted Diseases 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-5):45-51. Abbreviations: bid = twice a day; h = hour; IM = intramuscularly; PO = orally.

Parenteral Therapy Parenteral therapy is usually started on an inpatient basis. After 24 hours of clinical improvement, transition to oral therapy can be considered. Table 16-3 shows both regimens. In Regimen A, the bioavailability of intravenous (IV) and oral doxycycline are equivalent, and the IV route can cause discomfort. Thus, doxycycline should be given orally whenever possible. Doxycycline should be continued for a total of 14 days. Other second or third generation cephalosporins could substitute for cefoxitin, such as ceftizoxime, cefotaxime, and ceftriaxone. However, the anaerobic coverage may not be as good. Regimen B is also in Table 16-3. although not studied in PID, singledose gentamicin may be substituted. After 24 hours of clinical improvement, parenteral therapy may be switched to oral therapy with either doxycycline 100 mg twice per day or clindamycin 450 mg 4 times per day. A total of 14 days of therapy should be given. In cases of a TOA, oral clindamycin may be preferred over doxycycline because of better anaerobic coverage. Alternative parenteral regimens are also shown (Table 16-4). These regimens are supported by at least 1 clinical trial and provide broad-spectrum coverage. A switch to oral therapy can be considered after 24 hours of clinical improvement with continuation to 14 days of total therapy.

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Table 16-3 Parenteral Pelvic Inflammatory Disease Regimens Regimen A

Cefoxitin 2 g IV q6h plus Doxycycline 100 mg IV or PO q12h after 24 h of clinical improvement Doxycycline 100 mg PO for a total treatment of 14 d Regimen B

Clindamycin 900 mg IV q8h plus Gentamicin IV or IM with a loading dose of 2 mg/kg body weight followed by maintenance of 1.5 mg/kg q8h after 24 h of clinical improvement Doxycycline 100 mg PO for a total treatment of 14 d or Clindamycin 450 mg PO 4 times a day for a total treatment of 14 d (especially in cases of a tuboovarian abscess) Republished with permission from Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-5):45-51. Abbreviations: bid = twice a day; h = hour; IM = intramuscularly; IV = intravenously; PO = orally; q = every.

Table 16-4 Alternative Parenteral Regimens Ofloxacin 400 mg IV q12h or Levofloxacin 500 mg IV once daily with or without Metronidazole 500 mg IV q8h or Ampicillin/Sulbactam 3 mg IV q6h or Doxycycline 100 mg IV or PO q12h Republished with permission from Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-5):45-51. Abbreviations: h = hour; IV = intravenously; PO = orally; q = every.

Follow-Up and Management of Sexual Partners The cure rates of the aforementioned CDC regimens are excellent. In the Walker meta-analysis, the inpatient regimens had clinical cure rates of 92% to 94% and microbiological cure rates of 97% to 100%. The outpatient regimen of cefoxitin and doxycycline had a clinical cure rate of 95% and microbiological cure rate of 91%. Ofloxacin had clinical and microbiological cure rates of 95% and 100%, respectively (22). Clinical improvement should be noted within 3 days of the start of therapy. Patients started with outpatient therapies should be evaluated within 72 hours. Follow-up rescreening tests for gonorrhea and chlamydia can be repeated 4 to 6

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weeks after the end of therapy. A 1-month interval after completion of therapy is needed for follow-up tests using polymerase chain or ligase chain reaction technology (18). Sexual partners in contact with the affected patient within 60 days of the onset of PID symptoms should be empirically evaluated and treated. The partners can be asymptomatic. One observation noted that 13% of male partners found to have urethral gonorrhea were asymptomatic (21). Treatment of both gonorrhea and chlamydia should be given. Table 16-5 shows the recommended treatment. In this manner, the risk of reinfection of the patient can be decreased. Follow-up rescreening may also be helpful.

Tuboovarian Abscess/Complex A TOA is a major complication resulting from an acute PID infection. It can occur in up to 34% of patients hospitalized with PID (2). Because of the inflammatory reaction occurring from the infection, the fallopian tube and ovary agglutinate and become a complex with walled-off pus. Other intraperitoneal organs including bowel and omentum may also become involved. More than two thirds of TOAs are unilateral. Early IUDs were associated with TOAs. It was felt the risk was related to the multifilament tail attached to the IUD (23). However, newer IUDs with monofilament tails have not been shown to be associated with an increased risk of PID except in the first 21 days after insertion (24). After 5 months of use of the IUD, the risk of PID is not increased in low-risk women compared to controls (25). Prophylaxis with doxycycline has not been shown to decrease this risk (26). Cultures for gonococcal infection and chlamydia are recommended

Table 16-5 Dual Treatment for Sexual Partners of Pelvic Inflammatory Disease Patients Cefixime 400 mg PO in single dose or Ceftriaxone 125 mg IM in a single dose or Ciprofloxacin 500 mg PO in a single dose or Ofloxacin 400 mg in a single dose or Levofloxacin 250 mg PO in a single dose plus If Chlamydia Infection Is Not Ruled Out

Azithromycin 1 gm in a single dose or Doxycycline 100 mg bid for 7 d Republished with permission from Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-5):45-51. Abbreviations: bid = twice a day; h = hour; PO = orally.

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before insertion of the IUD. Also, when IUD users have a new sexual partner, they are encouraged to be seen for counseling about the risk of PID and continued use of the IUD. Organisms shown to be involved in TOAs are predominantly anaerobes and facultative aerobes. N. gonorrhoeae and C. trachomatis can be isolated in the complex. However, the absence of gonorrhea or chlamydia does not exclude their involvement in the initiation of the infection. The anaerobic state in the abscess can inhibit the growth and viability of N. gonorrhoeae. Actinomyces israelii is an organism that has been associated with TOAs and IUD use (2,18,27,28). Treatment is initially antibiotic based. Between 3% and 5% will require initial surgical intervention. Response to antibiotics will occur in 60% to 70%. Thirty percent will require surgical intervention with either drainage or removal. Therapy aimed at anaerobes, specifically clindamycin, has been reported to have a success rate of 86%. It is recommended that 3 to 7 days of parenteral antibiotics with clindamycin and gentamicin be given with oral clindamycin afterwards to complete 14 days of therapy (29). A minimum of 24 hours inpatient parenteral therapy is recommended before switching to home parenteral therapy. If the cefoxitin plus doxycycline inpatient regimen was initially given before discovery of a TOA and clinical response is noted, there is no need to change to clindamycin and gentamicin. No difference in the need for surgical intervention was noted with either regimen. If enterococcus is suspected or the patient is septic, triple antibiotic therapy with ampicillin, clindamycin (or metronidazole) and gentamicin should be used. Because most TOAs are unilateral, surgery doesn’t necessarily require extirpation of an unaffected uterus or opposite adnexa. Drainage alone can be successful. Halperin and colleagues showed that bilaterality, increasing size, and increasing patient age were all associated with unsuccessful medical management (30). In the situation of an IUD and a TOA, at least 24 hours of parenteral therapy is needed before removal of the IUD. A ruptured abscess causes a generalized peritonitis and is a surgical emergency. Prompt intervention is required. The death from rupture is 3% to 8% (2,20,31-34).

Long-Term Sequelae The long-term sequelae of PID are chronic pelvic pain, infertility, and ectopic pregnancies. Rein and colleagues estimated that the 1998 PID attributable costs of chronic pelvic pain, ectopic pregnancy, and infertility were $166 million, $295 million, and $360 million, respectively. More than 500,000 visits per year were attributed to the three sequelae from PID (3). Westrom and colleagues estimated that in women with acute PID, 20% become infertile, 9% have ectopic pregnancies, and 18% experience chronic pelvic pain (33). After 1 episode of PID, 11% of women are infertile. After 2

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and 3 bouts of PID, the incidence of infertility increases to 34% and 54%, respectively. The risk of ectopic pregnancy is increased 7-fold after having PID (9). Immediate treatment after onset of symptoms is paramount in prevention of the aforementioned problems. Hillis and colleagues showed a lower incidence of infertility if treatment was started before 3 days of symptoms had occurred (34).

Summary Pelvic inflammatory disease has profound short- and long-term effects on patients and society. Prevention of ascending infections by treating lower genital tract infections is the best method of decreasing PID. Once symptoms develop, prompt treatment with 1 of the recommended CDC regimens has an excellent outcome and can prevent long-term sequelae.

REFERENCES 1. Jacobson L,Weström L. Objectivized diagnosis of acute pelvic inflammatory disease. Diagnostic and prognostic value of routine laparoscopy. Am J Obstet Gynecol. 1969; 105:1088-98. 2. Westrom L, Escenbach D. Pelvic inflammatory disease. In: Holmes KK, Sparling PD, Mardh PA, Lemon SM, Stamm WE, Piot P, Wasserheit JN, eds. Sexually Transmitted Diseases. 3rd ed. New York, NY: McGraw-Hill; 1999:783-803. 3. Rein DB, Kassler WJ, Irwin KL, Rabiee L. Direct medical cost of pelvic inflammatory disease and its sequelae: decreasing, but still substantial. Obstet Gynecol. 2000;95:397-402. 4. Siegel JE. Estimates of the economic burden of STD: Review of the literature with updates. In: Eng TR, Butler WT, eds. Institute of Medicine: The hidden epidemic. Washington DC: National Academy Press; 1997:330-56. 5. Washington AE, Katz P. Cost of and payment source for pelvic inflammatory disease. Trends and projections, 1983 through 2000. JAMA. 1991;266:2565-9. 6. Centers for Disease Control and Prevention. Gonorrhea—United States, 1998. MMWR Morb Mortal Wkly Rep. 2000;49(24):538-542. 7. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 1998. Atlanta, Ga: U.S. Department of Health and Human Services, Division of STD Prevention, CDC; 1999:39-47. 8. Eschenbach DA, Buchanan RM, Pollock HM, et al. Polymicrobial etiology of acute pelvic inflammatory disease. N Engl J Med. 1975;292:166-71. 9. Centers for Disease Control and Prevention. Pelvic inflammatory disease: Guidelines for prevention and management. MMWR Morb Mortal Wkly Rep. 1991;40(RR-5):1-25. 10. Levgur M, Duvivier R. Pelvic inflammatory disease after tubal sterilization: a review. Obstet Gynecol Surv. 2000;55:41-50. 11. Jossens MO, Schachter J, Sweet RL. Risk factors associated with pelvic inflammatory disease of differing microbial etiologies. Obstet Gynecol. 1994;83:989-97. 12. Sweet RL. Gynecologic conditions and bacterial vaginosis: implications for the non-pregnant patient. Infect Dis Obstet Gynecol. 2000;8:184-90. 13. Stamm WE. Chlamydia trachomatis infections of the adult. In: Holmes KK, Sparling PD, Mardh P-A, Lemon SM, Stamm WE, Piot P, Wasserheit JN, eds. Sexually Transmitted Diseases. 3rd ed. New York, NY: McGraw-Hill; 1999:407-22. 14. Hook EW, Handsfield HH. Gonococcal infections in the adult. In: Holmes KK, Sparling PD, Mardh P-A, Lemon SM, Stamm WE, Piot P, Wasserheit JN, eds. Sexually Transmitted Diseases. 3rd ed. New York, NY: McGraw-Hill; 1999:451-63. 15. Padian NS,Washington AE. Risk factors for pelvic inflammatory disease and associated sequelae. In: Landers DV, Sweet RL, eds. Pelvic Inflammatory Disease. New York, NY: Springer; 1997:21-9.

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16. Ness RB, Hillier SL, Kip KE, Richter HE, Soper DE, Stamm CA, et al. Douching, pelvic inflammatory disease, and incident gonococcal and chlamydial genital infection in a cohort of high-risk women. Am J Epidemiol. 2005;161:186-95. 17. Molander P, Finne P, Sjöberg J, Sellors J, Paavonen J. Observer agreement with laparoscopic diagnosis of pelvic inflammatory disease using photographs. Obstet Gynecol. 2003;101:875-80. 18. Molander P, Cacciatore B, Sjöberg J, Paavonen J. Laparoscopic management of suspected acute pelvic inflammatory disease. J Am Assoc Gynecol Laparosc. 2000;7:107-10. 19. Centers for Disease Control and Prevention. Guidelines for treatment of sexually transmitted diseases 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-5):45-51. 20. Molander P, Sjöberg J, Paavonen J, Cacciatore B. Transvaginal power Doppler findings in laparoscopically proven acute pelvic inflammatory disease. Ultrasound Obstet Gynecol. 2001;17:233-8. 21. Sweet RL. Treatment of acute pelvic inflammatory disease. In: Landers DV, Sweet RL, eds. Pelvic Inflammatory Disease. New York, NY: Springer; 1997:76-93. 22. Walker CK, Kahn JG,Washington AE, Peterson HB, Sweet RL. Pelvic inflammatory disease: metaanalysis of antimicrobial regimen efficacy. J Infect Dis. 1993;168:969-78. 23. Potts DM, Champion CB, Kozuh-Novak M,Alvarez-Sanchez F, Santiso-Galvez R,Tacla X, et al. IUDs and PID: a comparative trial of strings versus stringless devices. Adv Contracept. 1991;7:23140. 24. Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet. 1992;339:785-8. 25. Lee NC, Rubin GL, Borucki R. The intrauterine device and pelvic inflammatory disease revisited: new results from the Women’s Health Study. Obstet Gynecol. 1988;72:1-6. 26. Walsh TL, Bernstein GS, Grimes DA, et al. Effect of prophylactic antibiotics on morbidity associated with IUD insertion: Results of a private randomized controlled trial. Contraception. 1994;42:141-58. 27. Landers DV. Tubo-ovarian abscess complicating pelvic inflammatory disease. In: Landers DV, Sweet RL, eds. Pelvic Inflammatory Disease. New York, NY: Springer; 1997:94-106. 28. Sweet RL, Gibbs RS. Pelvic abscess. In: Sweet RL, Gibbs, RS. Infectious Diseases of the Female Genital Tract. Baltimore, Md: Williams & Wilkins; 1985:161-80. 29. Krivak TC, Cooksey C, Propst AM. Tubo-ovarian abscess: diagnosis, medical and surgical management. Compr Ther. 2004;30:93-100. 30. Halperin R, Levinson O, Yaron M, Bukovsky I, Schneider D. Tubo-ovarian abscess in older women: is the woman’s age a risk factor for failed response to conservative treatment? Gynecol Obstet Invest. 2003;55:211-5. 31. American College of Obstetricians and Gynecologists. Antibiotics and Gynecologic Infections (ACOG Educational Bulletin 237). Washington DC: American College of Obstetricians and Gynecologists; 1997. 32. Droegemueller W. Upper Genital Tract Infections. In: Droegemueller W, Herbst AL, Mishell DR, Stenchever MA, eds. Comprehensive Gynecology. St. Louis, Mo: The C. V. Mosby Company; 1987:635. 33. Weström L, Joesoef R, Reynolds G, Hagdu A,Thompson SE. Pelvic inflammatory disease and fertility. A cohort study of 1,844 women with laparoscopically verified disease and 657 control women with normal laparoscopic results. Sex Transm Dis. 1992;19:185-92. 34. Hillis SD, Joesoef R, Marchbanks PA,Wasserheit JN, Cates W Jr.,Westrom L. Delayed care of pelvic inflammatory disease as a risk factor for impaired fertility. Am J Obstet Gynecol. 1993;168:1503-9.

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Chapter 17

Vaginitis and Cervicitis J.D. SOBEL, MD

Key Learning Points 1. Vulvovaginal symptoms are extremely common in women and most often symptoms are due to non-infectious causes. 2. Successful therapy and eradication of signs and symptoms is dependent upon accurate diagnosis and every effort should be made to avoid empirical treatment. 3. Measurement of vaginal pH as a routine procedure is key to accurate diagnosis of vulvovaginitis. 4. Vaginal bacterial cultures have no role in the differential diagnosis of vaginitis.

Vaginitis Vaginal symptoms are extremely common, and vaginal discharge is among the 25 most common reasons for consulting a physician in private office practice in the United States (1). Vaginitis is not found in all women with vaginal symptoms but is found in some form in approximately 40% of such women. It is found in more than one fourth of women attending sexually transmitted disease (STD) clinics.

Bacterial Vaginosis Epidemiology Bacterial vaginosis is the most common cause of vaginitis in women of childbearing age and has been diagnosed in 17% to 19% of women who 326

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New Developments in the Diagnosis and Treatment of Vaginitis and Cervicitis • Long-term suppressive antimicrobial regimens are now available for controlling

recurrent and refractory vulvovaginal candidiasis and bacterial vaginosis. • Recent studies have identified new vaginal pathogens operative in bacterial

vaginosis using molecular methods as opposed to traditional culture techniques. • High-dose oral tinidazole regimen effective for metronidazole-resistant

trichomoniasis. • Quinolones are no longer recommended by the CDC for the treatment of

gonornea.

seek gynecologic care in family practice or in student health care settings (2). It also has been seen in 16% to 29% of pregnant women, and its prevalence increases considerably among symptomatic women in STD clinics, reaching a range of 24% to 37%. Although Gardnerella vaginalis has been found in 10% to 31% of virgin adolescent girls, it is still found significantly more often among sexually active women, reaching a prevalence of 50% to 60% in some populations at risk for infection. Evaluation of epidemiologic factors has revealed few clues to the cause of bacterial vaginosis. The use of intrauterine devices, intravaginal pessaries, smoking, and douches was found to be more common in women with bacterial vaginosis. Bacterial vaginosis is significantly more common in blacks and lesbians as well as in women with more sexual partners in the previous 12 months.

Pathogenesis Bacterial vaginosis is the result of massive overgrowth of mixed predominantly anaerobic flora, including peptostreptococci, Bacteroides, G. vaginalis, Mobiluncus, and genital mycoplasmas (3). There is little inflammation, and the disorder represents a disturbance of the vaginal microbial ecosystem rather than a true infection of tissues. The overgrowth of mixed flora is associated with a loss of the normal Lactobacillus-dominated vaginal flora. No single bacterial species is responsible for bacterial vaginosis. Experimental studies of human volunteers and animals indicate that inoculation of the vagina with individual species of bacteria associated with bacterial vaginosis (e.g., G. vaginalis) rarely results in the disease. Two factors support the role of sexual transmission of bacterial vaginosis: 1) the higher prevalence of bacterial vaginosis among sexually active young women than among sexually inexperienced women, and 2) the observation that bacterial vaginosisassociated microorganisms are isolated more often from the urethras of male partners of women with bacterial vaginosis (2). The cause of the overgrowth of anaerobes, Gardnerella, Mycoplasma, and Mobiluncus species that results in bacterial vaginosis is unknown. Theories include increased substrate availability, increased pH, and loss of the

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restraining effects of the predominant Lactobacillus flora of the vagina. Eschenbach and coworkers (4) reported that normal women are colonized by H2O2-producing strains of lactobacilli, whereas women with bacterial vaginosis have reduced numbers of lactobacilli and the species that are present lack the ability to produce H2O2 (4). The H2O2 produced by lactobacilli may inhibit the pathogens associated with bacterial vaginosis, either directly through the toxicity of H2O2 or as a result of the production of H2O2-halide complexes in the presence of natural cervical peroxidase. Molecular tools have recently identified new potential pathogens such as Atopobium vaginae (5). Accompanying the bacterial overgrowth in bacterial vaginosis is the increased production of amines by anaerobes, which is facilitated by microbial decarboxylases. Amines in the presence of an increased vaginal pH volatilize to produce the typical fishy odor of bacterial vaginosis, which is also produced when 10% potassium hydroxide (KOH) is added to vaginal secretions in the disease. Trimethylamine is the dominant abnormal amine in bacterial vaginosis. It is likely that bacterial polyamines together with the organic acids found in the vagina in bacterial vaginosis (acetic and succinic acid) are cytotoxic, resulting in exfoliation of vaginal epithelial cells and creating the vaginal discharge that occurs in the disease. G. vaginalis attaches avidly to exfoliated epithelial cells, especially at the alkaline pH found in bacterial vaginosis. The adherence of Gardnerella organisms results in formation of the clue cells that are pathognomonic for bacterial vaginosis. The abnormal disrupted vaginal flora results in increased levels of proinflammatory vaginal cytokines (interleukin [IL]-1-beta, IL-6, IL-8) although influx of reactive polymorphonuclear leukocytes is inhibited.

Clinical Features As many as 50% of women with bacterial vaginosis may be asymptomatic (2). An abnormal malodorous vaginal discharge (mentioned earlier and often described as fishy) is usually detected, often appears after unprotected coitus, and is infrequently profuse. Examination reveals a nonviscous, grayish-white, adherent discharge. Pruritus, dysuria, and dyspareunia are rare. Bacterial vaginosis has largely been considered to be only a nuisance; however, considerable evidence now exists of serious obstetric and gynecologic complications of bacterial vaginosis, including asymptomatic bacterial vaginosis diagnosed by Gram stain. Obstetric complications include chorioamnionitis, preterm labor, prematurity, and postpartum fever (6). Gynecologic sequelae include postabortion fever, posthysterectomy fever, cuff infection, and chronic mast cell endometritis. Although untreated bacterial vaginosis is reportedly associated with cervical inflammation and lowgrade dysplasia, confirmatory studies of this are needed (7). Most importantly, bacterial vaginosis is associated with increased HIV transmission by increasing HIV cervical shedding and susceptibility to male-tofemale transmission (Table 17-1) (8).

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Table 17-1 Complications of Bacterial Vaginosis Obstetric ● ● ● ● ● ●

Chorioamnionitis Premature rupture of membranes Preterm labor and delivery Low birth weight Amniotic fluid infections Postpartum endometritis

Gynecologic ● ● ● ● ● ● ● ● ●

Tubal infertility Pelvic inflammatory disease Postabortal pelvic inflammatory disease HIV transmission/acquisition/susceptibility Postsurgical infection Urinary tract infection Cervical intraepithelial neoplasia Mucopurulent endocervicitis Strong association with STDs (trichomoniasis, gonorrhea, chlamydia, herpes simplex virus, HPV)

Abbreviations: HPV = human papillomavirus; STD = sexually transmitted disease.

Diagnosis Signs and symptoms are unreliable indicators in the diagnosis of bacterial vaginosis (Table 17-2). The clinical diagnosis can be made reliably in the presence of at least 3 of the following objective criteria: 1) an adherent, white, nonfloccular, homogenous discharge; 2) a positive amine test, with release of fishy odor on addition of 10% KOH to vaginal secretions; 3) a vaginal pH more than 4.5; and 4) the presence of clue cells on light microscopy, which is the most reliable predictor. These clinical signs are simple and reliable, and tests for them are simple. Clue cells are exfoliated vaginal squamous epithelial cells covered with G. vaginalis, giving the cells a granular or stippled appearance with a characteristic loss of clearly defined cell borders. At least 20% of observed epithelial cells should be clue cells for this finding to be of diagnostic significance. Occasionally, epithelial cells covered exclusively with the curved gram-negative rods of Mobiluncus can be demonstrated. The offensive fishy odor of the disease may be apparent during the physical examination or may become apparent only during the amine test. A Gram stain of vaginal secretions is extremely valuable in making the diagnosis, with a sensitivity of 93% and specificity of 70% (2). Although cultures for G. vaginalis are positive in almost all cases of bacterial vaginosis, the organism also may be detected in 50% to 60% of women who do not meet the diagnostic criteria for the disease (2). Accordingly, vaginal culture has no part in the diagnosis of bacterial vaginosis.

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Table 17-2 Diagnostic Features of Infectious Vaginitis Normal

Symptoms

Discharge Amount Color

Candida Vaginitis

Bacterial Vaginosis

None or physiologic leukorrhea

Vulvar pruritus, Moderate soreness, inmalodorous creased disdischarge charge, dysuria, dyspareunia

Profuse purulent discharge, offensive odor, pruritus, dyspareunia

Variable, scant to moderate Clear or white

Scant to moderate Moderate

Profuse

White

Yellow

Consistency Floccular non- Clumped but homogeneous variable

White and/ or gray Homogeneous, uniformly coating walls Present No inflammation

“Bubbles” Absent Appearance Normal of vulva and vagina

Absent Introital and vulvar erythema, edema and occasional pustules, vaginal erythma

pH of vaginal fluid Amine test (10% KOH) Saline microscopy

<4.5

<4.5

>4.7

Negative

Negative

Positive

10% KOH microscopy

Trichomonas Vaginitis

Homogeneous

Present Erythema and swelling of vulvar and vaginal epithelium (strawberry cervix) 5.0–6.0

Occasionally present Normal Normal flora, Clue cells and PMNLs; motile epithelial cell; blastospores coccobaciltrichomonads lactobacilli (yeast); 40%– lary flora (80%-90%); predominate 50% pseudohypredominate; no clue cells; phae absence of abnormal leukocytes flora and motile curved rods Negative Positive Negative Negative (60%–90%) (except in mixed infections)

KOH = potassium hydroxide; PMNLs = polymorphonuclear leukocytes.

Treatment Poor efficacy has been seen in the treatment of bacterial vaginosis with triple sulfa creams, erythromycin, tetracycline, acetic acid gel, and providone–iodine vaginal douches (9). Only moderate cure rates of bacterial vaginosis have been obtained with ampicillin (mean 66%) and amoxicillin (2). The most successful oral therapy remains metronidazole. Most studies that used many divided-dose regimens

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of metronidazole at 800 to 1200 mg per day for 1 week achieved clinical cure rates in excess of 90% immediately and of approximately 80% at 4 weeks (9). Although single-dose therapy with 2 g of metronidazole achieves similar immediate clinical response rates, higher recurrence rates have been reported with this regimen. The beneficial effect of metronidazole results predominantly from its antianaerobic activity and because G. vaginalis is susceptible to the hydroxymetabolites of metronidazole. Although Mycoplasma hominis is resistant to metronidazole, the organisms usually are not detected at follow-up visits of successfully treated patients. Similarly, Mobiluncus curtisii is resistant to metronidazole but usually disappears after therapy. Topical therapy with 2% clindamycin (once daily for 7 days) cream or suppositories or metronidazole gel 0.75% (once daily for 5 days) has been shown to be as effective as oral metronidazole in eliminating bacterial vaginosis without the side effects of the oral drug. Single-dose vaginal clindamycin in a bioadhesive preparation is now available. In the past, asymptomatic bacterial vaginosis was not treated, especially because patients often alleviate spontaneously over several months. However, the growing evidence linking asymptomatic bacterial vaginosis with many obstetric and gynecologic complications that involve the upper reproductive tract has prompted a reassessment of this policy, especially with the availability of convenient topical therapies (6,10). Asymptomatic bacterial vaginosis should be treated before pregnancy, in women with cervical abnormalities, and before elective gynecologic surgery. Routine screening and treatment of asymptomatic bacterial vaginosis in pregnancy remains controversial pending the outcome of studies that prove that treating the disease reduces preterm delivery and prematurity (11). Some controlled studies have shown that treatment of bacterial vaginosis with topical clindamycin and oral metronidazole may reduce preterm labor and prematurity but only in women with a past history of preterm labor. At present, this category of women seems most suited for screening (11). Despite indirect evidence of its sexual transmission, no study has documented reduced recurrence rates of bacterial vaginosis in women whose partners have been treated with various regimens, including metronidazole. Accordingly, most clinicians do not routinely treat the male partners of affected women. After treatment with oral metronidazole, symptoms of bacterial vaginosis recur within 3 months in approximately 30% of patients who initially respond (2). The reasons for such recurrence are unclear and include the possibility of reinfection but more likely reflect vaginal relapse, with failure to eradicate the offending organisms and concurrent failure of the normally protective Lactobacillus-dominant vaginal flora to reestablish itself. Management of symptoms of acute bacterial vaginosis during relapse includes treatment with oral or vaginal metronidazole or topical clindamycin, usually prescribed for a longer (10- to 14-day) period than the initial treatment regimen. Maintenance regimens of antibiotic therapy have

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been largely disappointing, and new approaches to treating bacterial vaginosis include recolonization with exogenous Lactobacillus using selected bacteria-containing suppositories. A recent study found that long-term suppressive maintenance therapy with twice-weekly metronidazole gel (0.75%) is effective prophylaxis, but long-term cure occurred in less than 50% (12).

Prevention Because the pathogenesis of bacterial vaginosis is obscure, measures for its prevention have not been forthcoming. Although the disease is not typically sexually transmitted, barrier contraception may reduce its occurrence. Avoidance of douching is recommended.

Trichomoniasis Epidemiology Studies estimate that 2 to 3 million American women contract trichomoniasis annually, with a worldwide distribution of approximately 180 million cases of the disease each year (2). The prevalence of trichomoniasis correlates with the overall level of sexual activity of the specific group of women being studied, with the disease diagnosed in approximately 5% of women in family-planning clinics, 13% to 25% of women who attend gynecology clinics, 50% to 75% of prostitutes, and 7% to 35% of women in STD clinics. Recent surveys indicate a decline in the incidence of trichomoniasis in many industrialized countries.

Pathophysiology Sexual transmission is the dominant method of introduction of Trichomonas vaginalis into the vagina (2). The organism was found in 70% of urethral cultures of men who had had sexual contact with infected women within the previous 48 hours (13). Women with trichomoniasis also show a high prevalence of gonorrhea, with both diseases significantly associated with the use of nonbarrier methods of contraception. Recurrent trichomoniasis is common and indicative of a lack of significant protective immunity. Nevertheless, an immune response to T. vaginalis does develop, as indicated by low titers of serum antibody, but is insufficient for diagnostic serology. Antitrichomonal IgA has been detected in vaginal secretions, but a protective role for it has not been defined. Delayed hypersensitivity in natural infection with T. vaginalis also can be demonstrated. The predominant host-defense response is provided by the many polymorphonuclear leukocytes (PMNs) that respond to chemotactic substances released by trichomonads and are capable of killing T. vaginalis without ingesting it. T. vaginalis destroys epithelial cells by direct cell

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contact and cytotoxicity. The periurethral and Skene glands are infected in most patients, and T. vaginalis organisms can be seen in the urine specimens of some infected individuals.

Clinical Features The severity of Trichomonas infection in women ranges from an asymptomatic carrier state to severe acute inflammatory disease (13,14). A vaginal discharge, usually foul smelling, is reported by 50% to 75% of women with diagnosed trichomoniasis; however, the discharge is not always malodorous. Pruritus occurs in 25% to 50% of patients and is often severe. Other infrequent symptoms include dyspareunia, dysuria, and rarely frequent micturition. Lower abdominal pain occurs in fewer than 10% of patients and should alert the physician to the possibility of concomitant salinities caused by other organisms. Symptoms of acute trichomoniasis often appear during or immediately after menstruation. Although its duration is controversial, the estimated range of the incubation period is from 3 to 28 days (13,14). Physical findings in trichomoniasis represent a spectrum that varies with the severity of disease. Vulvar findings may be absent but are typically characterized in severe cases by diffuse vulvar erythema (10%-33%), edema, and a profuse purulent vaginal discharge (14). The discharge is often described as being yellow-green and frothy but is often grayish white. A frothy discharge is seen in a minority of patients with trichomoniasis and is more commonly seen in bacterial vaginosis. The vaginal walls in trichomoniasis are erythematous and, in severe cases, may have a granular appearance. Punctate hemorrhages (colpitis macularis) of the cervix may give its surface a strawberry-like appearance that, although apparent to the naked eye in only 1% to 2% of patients, is found in 45% patients on colposcopy (14). The clinical course of trichomoniasis in pregnancy is identical to that in the nonpregnant state; when untreated, the disease is associated with premature rupture of membranes and prematurity. Trichomoniasis facilitates transmission of HIV and metronidazole therapy dramatically reduces free HIV virus in vaginal secretions (15).

Diagnosis None of the clinical features of Trichomonas vaginitis is sufficiently specific to allow a diagnosis of trichomonal infection based on signs and symptoms alone (Table 17-2) (10). A definitive diagnosis requires demonstration of the organism. The vaginal pH is markedly increased, almost always more than 5.0, and sometimes as much as 6.0. On saline microscopy, an increase in PMNs is almost invariably present. The ovoid trichomonal parasites are slightly larger than PMNs and are best recognized by their motility. A wet mount is positive in only 40% to 80% of cases. The Gram stain is of little

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value because of its inability to differentiate PMNs from nonmotile trichomonads, and the use of Giemsa, acridine orange, and other stains has no advantage over saline preparation. Although trichomonads are often seen on Pap smears, this method has a sensitivity of only 60% to 70% when compared with saline preparation microscopy, and false-positive results have been reported. Several equivalent culture methods for T. vaginalis are available (Diamond TYM medium preferred), and growth is usually detected within 48 hours. Culture is now recognized as the most sensitive method for detecting the presence of trichomonads (95% sensitivity) and should be considered in patients with vaginitis in whom one finds an increased pH, PMN excess, and absence of motile trichomonads. A two-chambered plastic bag culture system (InPouch: Biomed Diagnostic, San Jose, CA) is equivalent to Diamond TYM medium for detection of T. vaginalis. PCR technology is extremely sensitive but not available commercially. OSOM Trichomonas Rapid Test, a new point-of-care antigen based diagnostic test (Genzyme Diagnostics, Cambridge, MA), has high sensitivity and specificity.

Treatment Treatment of trichomoniasis remains based on the 5-nitroimidazole group of drugs (metronidazole, tinidazole, and ornidazole), all of which have similar efficacy (9). Oral therapy is preferred to topical vaginal therapy because of the frequency of infection of the urethra and periurethral glands, which provide sources for the endogenous recurrence of infection. Treatment consists of oral metronidazole 500 mg twice daily for 7 days, which produces a cure rate of 95%. Similar results have been obtained with a single dose of oral metronidazole 2 g, which produced cure rates of 82% to 88%. The latter cure rate increases to more than 90% when sexual partners are treated simultaneously (9). The advantages of single-dose therapy include better patient compliance, a lower total dose, a shorter period of alcohol avoidance, and possibly decreased subsequent Candida vaginitis. The 5-nitroimidazoles are not in themselves trichomonacidal, but lowredox proteins reduce the nitro group of these drugs, resulting in the formation of highly cytotoxic products within the infecting organisms. Aerobic conditions interfere with this reduction process and decrease the antianaerobic activity of the 5-nitroimidazoles. Most strains of T. vaginalis are highly susceptible to metronidazole, which has a minimal inhibitory concentration of 1 µg/mL against this organism. Patients who do not respond to an initial 7-day course of treatment often respond to an additional standard 7-day course of therapy. Some patients are refractory to repeated courses of therapy even when compliance is assured and sexual partners are known to have been treated. If reinfection is excluded, these rare patients may have strains of T. vaginalis that are resistant to metronidazole, which can be confirmed in vitro. Increased doses

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of metronidazole and a longer duration of therapy are necessary to cure these refractory cases of the disease; patients should be given maximum tolerated doses of oral metronidazole of 2 to 4 g/day for 10 to 14 days. Rarely, intravenous metronidazole in doses as high as 2 to 4 g/d may be necessary, with careful monitoring for drug toxicity. Considerable success has been seen in the treatment of resistant trichomonal infections with oral tinidazole (16). Most investigators use high-dose tinidazole at 1 to 4 g/d for 14 days (17). Rare patients who do not respond to nitroimidazoles can be treated with topical paromomycin. Side effects of metronidazole include an unpleasant or metallic taste, nausea (10%), transient neutropenia (7.5%), and a disulfiram-like effect when alcohol is ingested (7). Caution should be taken when 5-nitroimidazoles are used in patients taking warfarin. Long-term and high-dose therapy increases the risk of neutropenia and peripheral neuropathy. In experimental studies, metronidazole has been mutagenic for certain bacteria, indicating a carcinogenic potential; however, cohort studies have not established an increase in cancer illness with this drug. Thus, the risk of short-term, low-dose metronidazole treatment is extremely small. Superinfection with Candida is by no means uncommon. Nonmetronidazole treatments of trichomoniasis in pregnancy gives unsatisfactory results (9). Metronidazole readily crosses the placenta; and because of concern for teratogenicity, some consider it prudent to avoid the use of this drug in the first trimester of pregnancy. However, because considerable human and animal data support the safety of metronidazole in pregnancy, investigators have become more comfortable using it throughout pregnancy. Topical clotrimazole and povidone–iodine jelly offer minimal benefit in trichomoniasis.

Prevention Sexual transmission of trichomonads is prevented efficiently by the use of barrier contraception. Spermicidal agents such as nonoxynol-9 also reduce transmission. However, reinfection of women is common and, therefore, mandates treatment with metronidazole of all sexual partners of the patient, preferably simultaneously.

Vulvovaginal Candidiasis Epidemiology Data from the United Kingdom reveal a sharp increase in the incidence of vulvovaginal candidiasis in that country. In the United States, Candida is now the second most common cause of vaginal infection (1,18). It is estimated that 75% of women experience at least 1 episode of vulvovaginal candidiasis

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during their childbearing years, and approximately 40% to 50% experience a second attack. A small subpopulation of women, of unmeasured magnitude but probably constituting less than 5% of adult women, suffers from repeated, recurrent, often intractable episodes of Candida vaginitis (18). Point-prevalence studies indicate that Candida is isolated from the genital tract of approximately 20% of asymptomatic, healthy women of childbearing age (18). The natural history of asymptomatic colonization is unknown; however, animal and human studies suggest that vaginal carriage continues for several months and perhaps for years. Several factors are associated with increased rates of asymptomatic vaginal colonization with Candida, including pregnancy (30%-40%), use of oral contraceptives, uncontrolled diabetes mellitus, and frequent visits to STD clinics (Table 17-3). The rarity of isolating Candida from premenarchal girls, the lower prevalence of postmenopausal Candida vaginitis, and the possible association of vulvovaginal candidiasis with hormone replacement therapy emphasize the hormonal dependence of this condition.

Pathogenesis Infecting Organisms Between 85% and 90% of yeasts isolated from the vagina are strains of Candida albicans. The remainder belong to other species, the most common of which are Candida glabrata and Candida tropicalis. Non-albicans Candida species are capable of inducing vaginitis and are often more resistant to conventional therapy than is C. albicans. Some, but not all, surveys indicate an increase in vulvovaginal candidiasis caused by non-albicans Candida species, particularly C. glabrata (18,19).

Table 17-3 Host Factors Associated with Increased Asymptomatic Vaginal Colonization with Candida and Candida Vaginitis Genetic Blood-group antigen and/or secretor status Acquired Biological Pregnancy Uncontrolled diabetes mellitus Corticosteroid and/or immunosuppressive therapy Antimicrobial therapy (systemic, topical) HIV infection Behavioral (Sexual) Oral contraceptives Intrauterine device or contraceptive sponge Nonoxynol-9 spermicide Receptive oral sex Coital frequency (?)

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Germination of Candida enhances colonization and facilitates tissue invasion by the organism. Factors that enhance or facilitate germination (e.g., estrogen therapy, pregnancy) tend to precipitate symptomatic vaginitis, whereas measures that inhibit germination (e.g., bacterial flora, local mucosal cell-mediated immunity) may prevent acute vaginitis in women who are asymptomatic carriers of yeasts. Candida organisms gain access to the vaginal lumen and secretions predominantly from the adjacent perianal area. This finding is borne out by epidemiologic typing studies. Candida vaginitis is seen predominantly in women of childbearing age, and only in the minority of cases can a precipitating factor be identified to explain the transformation from asymptomatic carriage of Candida organisms to symptomatic vaginitis in individual patients.

Host Factors Host factors associated with increased asymptomatic vaginal Candida colonization and Candida vaginitis are shown in Table 17-3. During pregnancy, the vagina is more susceptible to vaginal infection, resulting in higher incidences of vaginal colonization and vaginitis and lower cure rates of infection. The clinical attack rate is the highest in the third trimester, but symptomatic recurrences are also common throughout pregnancy. The high levels of reproductive hormones during pregnancy result in a higher glycogen content in the vaginal environment and provide an excellent carbon source for the growth and germination of Candida. A more likely mechanism for susceptibility to infection is that estrogens enhance vaginal epithelial cell avidity for the adherence of Candida. Furthermore, a yeast cytosol receptor or binding system for female reproductive hormones has been documented. These hormones also enhance yeast mycelial formation. Several studies have shown increased vulvovaginal candidiasis associated with oral contraceptive use (20) and uncontrolled diabetes mellitus. Glucose tolerance tests have been recommended for women with recurrent vulvovaginal candidiasis, but their yield is low and such testing is not justified in otherwise healthy premenopausal women. Symptomatic vulvovaginal candidiasis is often seen during or after courses of systemic antibiotic therapy. Antibiotics are responsible for approximately 20% of sporadic Candida vaginitis episodes (21). Although all antimicrobial agents can cause this complication, broad-spectrum antibiotics such as tetracycline and the beta-lactams are chiefly responsible for it and are thought to act by eliminating the normal protective vaginal bacterial flora. The dose and duration of antibiotic therapy further influence the risk of developing Candida vaginitis. The natural flora of the vagina provides a colonization-resistance mechanism and prevents Candida from germinating. Lactobacillus species have been singled out as providing this protective function (22). The interaction between Lactobacillus and Candida includes competition for nutrients, steric interference with

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Candida adherence, and elaboration of bacteriocins that inhibit yeast proliferation and germination. Other factors that contribute to an increased incidence of Candida vaginitis include the use of tight, poorly ventilated clothing and nylon underclothing, which increases perineal moisture and temperature. Chemical contact, local allergy, and hypersensitivity reactions also may predispose to symptomatic Candida vaginitis by altering the local superficial vulvovaginal environment and facilitating tissue invasion by Candida organisms. Candida may cause cell damage and resulting inflammation by direct hyphal invasion of epithelial tissue. It is possible that proteases and other hydrolytic enzymes of the organism facilitate its cell penetration with resultant inflammation, mucosal swelling, erythema, and exfoliation of vaginal epithelial cells. The characteristic nonhomogenous vaginal discharge of vaginal candidiasis consists of a conglomerate of hyphal elements and exfoliated nonviable epithelial cells, with few PMNs. Candida also may induce symptoms by hypersensitivity or allergic reaction, particularly in women with idiopathic recurrent vulvovaginal candidiasis (see discussion of allergic vaginitis in the following section).

Pathogenesis of Recurrent and Chronic Candida Vaginitis Careful evaluation of women with recurrent vaginitis usually fails to reveal any precipitating or causal mechanism for such a disease (23). In the past, investigators attributed recurring episodes of Candida vaginitis to repeated fungal reinoculation of the vagina from a persistent intestinal source or sexual transmission of the infecting organism. The intestinal reservoir theory for the recurrence of Candida vaginitis is based on the report of Candida having been recovered from rectal cultures in almost 100% of women with vulvovaginal candidiasis. Furthermore, typing of simultaneously obtained vaginal and rectal isolates almost invariably reveals identical strains of the organism. This theory has been criticized in the past few years because of a lower concordance between rectal and vaginal culture results in patients with recurrent vulvovaginal candidiasis. Moreover, long-term therapy with oral nonabsorbable nystatin is ineffective in preventing recurrences. Although sexual transmission of Candida organisms occurs by means of vaginal intercourse and orogenital contact, the role of sexual reintroduction of yeast as a cause for recurrent vulvovaginal candidiasis is doubtful. Recurrent vulvovaginal candidiasis frequently occurs in celibate women, whereas only the minority of male partners of women with recurrent vulvovaginal candidiasis have been colonized with Candida. Although most studies aimed at treating male partners of infected women have not reduced the frequency of recurrent episodes of vaginitis, Spinillo and coworkers (24) achieved reduction in recurrent vulvovaginal candidiasis by treating the colonized male partners of such patients. Vaginal relapse implies incomplete eradication or clearance of Candida from the vagina with antimycotic therapy. According to this concept,

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Candida organisms persist in small numbers in the vagina, causing their continued carriage. When host environmental conditions permit, the colonizing organisms increase in number and undergo mycelial transformation, resulting in a new clinical episode of infection. Whether recurrence is caused by vaginal reinfection or relapse, women with recurrent vulvovaginal candidiasis differ from those with infrequent episodes of such infection in their inability to tolerate small numbers of Candida reintroduced into or persisting in the vagina. On the basis of typing of organisms, women with recurrent and infrequent infection are found to have the same distribution frequency of Candida strains as are women without symptoms. Host factors responsible for frequent episodes of vulvovaginal candidiasis are not delineated clearly, and more than 1 mechanism may be at work. Patients who experience frequent reinfection show no evidence of complement, phagocytic cells, or immunoglobulin deficiency. Recurrent vulvovaginal candidiasis is rarely caused by antimicrobial drug resistance (25). Current theories about the pathogenesis of recurrent vulvovaginal candidiasis include qualitative and quantitative deficiency of the normal protective vaginal bacterial flora and an acquired, often-transient, antigen-specific deficiency in T-lymphocyte function that similarly permits unchecked yeast proliferation (23,26). Another theory is that of an acquired acute hypersensitivity reaction to Candida antigen that is accompanied by increased vaginal titers of Candida antigen–specific IgE. This theory has a clinical basis in that patients with recurrent vulvovaginal candidiasis often present with severe vulvar manifestations of the disease (rash, erythema, swelling, and pruritus) with minimal exudative vaginal changes, little discharge, and lower organism titers. Allergic responses to Candida have been reported to involve the male genitalia immediately after coitus with Candida-infected female genitalia and are characterized by the acute onset of erythema, edema, severe pruritus, and irritation of the penis (23). As yet, only a minority of women with recurrent vulvovaginal candidiasis have been shown to have increased Candida-specific vaginal IgE. Limited studies have found that the use of Candida-antigen desensitization helps reduce the frequency of recurrent episodes of vaginitis. Women who are seropositive for HIV have higher vaginal colonization rates with Candida than do seronegative women, but the attack rate of symptomatic vulvovaginal candidiasis in the 2 groups seems similar. Reports of severe recurrent vulvovaginal candidiasis are largely unsubstantiated. Recurrent vulvovaginal candidiasis in the absence of other risk factors for HIV infection is not an indication for giving an HIV test (18).

Clinical Features The most frequent symptom of vulvovaginal candidiasis is vulvar pruritus, because vaginal discharge is not invariably present and is often minimal (18). Although typically described as having a cottage cheese–like

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character, the discharge may vary from watery to homogenously thick. Vaginal soreness, irritation, vulvar burning, dyspareunia, and external dysuria are commonly present. Odor, if present, is minimal and nonoffensive. Examination frequently reveals erythema and swelling of the labia and vulva, often with discrete pustulopapular peripheral lesions. The cervix is normal, and vaginal mucosal erythema with an adherent whitish discharge is present. Characteristically, symptoms are worst during the week before the onset of menses and are somewhat relieved with the onset of menstrual flow.

Diagnosis The relative lack of specificity of symptoms and signs of vulvovaginal candidiasis precludes a diagnosis that is based only on history and physical examination. Most patients with symptomatic vulvovaginal candidiasis may be diagnosed readily on the basis of a simple microscopic examination of vaginal secretions. A wet mount or saline preparation has a sensitivity of 40% to 60%. The 10% KOH preparation is even more sensitive in diagnosing the presence of germinated yeast. A normal vaginal pH (4.0-4.5) is found in Candida vaginitis; a pH finding higher than 4.5 suggests the possibility of bacterial vaginosis, trichomoniasis, or a mixed infection (18). Although routine fungal cultures are unnecessary in patients who test negative for Candida by microscopy, cultures should be obtained in patients who have the highest predicted positive culture yield (i.e., those with a past history of confirmed Candida vaginitis and/or many signs and symptoms of vulvovaginitis) and when it is important to confirm the diagnosis and avoid empirical therapy. The Pap smear is unreliable, being positive in only approximately 25% of cases of vulvovaginal candidiasis. There is no reliable serologic technique for the diagnosis of symptomatic Candida vaginitis.

Treatment Topical Agents for Acute Candida Vaginitis Antimycotic agents are available for local use as creams, vaginal tablets, suppositories, and coated tampons (Table 17-4). There is little evidence to suggest that the formulation of a topical antimycotic influences its clinical efficacy in vulvovaginal candidiasis (27). Extensive vulvar inflammation dictates local vulvar application of a topical cream preparation. The average mycologic cure rate of 7- and 14-day courses of nystatin in vulvovaginal candidiasis is approximately 75% to 80%. Azoles seem to achieve slightly higher clinical mycologic cure rates (approximately 85%90%) than do polyenes (nystatin). Although many studies have compared the clinical efficacy of the various azoles, there is little evidence that any 1 azole agent is superior to the others (27).

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Table 17-4 Therapy for Vaginal Candidiasis: Topical Agents Drug

Formulation

Dosage Regimen

Butoconazole Clotrimazole

2% cream 1% cream 100-mg vaginal tablet 100-mg vaginal tablet 500-mg vaginal tablet 2% cream 100-mg vaginal suppository 200-mg vaginal suppository 1200-mg vaginal suppository 150-mg vaginal tablet 2% cream 2% cream 6.5% cream 0.4% cream 0.8% cream 80-mg vaginal suppository 100,000-U vaginal tablet

5 g for 1–3 days 5 g for 7–14 days 1 tablet for 7 days 2 tablets for 3 days 1 tablet, single dose 5 g for 7 days 1 suppository for 7 days 1 suppository for 3 days 1 suppository, single dose 1 tablet for 3 days 5 g for 7 days 5 g for 3 days 5 g, single dose 5 g for 7 days 5 g for 3 days 80 mg for 3 days 1 tablet for 14 days

Miconazole

Econazole Fenticonazole Tioconazole Terconazole

Nystatin

Topical azoles are remarkably free of local and systemic side effects; nevertheless, the initial application of topical agents is not infrequently accompanied by local burning and discomfort. There has been a major trend toward shorter courses of treatment of vulvovaginal candidiasis with progressively higher doses of antifungal agents, culminating in highly effective single-dose topical regimens. However, although short-course regimens are effective for mild and moderate vaginitis, cure rates for severe and complicated vaginitis are lower. Oral systemic azoles available for the treatment of vulvovaginal candidiasis include ketoconazole (400 mg twice daily for 5 days), itraconazole (200 mg/d for 3 days or twice daily for 1 day), and fluconazole (150-mg single dose) (28). All these oral regimens achieve clinical cure rates in excess of 80%; however, only fluconazole is approved for use in the United States. Women generally prefer oral treatment regimens for vulvovaginal candidiasis because of their convenience and lack of local side effects. None of the systemic regimens should be prescribed during pregnancy, and these regimens carry the potential for systemic side effects and toxicity. In particular, hepatotoxicity with ketoconazole precludes its widespread use in vulvovaginal candidiasis (27). Vulvovaginal candidiasis is classified as either uncomplicated or complicated based on its likelihood of being cured clinically and mycologically with short-course therapy (Table 17-5). Uncomplicated vulvovaginal candidiasis, which by far represents the most common form of vaginitis seen clinically, is caused by highly sensitive strains of C. albicans and, when of mild to moderate severity, responds well to all topical or oral antimycotic therapy (including single-dose therapy), with cure rates exceeding 90% (29). In contrast, patients with complicated vulvovaginal candidiasis have

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Table 17-5 Classification of Vulvovaginal Candidiasis Complicated

Uncomplicated

Non-albicans Candida Resistant C. albicans (rare) History of recurrent VVC Severe VVC Abnormal host (e.g. uncontrolled diabetes, pregnant patient, immunocompromised patient)

Candida albicans Infrequent episodes Vaginitis mild to moderate Normal host

VVC = vulvovaginal candidiasis.

either an organism, host factor, or severity of infection that dictates more intensive and prolonged treatment that lasts 7 to 14 days. Most infections with nonalbicans species of Candida respond to conventional topical or oral antifungal agents, provided they are administered for a sufficient period of time. Vaginitis caused by C. glabrata often fails to respond to azoles and may require treatment with vaginal capsules of boric acid at 600 mg per day for 14 days (30).

Recurrent Vulvovaginal Candidiasis The management of recurrent vulvovaginal candidiasis is directed at its control rather than its cure, and requires long-term maintenance therapy with a suppressive prophylactic regimen. The clinician should first confirm the diagnosis of recurrent vulvovaginal candidiasis. Uncontrolled diabetes must be controlled, and the use of corticosteroids and other immunosuppressive agents should be discontinued when possible. Unfortunately, no underlying or predisposing factor can be identified in most women with recurrent vulvovaginal candidiasis. Because of the chronicity of therapy for recurrent vulvovaginal candidiasis, the convenience of oral treatment is apparent; the best suppressive prophylaxis has been achieved with weekly fluconazole orally at a dose of 150 mg (31). An effective topical prophylactic regimen consists of weekly vaginal suppositories of clotrimazole in a dose of 500 mg (18,29).

Prevention In women with confirmed recurrent vulvovaginal candidiasis linked to frequent courses of systemic antibiotic therapy, prophylactic antimycotic therapy is justified. A useful regimen is fluconazole at 100 mg once weekly for the duration of antibiotic therapy. No other dietary or alternative method has stood the test of time in preventing vulvovaginal candidiasis. Women prone to vulvovaginal candidiasis should avoid the use of oral contraceptives, intrauterine devices, and the contraceptive sponge.

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Atrophic Vaginitis Clinically significant atrophic vaginitis is by no means uncommon, and most women with atrophic vaginitis are asymptomatic. Because of reduced endogenous estrogen production, the epithelium becomes thin and lacking in glycogen, which contributes to a reduction in lactic acid production and an increase in vaginal pH. This change in the environment encourages the overgrowth of nonacidophilic coliform organisms and the disappearance of Lactobacillus organisms. Despite these major but usually gradual changes, symptoms are rare, especially in the absence of coitus. With advanced atrophy, symptoms of atrophic vaginitis include vaginal soreness, dyspareunia, and occasional spotting or discharge. Burning is frequently reported and often precipitated by intercourse. The vaginal mucosa is thin, with diffuse redness, occasional petechiae, or ecchymoses with few or no vaginal folds. Vulvar atrophy also may be apparent. A serosanguineous, thick, or watery vaginal discharge may be present, and the pH of vaginal secretions ranges from 5.5 to 7.0. The wet smear frequently shows increased PMNs associated with small, round epithelial cells. These parabasal cells represent immature squamous epithelial cells that have not been exposed to sufficient estrogen. The Lactobacillus-dominated flora of the vagina is replaced by a mixed flora of gram-negative rods. Bacteriologic cultures in these patients are necessary and can be misleading. The treatment of atrophic vaginitis, especially in the absence of systemic symptoms, consists primarily of topical application of vaginal estrogen. Nightly use of half or all the contents of an applicator for 1 to 2 weeks is usually sufficient to alleviate atrophic vaginitis.

Noninfectious Vaginitis and Vulvitis Women often present with acute or chronic vulvovaginal symptoms of noninfectious cause. Theses symptoms are indistinguishable from those of infectious syndromes but are most commonly confused with those of acute Candida vaginitis, such as pruritus, irritation, burning, soreness, and variable discharge. Noninfectious causes of vaginitis and vulvitis include physical irritants (e.g., minipads), chemical irritants (e.g., spermicides, Betadine, topical antimycotics, soaps and perfumes, and topical 5flurouracil), and allergens responsible for immunologic acute and chronic hypersensitivity reactions, including contact dermatitis (e.g., latex condoms and antimycotic creams) (Table 17-6). There is an enormous list of topical factors that are responsible for local inflammatory reactions and symptoms, and many more have yet to be defined. Depending on the site of contact, symptoms may be vaginal or vulvar. A noninfectious mechanism may coexist with or follow an infectious process and should be considered when 1) the 3 common infectious causes of vulvovaginal symptoms, as well as

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Table 17-6 Differential Diagnosis of Vulvar Inflammation Noninfectious Causes

Infectious Causes

Diffuse Atopic dermatitis Allergy/hypersensitivity (e.g., azoles, latex, nickel) Chemicals (e.g., chlorine, betadyne, parobens, detergents) Trauma Drug-related (e.g., topical 5-fluorouracil) Idiopathic vestibulitis Erosive lichen planus Lichen sclerosus Crohn’s disease Other (e.g., minipads) Focal Behçets syndrome Pemphigus Idiopathic vestibulitis (vestibular adenitis) Lichen sclerosus Psoriasis

Diffuse Candidiasis Trichomoniasis Bacterial cellulitis (rare) Fournier’s gangrene (rare) Focal Bartholin’s abscess Folliculitis Herpes simplex Herpes zoster HIV idiopathic ulceration LGV Syphilis Chancroid

hormone deficiency, are excluded; 2) the vaginal pH and saline content are normal; and 3) KOH microscopy and a yeast culture are negative. Unfortunately, given the anticipated 20% colonization rates in normal asymptomatic women, a positive yeast culture sometimes reflects the presence of an innocent bystander organism rather than the cause of a patient’s vulvovaginal symptoms. The only logical way of establishing the role of Candida in this context is to treat the patient with an oral antifungal agent and assess the clinical response. Once a local chemical, irritant, or allergic reaction is suspected as the cause of vaginitis and/or vulvitis, a detailed inquiry into possible etiologic factors is essential. Offending agents or behaviors should be eliminated whenever possible, including the avoidance of chemical irritants and allergens, such as soaps and detergents. The immediate management of severe vulvovaginal symptoms of noninfectious cause should not rely on topical corticosteroids, which are rarely the solution to such symptoms; moreover, high-potency steroid creams often cause intense burning. Local relief measures include sodium bicarbonate sitz baths and oral antihistamines. The diagnosis and management of vaginitis are summarized in Figures 17-1, 17-2, and 17-3.

Cervicitis Epidemiology The presence of purulent exudate in the cervical os (mucopurulent cervicitis) has been associated with cervical infection with Chlamydia trachoma-

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Vulvovaginal symptoms

Obtain sexual history Conduct speculum examination Assess vaginal pH Perform 10% KOH amine elaboration test Perform saline and 10% KOH microscopic examination

Purulent discharge present, but not mucopus cervicitis

Cervical mucopus present (indicated by purulent yellow stain on endocervical swab and Gram-stain finding of >30 PMNLs per high-power field)

pH elevated?

Test for Chlamydia trachomatis, Neisseria gonorrhoeae

No

Yes

PMNLs

Trichomonads present?

No

Yes

Normal

Review for cervical ectopia or an idiopathic source

Patient at high risk for STD or unlikely to return for follow-up?

No

Yes

PMNLs elevated?

Treat for trichomoniasis

No

Yes

Reevaluate

Culture for trichomonads positive?

No

Yes

Treat on the basis of test results

Treat for gonorrhea and chlamydial infection

No

Yes

Consider desquamative inflammatory vaginitis, and search for cause

Treat for trichomoniasis

Figure 17-1 Approach to the patient with a purulent vaginal discharge. Abbreviations: KOH = potassium hydroxide; PMNs = polymorphonuclear leukocytes; STD = sexually transmitted disease.

tis, Neisseria gonorrhoeae, Herpes simplex virus, and cytomegalovirus (CMV). Infection with Trichomonas vaginalis correlates with colpitis macularis and inflammatory changes of the ectocervix (22,32,33). Not infrequently patients with mucopurulent endocervicitis or ectocervicitis (mucopurulent cervicitis; MPC) are seen in the absence of these pathogens indicating that additional, as yet unrecognized causes exist. A role for disruption of vaginal

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Vulvovaginal symptoms

Obtain sexual history Conduct speculum examination Assess vaginal pH Perform 10% KOH amine elaboration test Perform saline and 10% KOH microscopic examination

pH elevated?

No

Yes

Yeast present on saline and 10% KOH microscopy?

PMNLs elevated?

No

Yes

No

Yes

Submit yeast culture

Treat for vulvovaginal candidiasis

Diagnose bacterial vaginosis if three or four of the following are present: • Homogeneous, adherent, white/gray, nonfloccular discharge • Vaginal discharge pH >4.5 • Positive amine test • Clue cells

Trichomonads present on wet mount?

−

+

Consider: • Allergy • Hypersensitivity • Chemical/irritant

Treat for vulvovaginal candidiasis

No

Yes

Treat for Trichomonads trichomoniasis culture positive?

No

Yes

Possibilities include postcoital, post-douche, or atrophic vaginitis

Treat for bacterial vaginosis

No

Yes

Consider desquamative inflammatory vaginitis, erosive lichen planus, foreign body

Treat for trichomoniasis

Figure 17-2 Algorithm for the management of the patient with vulvovaginal symptoms. Abbreviations: KOH = potassium hydroxide; PMNs = polymorphonuclear leukocytes.

flora, specifically overgrowth of anaerobes in causing cervical inflammation, has been proposed. More specifically, bacterial vaginosis has recently been associated with cervical inflammation, both macroscopic and subclinical inflammation, identified on Pap smears (34). Rare causes of cervicitis include Mycobac-terium tuberculosis and Actinomyces israeli, the latter almost invariably in the presence of intrauterine devices. Although the most important and prevalent infection of the cervix is undoubtedly human papillomavirus (HPV), this virus does not cause cervicitis.

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Pap smear report of inflammation

Speculum examination

Appearance of cervix

Normal

Ectopy

Screen for Chlamydia trachomatis and Neisseria gonorrhoeae in women with high-risk characteristics‡

Mucopurulent cervicitis*

"Inflammatory" cervicitis

Confirm by Gramstain wet mount†

Exclude bacterial vaginosis (pH, microscopy)

Positive Positive in patient unlikely to follow-up Consider PID

Absent

Positive in Negative reliable patient

Test for C. trachomatis and N. gonorrhoeae

Consider colposcopy; refer to Ob-Gyn

Present Positive

Culture probe, DNA probe, or LCR urine test

Test for C. trachomatis or N. gonorrhoeae cervicitis

Treat PID

Positive

Negative

Observe

Trace and notify contacts

∗ Mucopurulent cervicitis is recognized by purulent endocervical discharge and friability. † Positive Gram stain is considered >30 PMNL/high-power field. ‡ High-risk characteristics include age <25 years, multiple sex partners, and recent or new sexual partner.

Figure 17-3 Algorithm for the evaluation of cervicitis. Abbreviations: LCR = ligase-chain reaction; PID = pelvic inflammatory disease; PMNs = polymorphonuclear leukocytes.

The prevalence of genital chlamydia infection ranges from 8% to 40% (35). Risk factors include young age, unmarried status, lower socioeconomic conditions, number and recent change of sexual partners, ectopy, oral contraceptive use, and concurrent gonococcal infection; the latter may reactivate latent chlamydial infection and increases shedding of chlamydia from endocervix (34,35). Risk factors for gonococcal mucopurulent cervicitis are identical but also include urban dwellers, prostitution, illicit drug use, and minority racial status. Up to 60% of women with N. gonorrhoeae have confection with

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chlamydia (35). Herpetic cervicitis is rare in the absence of genital lesions and is most commonly associated with first-episode, primary disease with an 80% isolation rate (33). CMV is thought to be responsible for approximately 5% of cases of cervicitis; is usually asymptomatic; and when CMV is isolated for cervical secretions, the detection should not imply a etiologic relationship with present pathology.

Clinical Features Cervicitis is frequently asymptomatic and detected on routine pelvic examination. Alternatively, cervical inflammation is recognized because of signs and symptoms of concomitant infection, such as vaginal trichomoniasis, genital herpes, or salpingitis. MPC may result in a purulent vaginal discharge in its own right. Accordingly, cervical speculum evaluation should be an essential part of vaginal examination in women with an abnormal discharge. Mucopurulent endocervicitis results in swelling and erythema of the zone of ectopy associated with friability, contact bleeding, spotting, and a yellow or a green endocervical exudate. The purulent discharge is best appreciated by obtaining an endocervical swab specimen and observing the latter against a white background. Trichomoniasis is associated with ectocervical squamous epithelial mucosal inflammation giving the cervix a strawberry appearance caused by microscopic focal patchy petechiae (colpitis macularis) in 5% to 20% of patients (13). Primary herpes cervicitis may be associated with severe necrosis reminiscent of cervical cancer. Most commonly, primary herpetic cervicitis is characterized by increased surface vascularity as well as microand macroulcerations with and without necrotic areas. Asymptomatic shedding of herpes virus occurs in the absence of cervical lesions.

Diagnosis MPC is confirmed when a Gram stained specimen of green or yellow endocervical exudate reveals more than 30 PMNs per high-power field. Microscopic examination of cervical mucus from a patient with mucopurulent endocervicitis reveals an overabundance of inflammatory cells obliterating the background ferning pattern. A similar excess of inflammatory cells can be found from Pap smear. These 2 microscopic studies are unreliable in identifying the underlying cause of MPC. For diagnosis of C. trachomatis cervicitis, in the past, culture techniques to identify the obligate intraparasites served as the gold standard. Even the more widely available enzyme-linked immunoabsorbent assay antigen detection tests have been replaced by the highly sensitive DNA amplification techniques, particularly ligase chain reaction, allowing diagnosis not only from cervical specimens but by screening urine specimens. Gram stain of cervical mucopus may reveal intracellular gram-negative diplococci but has low sensitivity and

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specificity in the diagnosis of gonococcal cervicitis. Diagnosis mainly relies on culture of the endocervix using a modified Thayer-Martin medium; however, diagnostic methodologies now include use of DNA probes especially for screening purposes, given the high sensitivity of these newer techniques. Although Papanicolaou smears in herpetic cervicitis are useful in revealing multinucleated giant cells, viral culture and fluorescein-conjugated monoclonal antibodies are the mainstay of clinical diagnosis. PCR is used for monitoring asymptomatic viral shedding in a research context. The differentiation of the various causes of cervicitis is not clinical but requires the aforementioned diagnostic tests recognizing that, frequently, more than 1 etiologic agent may be present simultaneously because many of the pathogens share risk factors and behavior. The most important diagnostic problem is that of overdiagnosis of cervicitis. All too frequently, despite the use of colposcopy, physiological changes in the appearance of the cervix are interpreted as reflecting pathologic cervicitis. Regrettably, after several failed attempts to identify pathogenic microorganisms, patients are needlessly treated with cervical ablative techniques. Often mistaken for cervicitis, cervical ectopy with eversion of endocervical columnar cells is common in healthy women, especially those on oral contraceptives (36). Other physiological changes related to childbirth and dilatation of the cervical canal are diagnosed as cervicitis. Equally important is the failure to recognize that a friable, abnormal cervix may reflect dysplasia and neoplasia. If the Papanicolaou smear reports inflammatory cells with or without atypia, the presence of ASCUS (atypical squamous cells of undetermined significance) is considered in differential diagnosis between a benign change in reaction to a stimulus and low-grade squamous intraepithelial lesions. Accordingly, women with a Papanicolaou smear showing ASCUS should have their smears repeated. Persistence of an ASCUS smear should prompt colposcopy or probing for HPV types predictive of cervical neoplasia.

Treatment Antimicrobial regimens of infectious cervicitis are discussed in the chapter dealing with Chlamydia and Neisseria gonorrhoeae infections and pelvic inflammatory disease (Chapter 16). Of note, quinolones are no longer recommended for the treatment of gonorrhea because of concerns about resistance.

REFERENCES 1. Kent HL. Epidemiology of vaginitis. Am J Obstet Gynecol. 1991;165:1168-76. 2. Holmes KK. Lower genital tract infections in women: Cystitis, urethritis, vulvovaginitis, and cervicitis. In: Holmes KK, Mardh P-A, Sparling PF, et al, eds. Sexually Transmitted Diseases. 2nd ed. New York, NY: McGraw Hill; 1990.

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3. Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol. 1993;169:450-4. 4. Eschenbach DA, Davick PR, Williams BL, Klebanoff SJ, Young-Smith K, Critchlow CM, et al. Prevalence of hydrogen peroxide-producing Lactobacillus species in normal women and women with bacterial vaginosis. J Clin Microbiol. 1989;27:251-6. 5. Fredricks DN, Fiedler TL, Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med. 2005;353:1899-911. 6. Hillier SL, Krohn MA, Cassen E, et al. The role of bacterial vaginosis and vaginal bacteria in amniotic fluid infection in women in preterm labor with intact fetal membranes. Clin Infect Dis. 1995;20(Suppl 2):276-8. 7. Platz-Christensen JJ, Sundström E, Larsson PG. Bacterial vaginosis and cervical intraepithelial neoplasia. Acta Obstet Gynecol Scand. 1994;73:586-8. 8. Myer L, Denny L,Telerant R, Souza M,Wright TC Jr., Kuhn L. Bacterial vaginosis and susceptibility to HIV infection in South African women: a nested case-control study. J Infect Dis. 2005;192:1372-80. 9. Centers for Disease Control and Prevention. 2002 Sexually transmitted diseases treatment guidelines. MMWR Morb Mortal Wkly Rep. 2002;51:22. 10. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N Engl J Med. 1995;333:1737-42. 11. Hauth JC, Goldenberg RL,Andrews WW, DuBard MB, Copper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med. 1995;333:1732-6. 12. Sobel JD, Ferris D, Schwebke J, Nyirjesy P, Wiesenfeld HC, Peipert J, et al. Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol. 2006;194:1283-9. 13. Spence MR, Hollander DH, Smith J, McCaig L, Sewell D, Brockman M. The clinical and laboratory diagnosis of Trichomonas vaginalis infection. Sex Transm Dis. 1980;7:168-71. 14. Wølner-Hanssen P, Krieger JN, Stevens CE, Kiviat NB, Koutsky L, Critchlow C, et al. Clinical manifestations of vaginal trichomoniasis. JAMA. 1989;261:571-6. 15. Wang CC, McClelland RS, Reilly M, Overbaugh J, Emery SR, Mandaliya K, et al. The effect of treatment of vaginal infections on shedding of human immunodeficiency virus type 1. J Infect Dis. 2001;183:1017-22. 16. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole-resistant vaginal trichomoniasis. Clin Infect Dis. 2001;33:1341-6. 17. Hager WD. Treatment of metronidazole-resistant Trichomonas vaginalis with tinidazole: case reports of three patients. Sex Transm Dis. 2004;31:343-5. 18. Sobel JD. Candidal vulvovaginitis. Clin Obstet Gynecol. 1993;36:153-65. 19. Spinillo A, Capuzzo E, Egbe TO, Baltaro F, Nicola S, Piazzi G. Torulopsis glabrata vaginitis. Obstet Gynecol. 1995;85:993-8. 20. Foxman B. The epidemiology of vulvovaginal candidiasis: risk factors. Am J Public Health. 1990;80:329-31. 21. Spinillo A, Capuzzo E, Acciano S, De Santolo A, Zara F. Effect of antibiotic use on the prevalence of symptomatic vulvovaginal candidiasis. Am J Obstet Gynecol. 1999;180:14-7. 22. Hooton TM, Roberts PL, Stamm WE. Effects of recent sexual activity and use of a diaphragm on the vaginal microflora. Clin Infect Dis. 1994;19:274-8. 23. Fidel PL Jr., Sobel JD. Immunopathogenesis of recurrent vulvovaginal candidiasis. Clin Microbiol Rev. 1996;9:335-48. 24. Spinillo A, Carrato L, Pizzoli G. Recurrent vulvovaginal candidiasis: Results of a cohort study of sexual transmission and intestinal reservoir. J Reprod Med. 1992;37:353-7. 25. Lynch ME, Sobel JD. Comparative in vitro activity of antimycotic agents against pathogenic vaginal yeast isolates. J Med Vet Mycol. 1994;32:267-74. 26. Fidel PL Jr., Lynch ME, Redondo-Lopez V, Sobel JD, Robinson R. Systemic cell-mediated immune reactivity in women with recurrent vulvovaginal candidiasis. J Infect Dis. 1993;168:1458-65. 27. Reef S, Levine WC, McNeil MM, et al. Treatment options for vulvovaginal candidiasis, background paper for development of 1993 STD treatment recommendations. Clin Infect Dis. 1995;20(Suppl 1):580-90. 28. Sobel JD, Brooker D, Stein GE,Thomason JL,Wermeling DP, Bradley B, et al. Single oral dose fluconazole compared with conventional clotrimazole topical therapy of Candida vaginitis. Fluconazole Vaginitis Study Group. Am J Obstet Gynecol. 1995;172:1263-8.

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29. Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol. 1998;178:203-11. 30. Sobel JD, Chaim W. Treatment of Torulopsis glabrata vaginitis: retrospective review of boric acid therapy. Clin Infect Dis. 1997;24:649-52. 31. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, et al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J Med. 2004;351:876-83. 32. Kiviat NB, Paavonen JA, Wølner-Hanssen P, Critchlow CW, Stamm WE, Douglas J, et al. Histopathology of endocervical infection caused by Chlamydia trachomatis, herpes simplex virus, Trichomonas vaginalis, and Neisseria gonorrhoeae. Hum Pathol. 1990;21:831-7. 33. Wald A, Zeh J, Selke S, Ashley RL, Corey L. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med. 1995;333:770-5. 34. Eltabbakh GH,Eltabbakh GD,Broekhuizen FF,Griner BT. Value of wet mount and cervical cultures at the time of cervical cytology in asymptomatic women. Obstet Gynecol. 1995;85:499-503. 35. Cates W Jr., Wasserheit JN. Genital chlamydial infections: epidemiology and reproductive sequelae. Am J Obstet Gynecol. 1991;164:1771-81. 36. Critchlow CW, Wölner-Hanssen P, Eschenbach DA, Kiviat NB, Koutsky LA, Stevens CE, et al. Determinants of cervical ectopia and of cervicitis: age, oral contraception, specific cervical infection, smoking, and douching. Am J Obstet Gynecol. 1995;173:534-43.

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Chapter 18

Papilloma Virus and Cervical Cancer JAMES FANNING, DO KATHRYN WRIGHT, MD BRADFORD W. FENTON, MD, PHD ROBERT F. FLORA, MD

Key Learning Points 1. Over 80% of high-grade intraepithelial neoplasia and cancers of the external genital tract are due to HPV 16 or 18. 2. The majority of genital warts are due to HPV 6 or 11. 3. Most HPV infections are asymptomatic and transient, usually resolving in 6-8 months. 4. Maximum prevalence occurs between ages 15 and 25 years. 5. At least 90% of young women and 50% of men who have intercourse will acquire HPV. 6. Main risk factors for progression of HPV infections into intraepithelial neoplasia or cancer are: early age of first intercourse, multiple sexual partners, smoking, immunosuppression (HIV) and men having sex with men. 7. Indications for HPV testing for high-risk HPV: ● Triage of screening PAP of ASC ● Screening PAP with HPV testing in women > 30 years ● A test for cure at 6 months after treatment of CIN 8. Treatment options for condyloma acumanata include: ● No treatment ● Patient-applied therapy ● Provider-applied therapies ● Surgical treatment 9. No prospective randomized trials have clearly shown that any one treatment for condyloma acumanata is superior. 10. HPV vaccine offers the best promise of effective HPV prevention. 352

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New Developments in the Management of Human Papillomavirus ●

●

The use of HPV testing for high-risk HPV: for follow-up of screening PAP of ASC, in addition to a screening PAP in women older than age 30 years; test for cure 6 months after treatment of CIN The development of HPV vaccines for the prevention of HPV associated intraepithelial neoplasia and cancer

Abbreviations: ASC = atypical squamous cells; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus.

H

uman papillomaviruses (HPVs) are DNA viruses associated with genital warts (condyloma acuminata), intraepithelial neoplasia and cancer of the female external genital tract (cervix, vagina and vulva), and the male external genital tract (penis and anus). Approximately 40 of the greater than 100 human papillomaviruses affect the external genital tract; the 4 most common are HPV 6, 11, 16, and 18 (1,2). More than 80% of highgrade intraepithelial neoplasia and cancers of the external genital tract are caused by HPV 16 or 18 (1,2). Most genital warts (condyloma acuminata) are caused by HPV 6 or 11 (1,2). Most HPV infections are transient with most men and women clearing their infection in 6 to 8 months (1,3,4).

Pathogenesis The ability of HPV infections to progress to intraepithelial neoplasia and cancer is caused by the incorporation of HPV DNA genes E6 and E7 into the human genome. HPV E6 and E7 interfere with tumor suppressor genes p53 and RB resulting in unregulated cell growth, intraepithelial neoplasia, and cancer (1,2). Histologically, the first sign of HPV infection is koilocytosis, which is described as perinuclear halos. Intraepithelial neoplasia develops as the HPV neoplastic process progresses. This is seen as abnormal maturation and atypia confined to the epithelium. Ultimately, intraepithelial neoplasia can progress to cancer with invasion through the epithelial basement membrane into the underlying stroma.

Epidemiology HPV is 1 of the most common sexually transmitted infections. Greater than 15% of the population or approximately 20 million people are infected with HPV (1,5). Maximum prevalence occurs between ages 15 and 25 years followed by a decrease until plateauing at age 35 years (1,5). At least 90% of young women and at least 50% of men who have intercourse will acquire

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HPV. The prevalence of HPV in men who have sex with men (MSM) is almost 100% (6). Genito-oral transmission is rare and neonatal transmission is infrequent (1). Although HPV infection is rampant, most infections are subclinical and transient with resolution in 6 to 8 months without treatment. Fewer than 1% of women with HPV infections will develop genital warts and 4% will develop cervical intraepithelial neoplasia (7). The lifetime risk of developing cervical cancer in the United States is less than 1% (7). Risks of vaginal and vulvar intraepithelial lesions and cancers are even lower. The incidence of anal intraepithelial neoplasia (AIN) and anal cancer has increased 2 to 3 times in the last 30 years. The main risk factors for progression of HPV infections into intraepithelial neoplasia or cancer are early age of first intercourse, multiple sexual partners, smoking, immunosuppression (HIV), and MSM. During puberty, the cervix undergoes metaplasia from a glandular to a squamous epithelium, and during this time the cervix is vulnerable to HPV. Early age of intercourse before age 15 years increases the relative risk of cervical cancer by 2.9 (8). An increased number of sexual partners increases a woman’s exposure to HPV and increases the odds of infection by an HPV to which she is not immunocompetent. Intercourse with 6 or more lifetime sexual partners increases the chance of developing cervical cancer by a relative risk of 2.1 (8). Smoking exposes the cervix to carcinogens, is immunosuppressive, and increases the relative risk of cervical cancer by 3.4 (9). Immunosuppression, such as in HIV or after transplantations, significantly increases the risk for HPV leading to intraepithelial neoplasia and cancer. HIV-seropositive women with CD4 counts less than 500/µL have an increased chance of developing cervical intraepithelial neoplasia (CIN) by a relative risk of 2.9 (10). HIV-seropositive MSM have a 95% prevalence of HPV infection and a 52% prevalence of high-grade AIN (6). HIV-seronegative MSM have a 5% prevalence of high-grade AIN (11).

Clinical Manifestations Condyloma Acuminata Condyloma acuminata appears most commonly on the vulvar and perianal area but may also infect the vagina and cervix. In men, condyloma acuminata appear most commonly on the penile shaft but may affect the glands, scrotum, or urethral meatus. Typical condyloma acuminata present as many wellcircumscribed exophytic cauliflower-like lesions (Table 18-1). Condylomas are usually approximately 5 mm in diameter but may be any size and in some instances may be so numerous that they form a confluent patch. Rather than the typical cauliflower-like lesions, condylomas may also be flat and sessile. The main presenting symptom of condyloma acuminata is pruritus.

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Table 18-1 Clinical Manifestations Condyloma Acuminata

Symptoms

Intraepithelial Neoplasia: VIN AIN CIN, VAIN

Pruritus Pruritus and bleeding Asymptomatic

Cancer: Vulvar

Cervical, vaginal

Anal

Physical Exam Multiple exophytic lesions

Brown, red, white raised lesion Brown, red, white raised lesion Needs colposcopy for visualization Postmenopausal pruritus ● Red, raised and exophytic or ulcerative ● Red, raised and exophytic or ulcerative ● Postcoital bleeding ● Postmenopausal bleeding ● Vaginal discharge ● Urological or intestinal symptoms ● Bleeding Red, raised and exophytic or ● Pruritus ulcerative ● Pain

Abbreviations: CIN = cervical intraepithelial neoplasia; VAIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia.

Intraepithelial Neoplasia Vulvar intraepithelial neoplasia (VIN) can present anywhere on the vulva. These lesions can be any color but are usually brown in premenopausal women and red or white in postmenopausal women. Typically the lesions are well circumscribed and raised. The most common presenting symptom of VIN is persistent, vulvar pruritus. CIN and vaginal intraepithelial neoplasia (VAIN) are routinely invisible to the naked eye. They can be visualized by the use of a colposcope after the application of acidic acid. During colposcopy, VAIN typically appears as a thickened, white, discrete lesion; and CIN appears as a thickened, white, discrete area, which may also have red blood vessels giving a punctation or mosaic tile–like appearance. Routinely, CIN and VAIN are asymptomatic and are picked up during PAP screening. Similar to VIN, anal intraepithelial neoplasia (AIN) can be any color but usually are red, well circumcised, and raised. The most common presenting symptoms of AIN are pruritus or bleeding.

Cancer The main symptoms of vulvar cancer are persistent, postmenopausal pruritus; bleeding; and pain. The lesions tend to be raised and exophytic or

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ulcerative. The lesions may be any color but are typically red. Cervical cancer typically presents with postcoital bleeding. Other symptoms may include postmenopausal bleeding or vaginal discharge. As cervical cancer progresses, it may cause pressure on the bladder or rectum resulting in urologic or intestinal symptoms. The terrible triad of advanced cervical cancer includes sciatic back pain, hydroureter, and leg swelling. Cervical cancers tend to be red and exophytic or ulcerative. Vaginal cancer typically presents with postmenopausal bleeding or postcoital bleeding. Symptoms caused by pressure on the bladder or rectum appear sooner than in cervical cancer. Vaginal cancers tend to be red and exophytic or ulcerative. The main symptoms of anal cancer are bleeding, pruritus, and pain. The lesions tend to be raised, exophytic, or ulcerative and are usually red.

Diagnosis Condyloma Acuminata Visual inspection is usually sufficient for diagnosis of genital warts. Biopsy is usually unnecessary unless the wart has an unusual appearance or grows despite adequate treatment. Unusual appearances of warts that may necessitate biopsy include atypical size or shape, unusual pigmentation, or a fixed or ulcerative lesion. To differentiate condyloma acuminata from a verrucous type of squamous cancer, the biopsy must be taken at the base of the lesion.

Intraepithelial Neoplasia The diagnosis of VIN and AIN is made by full thickness biopsy usually obtained using a dermal Keyes punch after local anesthesia is administered. Application of silver nitrate along with 5 to 10 minutes of direct pressure is usually sufficient to prevent hemorrhage. The diagnosis of CIN and VAIN is usually first suggested after PAP screening. PAP screen follow-up is shown in Table 18-2. A screening PAP result of squamous intraepithelial lesion, high grade, requires colposcopic examination for definitive diagnosis. Biopsy is required at colposcopy unless an excisional procedure (loop electrosurgical excision procedure [LEEP] or conization) is done for treatment. Colposcopic biopsy should not occur during pregnancy unless it is needed to rule out invasive cancer. Because a screening PAP result of squamous intraepithelial lesion— low-grade or ASC is rarely associated with a high-grade CIN (15% and 5%, respectively), colposcopy is not always required (12,13). A screening PAP result of squamous intraepithelial lesion, low grade, or ASC can be followed by repeat PAP in 3 to 6 months or colposcopic examination. Alternatively,

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Table 18-2 Pap Screening Follow-Up Pap

Normal ASC

Follow-Up

Repeat 1 year Repeat Pap in 6 months, or ● Colposcopy, or ● HPV testing for high risk HPV ●

ASC-H LGSIL

Colposcopy

HGSIL

Colposcopy

Comment

If HPV high risk positive: perform colposcopy ● If HPV high risk negative: repeat Pap in 1 year ● Alternate to colposcopy would repeat Pap in 6 months, especially in adolescence ● Do not perform HPV testing Do not perform HPV testing ●

Abbreviations: ASC = atypical squamous cells; HPV = human papillomavirus; HGSIL = high-grade squamous intraepithelial lesion; LGSIL = low-grade squamous intraepithelial lesion.

a screening PAP of ASC can be triaged by HPV testing for high-risk HPV types. If HPV testing is positive for high-risk HPV types (HPV 16 or 18), colposcopy should be done. If HPV testing is negative for high-risk HPV types, repeat PAP can be done in 1 year. HPV testing is not indicated for triage of a screening PAP of squamous intraepithelial lesion, low or high grade, because HPV testing is routinely positive in these cases. Other indications for HPV testing for high-risk HPV, besides its use in the management of ASC, are described in Table 18-3. Women older than 30 years can have HPV testing in addition to routine PAP screening; and if both are negative, screening can be repeated in 3 years rather than annually (12,14,15). Also, HPV testing can be used as a test of cure at 6 months after treatment of CIN2-3 (12,16).

Cancer Any tumor of the vulva, vagina, cervix, or anus suspicious for cancer should be biopsied.

Table 18-3 Indications for Human Papillomavirus Testing for High-Risk Human Papillomavirus ●

●

●

Triage of screening PAP of ASC; do not do HPV testing for triage of ASC-H, LGSIL, or HGSIL because HPV testing is routinely positive in these situations. Screening PAP with HPV testing in women older than age 30 years. If both tests are negative, screening PAP can be repeated in 3 years instead of annually. A test for cure 6 months after treatment of CIN with LEEP, laser cone, etc.

Abbreviations: ASC = atypical squamous cells; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HGSIL = high-grade squamous intraepithelial lesion; LEEP = loop electrosurgical excision procedure; LGSIL = low-grade squamous intraepithelial lesion.

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Treatment Condyloma Acuminata Treatment options for condyloma acuminata include no treatment, patientapplied therapy, provider-applied therapies, and surgical treatment (Table 184). Prospective studies have shown that up to 30% of warts will spontaneously resolve in 3 months; and therefore, no treatment with repeat evaluations is an option (17). There are no prospective randomly assigned trials, which have clearly shown that any 1 treatment is superior. The 2 most common patientapplied therapies are podofilox (0.5% solution or gel) and imiquimod (5% cream). These therapies have approximately a 70% cure rate with a 30% recurrence rate (17-19). Neither podofilox or imiquimod should be used during pregnancy. The most common physician-administered local therapies are podofilox resin (10%-25%) and trichloroacetic acid (80%-90%). The cure rates and recurrence rates are similar to patient-applied therapy (17-19). Surgical treatment includes cryotherapy, surgical excision, and laser ablation. Surgical treatment tends to have a slightly higher cure rate (approaching 90%) with similar recurrence rates compared to patient or physician applied therapies (17). A small percentage of patients treated with laser ablation develop postlaser severe pain, which can last for up to a month.

Intraepithelial Neoplasia Moderate to severe VIN should be treated with surgical excision (20). If microinvasive cancer can be ruled out, laser ablation is also appropriate. Lowgrade VIN can be treated with excision, laser ablation or close follow-up. Moderate to severe CIN can be treated with LEEP, knife conization, laser ablation, or cryotherapy. Prospective studies have shown similar cure rates with all modalities except for slightly inferior results with cryotherapy when treating large, high-grade lesions (21). An advantage of LEEP is that it is an office procedure and also obtains a pathologic specimen to rule out invasive cancer.

Table 18-4 Treatment of Genital Warts Treatment

Notes

Observation Patient-applied therapies ● Podofilox ● Imiquimod Physician-applied therapies ● Podofilox resin ● Trichloroacetic acid Surgical excision

30% regression rate ● ●

Podofilox: bid × 3 dqwk, total area 10 cm2 Imiquimod: qHS × 3 dqwk, total area 20 cm2

Abbreviations: bid = twice daily; d = day; HS = at bedtime; q = every; wk = week.

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Moderate to severe VAIN can be treated with surgical excision or laser ablation. Technically, excision of VAIN is more difficult than the excision of CIN (22). Low-grade CIN, VAIN, and VIN can be treated expectantly with close follow-up because up to 70% of these lesions will resolve spontaneously without treatment. Treatment of AIN is challenging. Surgical excision is the mainstay of treatment, but recurrence in HIV seropositive men is common (23).

Cancer Vulvar, vaginal, and cervical cancers should be treated using the modified Halsted philosophy of cancer surgery, which involves removing the tumor en bloc, with an adequate margin (usually 2 cm) and regional lymph nodes. For vulvar cancer this entails a modified radical vulvectomy with inguinal lymphadenectomy. For cervical cancer this requires a radical hysterectomy with pelvic lymphadenectomy. For vaginal cancer this requires a modified radical vaginectomy with pelvic lymphadenectomy. Advanced-stage cervical and vaginal cancers are treated with chemoradiation. Chemoradiation has replaced radical surgery (abdominoperineal resection with colostomy) as the initial treatment of anal cancer. 5-Fluoracil and mitomycin C or 5-fluorouracil and cisplatinum is administered concomitantly with external beam radiation (24).

Prevention Presently, the best HPV prevention measures are through sexual abstinence. Because this is not necessarily practical, an alternate strategy is emphasis on patient education about decreasing the risk factors for progression of HPV infections into intraepithelial neoplasias or cancers (Table 18-5). This includes delaying the onset of sexual debut; limiting the number of sexual partners, preferably remaining in a monogamous relationship; and avoiding cigarettes. Using condoms provides some protection against HPV transmission. HPV vaccine offers the best promise of effective HPV prevention if administered in preadolescence before their sexual debut. Presently, 2 large studies have been done, and early data indicated that the vaccines are highly effective in preventing persistent infection and CIN. In a study of more than 2000 women receiving an HPV 16 vaccine, no patients in the vaccine group developed persistent HPV infection versus 4% in the placebo group (25). Even more importantly, at 4-year follow-up, no patient in the vaccine group developed high-grade CIN versus 2% in the placebo group (26). In a study using a HPV 16 or 18 vaccine in more than 1000 women, 0.1% of patients who received the vaccine developed persistent infections versus 4% in the placebo group (27).

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Table 18-5 Patient Education on Human Papillomavirus Infection ●

● ●

● ●

● ● ●

● ●

HPV infection is very common. Almost all sexually active men and women are infected with HPV sometime in their lives. Most HPV infections are asymptomatic and resolve spontaneously. Reduce risk of developing HPV-related diseases by delaying sexual debut, limiting the number of sexual partners, not smoking, and using condoms. If both partners remain monogamous, rarely can partners reinfect each other. If a patient is in a monogamous relationship and develops HPV, it does not mean the partner cheated. The Pap test is an excellent screen for cervical cancer. Annual Pap screening decreases chances of dying from cervical cancer by 95%. Patients with persistent vulva or anal pruritus, a vulvar mass, anal bleeding, or postcoital bleeding should seek medical attention. Genital warts cannot be spread to other parts of the body. Genital warts in pregnancy rarely cause complications, rarely will the child be infected, and caesarean delivery is not useful in preventing HPV transmission to the baby.

Abbreviation: HPV = human papillomavirus.

REFERENCES 1. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Number 61, April 2005. Human papillomavirus. Obstet Gynecol. 2005;105:905-18. 2. International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518-27. 3. Franco EL,Villa LL, Sobrinho JP, Prado JM, Rousseau MC, Désy M, et al. Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis. 1999;180:1415-23. 4. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423-8. 5. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep. 2002;51(RR-6):1-78. 6. Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005;19:1407-14. 7. Lawson HW, Lee NC, Thames SF, Henson R, Miller DS. Cervical cancer screening among lowincome women: results of a national screening program, 1991-1995. Obstet Gynecol. 1998;92:745-52. 8. Herrero R, Brinton LA, Reeves WC, Brenes MM,Tenorio F, de Britton RC, et al. Sexual behavior, venereal diseases, hygiene practices, and invasive cervical cancer in a high-risk population. Cancer. 1990;65:380-6. 9. Slattery ML, Robison LM, Schuman KL, French TK, Abbott TM, Overall JC Jr., et al. Cigarette smoking and exposure to passive smoke are risk factors for cervical cancer. JAMA. 1989;261:1593-8. 10. Harris TG, Burk RD, Palefsky JM, Massad LS, Bang JY,Anastos K, et al. Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results. JAMA. 2005;293:1471-6. 11. Chin-Hong PV,Vittinghoff E, Cranston RD, Browne L, Buchbinder S, Colfax G, et al. Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst. 2005;97:896-905. 12. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin number 66, September 2005. Management of abnormal cervical cytology and histology. Obstet Gynecol. 2005;106:645-64.

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13. ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188:1393-400. 14. Sherman ME, Lorincz AT, Scott DR, Wacholder S, Castle PE, Glass AG, et al. Baseline cytology, human papillomavirus testing, and risk for cervical neoplasia: a 10-year cohort analysis. J Natl Cancer Inst. 2003;95:46-52. 15. Bory JP, Cucherousset J, Lorenzato M, Gabriel R, Quereux C, Birembaut P, et al. Recurrent human papillomavirus infection detected with the hybrid capture II assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women. Int J Cancer. 2002;102:519-25. 16. Wright TC Jr., Schiffman M, Solomon D, Cox JT, Garcia F, Goldie S, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103:304-9. 17. Beutner KR, Reitano MV, Richwald GA,Wiley DJ. External genital warts: report of the American Medical Association Consensus Conference. AMA Expert Panel on External Genital Warts. Clin Infect Dis. 1998;27:796-806. 18. Gunter J. Genital and perianal warts: new treatment opportunities for human papillomavirus infection. Am J Obstet Gynecol. 2003;189:S3-11. 19. Wiley DJ, Douglas J, Beutner K, Cox T, Fife K, Moscicki AB, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis. 2002;35:S210-24. 20. Modesitt SC, Waters AB, Walton L, Fowler WC Jr., Van Le L. Vulvar intraepithelial neoplasia III: occult cancer and the impact of margin status on recurrence. Obstet Gynecol. 1998;92:962-6. 21. Mitchell MF,Tortolero-Luna G, Cook E,Whittaker L, Rhodes-Morris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Am J Obstet Gynecol. 1998;92, S737-44. 22. Fanning J, Manahan KJ, McLean SA. Loop electrosurgical excision procedure for partial upper vaginectomy. Am J Obstet Gynecol. 1999;181:1382-5. 23. Chang GJ, Berry JM, Jay N, Palefsky JM,Welton ML. Surgical treatment of high-grade anal squamous intraepithelial lesions: a prospective study. Dis Colon Rectum. 2002;45:453-8. 24. Sato H, Koh PK, Bartolo DC. Management of anal canal cancer. Dis Colon Rectum. 2005;48:1301-15. 25. Proof of Principle Study Investigators. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645-51. 26. Mao C, Koutsky LA,Ault KA,Wheeler CM, Brown DR,Wiley DJ, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol. 2006;107:18-27. 27. GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364:1757-65.

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Part VI

Respiratory Tract Infections

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Chapter 19

Pharyngotonsillitis, Peritonsillar, Retropharyngeal, and Parapharyngeal Abscesses, and Epiglottitis ITZHAK BROOK, MD, MSC

Key learning points 1. Antimicrobials should be administered only to treat pharyngotonsillitis caused by Group A streptococci, documented by rapid test or culture. 2. Antimicrobials other than penicillins (e.g. cephalosporins, clindamycin) may be more efficacious in eradicating Group A streptococci. However, presently penicillin remains the recommended treatment for Group A streptococcal pharyngitis. 3. Most peritonsillar, retropharyngeal, and lateral pharyngeal abscesses are caused by polymicrobial aerobic-anaerobic flora. 4. The treatment of choice for oral cavity abscess is surgical drainage combined with the administration of parenteral antimicrobial therapy directed at the polymicrobial flora. 5. Complete airway obstruction is the major risk in acute epiglottitis. 6. The H. influenzae vaccine has decreased but not eliminated the number of epiglotittis due to infection with this organism.

Pharyngotonsillitis Pharyngotonsillitis (PT) is characterized by the presence of increased redness and an exudate or ulceration in the pharynx or tonsil or a membrane that covers the tonsils. Because the pharynx is served by lymphoid tissues of Waldeyer ring, an infection can spread to include various parts of the ring, such as the nasopharynx, uvula, soft palate, tonsils, adenoids, and 365

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Box 19-1 New Developments in the Management Streptococcal Infection ● ● ● ●

Group A streptococci resistance to the macrolides is growing. Penicillin failure rate in eradicating group A streptococci may reach up to 35%. Toothbrushes may serve as a source of reinoculation of group A streptococci. Anaerobic bacteria may be involved in nonstreptococcal tonsillitis.

cervical lymph glands (1,2). Based on its extent, the infection can be called pharyngitis, tonsillitis, tonsillopharyngitis, or nasopharyngitis. Furthermore, any of these illnesses can be acute, subacute, or recurrent.

Etiology The finding of PT generally requires the consideration of infection with group A β-hemolytic streptococci (GABHS); however, many other bacteria, viruses, other infectious agents, and noninfectious causes should be considered sources of PT (1). Recognizing the causative agent(s) and choosing appropriate therapy are of the utmost importance in ensuring a rapid recovery and for preventing complications. The different agents that cause PT and the characteristic clinical features they produce are shown in Table 19-1. The occurrence of a particular etiologic agent depends on numerous variables, including environmental conditions (e.g., season, geographic location, exposure) and individual variables (e.g., age, host resistance, immunity). The most prevalent agents responsible for PT are GABHS, adenoviruses, influenza and parainfluenza viruses, Epstein-Barr virus, and enteroviruses. However, the precise cause is generally not measured, and the role of some potential pathogens is uncertain. Recent studies have suggested that interactions between various organisms, including GABHS, other aerobic and anaerobic bacteria, and viruses, may occur during PT. Some interactions may be synergistic (e.g., the relationship between Epstein-Barr virus and anaerobic bacteria) (3), thus enhancing the virulence of some pathogens. Others may be antagonistic (e.g., the relationship between GABHS and certain interfering β-hemolytic streptococci) (4). Furthermore, β-lactamase–producing bacteria (BLPB) can protect themselves and other bacteria from β-lactam antibiotics (5).

Aerobic Bacteria Infection with GABHS is the most common bacterial cause of PT. It is an endemic infection, peaks in late winter and early spring, is rare in children younger than 2 years of age, and generally occurs in children 5 to 11 years of age. However, people of all ages are susceptible. Non-GABHS organ-

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Table 19-1 Infectious Agents of Pharyngotonsillitis Organism

Bacteria Aerobic Groups A, B, C, and G streptococci Streptococcus pneumoniae Staphylococcus aureus Neisseria gonorrhoeae Neisseria meningitidis Corynebacterium diphtheriae Corynebacterium haemolyticum Arcanobacterium haemolyticum Bordetella pertussis Haemophilus influenzae Haemophilus parainfluenzae Salmonella typhi Francisella tularensis Yersinia pseudotuberculosis Treponema pallidum Mycobacterium spp. Anaerobic Peptostreptococcus spp. Actinomyces spp. Pigmented Prevotella and Porphyromonas spp. Bacteroides spp. Mycoplasma Mycoplasma pneumoniae Mycoplasma hominis Viruses and Chlamydia Adenovirus Enteroviruses (e.g., poliovirus, echovirus, coxsackie virus) Parainfluenza virus types 1–4 Epstein–Barr virus Herpesvirus hominis Respiratory syncytial virus Influenza virus A and B Cytomegalovirus Rheovirus Measles virus Rubella virus Rhinovirus Chlamydia trachomatis and C. pneumoniae Fungi Candida spp. Parasites Toxoplasma gondii Rickettsia Coxiella burnetii

Clinical Lesions

Clinical Frequency

Er, E Er, Er, Er, Er, Er, Er, Er, Er, Er, Er Er, Er Er, Er

Ex, F, P

A C C C C C C C C C C C C C C C

Er, Er, Er, Er,

E U Ex, U Ex, U

C C C C

Er, Ex, F Er, Ex

B C

Er, Ex, F Er, Ex, U

A A

Er Er, Ex, F Er, Ex, U Er Er Er Er Er, P P Er Er

A B C C A C C C C C C

Er, Ex

B

Er

C

Er

C

Ex, F Ex Ex Ex Ex Ex Ex Ex Ex Ex F

A = most frequent (>66% of cases); B = frequent (33%–66% of cases); C = uncommon (<33% of cases); Er = erythematous; Ex = exudative; F = follicular; U = ulcerative; P = petechial.

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isms are more often obtained from adults than from children with PT. Crowded settings are a risk factor for the transmission of the organisms responsible for PT. Infection with GABHS can have many, potentially suppurative and nonsuppurative, complications. Suppurative complications include peritonsillar abscess, retropharyngeal cellulitis and abscess, cervical adenitis, otitis media, mastoiditis, sinusitis, and bacteremia. Nonsuppurative complications include acute rheumatic fever, acute glomerulonephritis, scarlet fever, and toxin-mediated streptococcal shock syndrome. Because of the potential for serious suppurative and nonsuppurative sequelae of GABHS infection, these organisms are the best known cause of sore throat (1); however, groups B, C, and G β-hemolytic streptococci also occasionally are responsible for pharyngitis (6-11). PT caused by all types of streptococci generally has an identical clinical presentation, characterized by exudation, petechiae, and follicles (11). Streptococcal tonsillitis can be a serious illness because of the occurrence of rheumatic fever and the increased virulence of GABHS noted in recent years (10). Increased numbers of cases of streptococcal sepsis and toxic shock syndrome have been seen in the past decade. Streptococci also can be involved in suppurative complications of tonsillitis, such as peritonsillar and retropharyngeal abscesses. Less common causes of PT are described in the ensuing discussion. Streptococcus pneumoniae can be involved in PT that can either subside or spread to other sites. Corynebacterium diphtheriae and Corynebacterium haemolyticum cause an early exudative PT with a thick, grayish-green membrane that may be difficult to dislodge and often leaves a bleeding surface when removed. The infection can spread to the throat, palate, and larynx. C. haemolyticum produces a lethal systemic exotoxin (1). The incidence of PT caused by Arcanobacterium haemolyticum is from 2.5% to 10% and occurs mainly in individuals 15 to 18 years of age (12). Approximately half of affected patients have a scarlatiniform rash. Neisseria gonorrhoeae is commonly present in homosexual men and also can be detected in adolescents with pharyngitis. PT infection caused by this organism is often asymptomatic but may result in bacteremia and can persist after treatment. Neisseria meningitidis can cause symptomatic or asymptomatic PT that can be a prodrome of septicemia or meningitis. Nontypable Haemophilus influenzae and Haemophilus parainfluenzae can be recovered from inflamed tonsils. These organisms can cause invasive disease in infants and elderly persons, as well as acute epiglottitis, otitis media, and sinusitis. The role of Staphylococcus aureus in PT is unclear. S. aureus is often recovered from chronically inflamed tonsils and peritonsillar abscesses and can produce β-lactamase, which may interfere with the eradication of GABHS (5). Rare causes of PT are Francisella tularensis, Treponema pallidum, Mycobacterium species, and Toxoplasma gondii.

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Mycoplasma Both Mycoplasma pneumoniae and M. hominis can cause PT, usually as a manifestation of a generalized infection. The prevalence of Mycoplasma infection increases with age. Anaerobic Bacteria The anaerobic organisms that have been implicated in PT are species of Actinomyces, Fusobacterium, and pigmented Prevotella and Porphyromonas (13). Several observations support the role of anaerobic bacteria in acute PT, including the following: ●

●

●

●

●

Anaerobes outnumber their aerobic counterparts in the oral flora in a 100-to-1 ratio (14). Anaerobes (e.g., Prevotella, Porphyromonas, Fusobacterium species and spirochetes) are predominant in tonsillar or retropharyngeal abscesses (Prevotella, Porphyromonas, Fusobacterium species) (15) and cause Vincent angina (Fusobacterium species and spirochetes) (16). Encapsulated, pigmented Prevotella and Porphyromonas species have been isolated in greater numbers from acutely inflamed tonsils than from normal tonsils (17) and were recovered from the cores of recurrently inflamed, non–GABHS-infected tonsils (18). Patients with non–GABHS tonsillitis (e.g., including those with infectious mononucleosis) responded to antibiotics directed only against anaerobes (metronidazole) (18a,18b). Increased serum levels of antibodies to Prevotella intermedia and Fusobacterium nucleatum have been found in patients with infectious mononucleosis (3) recurrent non–GABHS tonsillitis (18c) and in those with peritonsillar cellulitis and abscess (19).

Viruses and Chlamydia The viruses known to cause PT are adenoviruses, parainfluenza viruses, enteroviruses (e.g., coxsackie A virus), Epstein-Barr virus, herpes simplex viruses, respiratory syncytial virus, and cytomegalovirus (1). Chlamydia pneumoniae may cause pharyngitis, which often accompanies pneumonia or bronchitis. Chlamydia trachomatis has been associated with nasopharyngeal infections and pneumonia in infants and with PT in individuals who have engaged in fellatio.

Clinical Manifestations Generally of sudden onset, PT exhibits fever, sore throat, nausea, vomiting, headache, and, rarely, abdominal pain. Redness of the throat and tonsils is

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seen at an early stage, and the cervical lymph glands become enlarged. The clinical manifestations may vary with different etiologic agents (Table 19-1) but are rarely specific to a particular agent. Erythema is common to most agents, but the occurrence of ulceration, petechiae, exudation, or follicles is variable (2). The common features of PT caused by specific etiologic agents are exudative pharyngitis in GABHS infection, ulcerative lesions in enterovirus infection, and membranous pharyngitis in C. diphtheriae infection. Petechiae often can be seen in GABHS, Epstein-Barr virus, measles virus, and rubella virus infections. Viral PT is generally self-limited (lasting 4 to 10 days) and associated with the presence of nasal secretions. Bacterial illness lasts longer if untreated. The unique features of anaerobic tonsillitis or PT are the enlargement and ulceration of the tonsils in association with a fetid or foul odor and the presence of Fusobacterium species, spirochetes, and other organisms seen with Gram stain (16).

Diagnosis Clinical Evaluation Commonly, antimicrobial therapy is indicated only for PT that is caused by GABHS; therefore, it must be determined clinically whether the infection is caused by this organism. Patients with acute PT caused by GABHS are between 5 and 11 years of age, present with infection during late winter and early spring, and generally have a sudden onset of sore throat, fever, and pain on swallowing (11). Younger members of this group typically have nausea, vomiting, abdominal pain, and headache and may have a PT exudate and/or cervical lymphadenitis (1). Palatal petechiae, a scarlatiniform rash, and a red, swollen uvula may be present (2). However, these findings are not specific for GABHS infection and can occur with other organisms, including viruses. Laboratory Evaluation Testing for the presence of GABHS should be considered when the clinical picture suggests that GABHS is present, that potential contact with a documented case of GABHS infection has occurred, or that the prevalence of GABHS infection in the community is high. Testing is not recommended in asymptomatic individuals at the conclusion of therapy. Scoring systems for predicting GABHS infection are accurate only in up to 80% of cases (11,20). Throat culture (with a specimen obtained by throat swabbing of both tonsillar surfaces and the posterior pharyngeal wall and plated on sheep blood agar media) is the standard laboratory test for the diagnosis of PT. Incubation under anaerobic conditions and the use of selective media can increase the recovery rate of pathogens (21,22). A single throat culture has a sensitivity of 90% to 95% for GABHS in the pharynx. False-negative results can occur in

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patients who have received antibiotics. Identifying GABHS by direct growth may take 24 to 48 hours. Reexamination of culture plates at 48 hours is advisable (23). Use of a Bacitracin disk provides presumptive identification through the absence of growth (24,25). Attempts to identify β-hemolytic streptococci other than those of group A may be worthwhile in older individuals (7-9). Commercial kits that contain group-specific antisera are available for identifying the specific group to which a streptococcal pathogen belongs (26). More than 10 colonies of GABHS per plate are considered to represent a true infection as opposed to a colonization. However, using the number of colonies of GABHS on the plate as an indicator for the presence of true infection may fail to yield reliable results, because there is an overlap between carriers and infected individuals (26). An increase in the titer of antistreptococcal O (ASO) antibody after 3 to 6 weeks can provide retrospective evidence for GABHS infection and can assist in differentiating between such infection and the carrier state (1). Determining the ASO titer is indicated when there is a need to prove the occurrence of GABHS infection. Rapid methods of identification for GABHS take 10 to 60 minutes. Although more expensive than routine culture, they allow the rapid initiation of therapy and the reduction of illness (27-30). However, these rapid methods have a 5% to 15% rate of false-negative results (31,32). Consequently, it is recommended that a bacterial culture be done in instances in which a rapid streptococcal test result is negative. Other pathogens should be identified in specific situations, either when no GABHS is found or when a search for other organisms is warranted. Because many of the other PT-causing pathogens are part of the normal pharyngeal flora, interpreting the findings in such cases is difficult. Attempts to identify corynebacteria should be made whenever a membrane is present in the throat. Cultures should be obtained from beneath the membrane using a special moisture-reducing transport medium. A Loeffler slant, sodium tellurite plate, and blood agar plate all should be inoculated. Corynebacteria also may be identified by the fluorescentantibody technique. Both viral culture methods and rapid tests for some viruses (e.g., respiratory syncytial virus) are available. A positive heterophil slide test or other rapid tests for detection of specific antibodies for Epstein-Barr virus can provide a specific diagnosis for infectious mononucleosis.

Treatment Many antimicrobial agents are available for treating PT caused by GABHS (26); however, the recommended optimal treatment of GABHS infection is penicillin administered 3 times daily for 10 days (Table 19-2 and Table 19-3). Oral penicillin-VK is used more often than is intramuscular benzathine penicillin-G

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Table 19-2 Ten-Day Oral-Antibiotic Treatment Course for Acute Pharyngotonsillitis Caused by Group A Beta-Hemolytic Streptococci Dosage Generic Name

Pediatric (mg/kg/d)

Adult (mg/dose)

Frequency (hours)

25–50 25–50 25–50 30 40 30 10 30 8 9 40 12 15 45 25–50

250 250 250 500 250 250 500 250 400 400 250 250‡ 500 875 150

q 6–8 q8 q 6–8 q 12 q8 q 12 q 12 q 12 q 24 q 24 q 8–12 q 24 q 12 q 12 q 6–8

Penicillin-V Amoxicillin Cephalexin* Cefadroxyl* Cefaclor* Cefuroxime-axetil* Cefpodoxime-proxetil* Cefprozil* Cefixime Ceftibuten Erythromycin estolate§ Azithromycin† Clarithromycin Amoxicillin-clavulanate¶ Clindamycin¶

* Also effective against aerobic beta-lactamase–producing bacteria. † Also effective against aerobic and anaerobic beta-lactamase–producing bacteria. ‡ First-day dose is 500 mg. § For Corynebacterium diphtheriae. ¶ Duration of therapy is 5 days.

Table 19-3 Oral Antimicrobials in Treatment of Tonsillitis Caused by Group A Beta-Hemolytic Streptococci* First-line therapy Second-line therapy

Acute

Recurrent or Chronic

Carrier State

Penicillin or amoxicillin Cephalosporins†, clindamycin, amoxicillin– clavulanate, or macrolides‡

Clindamycin or Clindamycin or amoxicillin–clavulanate penicillin + Metronidazole + rifampin macrolide or penicillin + rifampin

* For dosages and length of therapy, see Table 19-2. † All generations. ‡ GABHS may be resistant.

(20). However, intramuscular penicillin can be given to ensure compliance or as initial therapy to patients who cannot tolerate oral medication. Several classes of antimicrobial agents have been used to treat GABHS tonsillitis successfully. An alternative to penicillin is amoxicillin, which is as active against GABHS but has characteristics that give it a theoretical advantage (e.g., a more reliable absorption, higher blood-level yields, a longer plasma half-life, lower protein binding). Furthermore, oral liquid amoxicillin gives better compliance than oral penicillin (because of its more pleasing taste). However, amoxicillin should not be used in patients suspected of having infectious mononucleosis, in whom it can produce a skin rash.

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Alternative agents for treating acute GABHS tonsillitis are the macrolides. However, in countries in which these drugs have had extensive use, GABHS resistance to them has increased, reaching as high as 70% (33). The level of resistance of GABHS to macrolides in the United States is 5% to 10%. Of concern is the increased levels of macrolide-resistant GABHS in focal regions of the United States (33a), which peaked at a clonal outbreak of erythromycin resistance in pharyngeal isolates of group A streptococci in Pittsburgh where 48% of the isolates were resistant (33b). It is, therefore, advisable to limit the use of macrolides to patients with true allergy to penicillins. Compliance with the newer macrolides (clarithromycin and azithromycin) is better than that with erythromycin because of their longer half-lives and fewer adverse gastrointestinal side effects. All generations of oral cephalosporins have been found to be as effective as penicillin (or more so) for treating acute GABHS tonsillitis (34). The clinical failure rate with penicillin is 10% to 15%, and cephalosporins fail in 5% to 8% of cases. The greater efficacy of the cephalosporins against GABHS may be caused by their activity against aerobic BLPB such as S. aureus and Haemophilus species. Another possible reason for the greater efficacy of the cephalosporins is that the nonpathogenic αhemolytic streptococci that compete with GABHS and help to eliminate them are more resistant to cephalosporins than they are to penicillin (35,36). Therefore, these streptococci are more likely to survive cephalosporin therapy (36a). The duration of therapy for acute tonsillitis with antimicrobial agents other than penicillin has not been measured in large, comparative, controlled studies. However, certain new agents have been administered in short courses of 5 or more days (37). Until a large number of comparative studies are done, it is safe to use the same 10-day duration of therapy as with penicillin (Table 19-2 and Table 19-3). Early initiation of antimicrobial therapy results in faster resolution of signs and symptoms of disease (2628). However, the spontaneous disappearance of fever and other symptoms occurs generally within 3 to 4 days after their onset even without antimicrobial therapy (37). Furthermore, acute rheumatic fever can be prevented even when therapy is postponed for up to 9 days (37). When C. diphtheriae infection is suspected, erythromycin is the drug of choice (penicillin or rifampin are alternatives). Supportive therapy for PT includes giving antipyretic and analgesic agents (e.g., aspirin, acetaminophen) and ensuring proper hydration of the patient.

Recurrent and Chronic Tonsillitis Studies have documented bacteriologic failure rates of 37% or more in penicillin-treated patients with acute GABHS tonsillitis and even higher rates in retreatment (38). Although approximately half of all patients who harbor GABHS after therapy may be carriers, the remainder still may

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show signs of infection and may represent true cases of clinical failure (39). The greater failure rates with penicillin have necessitated the consideration of alternative therapies for patients in whom penicillin therapy has failed. Carriers harbor GABHS but have no immune response to these organisms (39). During the winter and spring, up to 20% of asymptomatic schoolage children may be carriers of GABHS. They are less likely to spread these organisms and suffer from complications of GABHS infection. Carriers of GABHS generally do not require antimicrobial therapy (39, 40). Exceptions include those who may spread the infection and those who have had a complication (e.g., rheumatic fever). It is often difficult to differentiate a carrier of GABHS from an infected individual. Antimicrobial agents that are effective in eradicating the carrier state are clindamycin and penicillin plus rifampin (Table 19-3) (39). Penicillin failure in eradicating PT caused by GABHS can have any of several explanations (Table 19-4). These include noncompliance with a 10-day course of therapy; existence of the carrier state (40); reinfection; bacterial internalization (41); bacterial interference (4,36); presence of Moraxella catarrhalis, which can enhance the colonization with GABHS through the mechanism of coaggregation (42a); and penicillin tolerance (42). Another explanation is that repeated penicillin administration shifts the balance among the oral microflora, with the selection of β-lactamase–producing bacteria (BLPB) such as S. aureus, Haemophilus species, M. catarrhalis, Fusobacterium species, pigmented Prevotella and Porphyromonas species, and Bacteroides species (5). That BLPB were recovered more often from patients treated with penicillin and from their household contacts suggests a possible transfer of these organisms within families (43). The organisms persisted in the oral flora of more than a quarter of treated children for as long as 3 months after the initial finding (43a). The recovery rate of BLPB infection in the community is highest during the winter season and in persons who have had recent antimicrobial therapy (44).

Table 19-4 Possible Reasons for Antibiotic Failure or Relapse in Tonsillitis Caused by Group A Beta-Hemolytic Streptococci Presence of beta-lactamase–producing oral microflora Resistance (e.g., erythromycin) or tolerance (e.g., penicillin) to antibiotic Inadequate bacterial interference or production of bacteriocins by oral flora (generally by alpha-hemolytic streptococci) Bacterial internalization Inappropriate dose, duration of therapy, or choice of antibiotic Poor compliance with taking medication Reacquisition from close contact or a fomite Carrier state, not disease

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It is possible that BLPB protects GABHS from penicillin by inactivating the antibiotic (5). Such organisms, present within the tonsils, could degrade penicillin in the area of the infection, thereby protecting not only themselves but also penicillin-susceptible pathogens such as GABHS. Thus, penicillin therapy directed against a susceptible pathogen might be rendered ineffective. An increase in the in vitro resistance of GABHS to penicillin was seen when GABHS was inoculated with S. aureus, Haemophilus species, and pigmented Prevotella and Porphyromonas species (5). Bacteroides species protected a penicillin–sensitive GABHS from penicillin therapy in mice (45); however, both clindamycin and the combination of penicillin and clavulanic acid (a β-lactamase inhibitor), which are active against both GABHS and anaerobic gram-negative bacilli, were effective in eradicating the infection. Considerable clinical data support the role of BLPB in the failure of recurrent streptococcal tonsillitis to respond to penicillin therapy. Also supporting this theory is a correlation between colonization with BLPB before the administration of penicillin therapy and failure to respond to penicillin. Approximately one quarter of individuals who respond to penicillin harbored BLPB before penicillin therapy was begun, whereas almost 70% of patients in whom penicillin had failed carried BLPB before therapy (46). If sufficient amounts of β-lactamase are excreted into the tonsillar tissue, streptococci would be surrounded by enough enzyme to shield them from β-lactam antibiotics. In other studies, aerobic and anaerobic BLPB were recovered from more than three fourths of tonsils removed from patients with recurrent GABHS tonsillitis (13,47-49), and β-lactamase activity was detected in extracts of tonsillar tissues (50). Several clinical studies demonstrated the superiority of lincomycin, clindamycin (51), and amoxicillin-clavulanic acid (38) over penicillin. Antimicrobial agents are effective against aerobic as well as anaerobic BLPB and GABHS in eradicating recurrent tonsillar infection. However, no studies have shown these agents to be superior to penicillin in treating acute tonsillitis. Other drugs that may be effective in treating recurrent tonsillitis are either the combination of penicillin plus rifampin or a macrolide (e.g., erythromycin) plus metronidazole (Table 19-3).

Peritonsillar, Retropharyngeal, and Lateral Pharyngeal Abscesses Peritonsillar, retropharyngeal, and lateral pharyngeal abscesses are deep neck infections that generally result from the contiguous spread of infection from local sites. They share some clinical features but have distinct manifestations and complications (Table 19-5). All 3 types of abscess are potentially life threatening if not recognized early.

Pharyngitis, trauma, dental infection

Usually <4 years

Older children, Tonsillitis, otitis adolescents, media, masadult toiditis, parotitis, dental manipulation

Retropharyngeal abscess

Lateral pharyngeal abscess

Sites of Origin

Tonsillitis

Age

Peritonsillar abscess Adolescents, adults

Abscess Type

Complications/ Extension Site

Management

Spontaneous rupture Antibiotic, and aspiration, surgical spread to pterygodrainage maxillary space Spontaneous rupture Antibiotics, and aspiration, surgical spread to posterior drainage, mediastinum and/ artificial or parapharyngeal airway space Anterior and posterior Anterior compartment: Carotid erosion; Antibiotics, pharyngomaxillary swelling of parotid airway obstruction; surgical space area, trismus, prolapse spread intracradrainage, of the tonsil/ nially, to lung, to artificial tonsillar fossa mediastinum; airway septicemia Posterior compartment: septicemia; minimal pain or trismus

Clinical Findings

Tonsillar capsule Swelling on one and space below tonsil, displacement superior constrictor of the uvula, trismus, muscle muffled voice Between posterior Unilateral posterior pharynx and pharyngeal bulging, prevertebral fascia hyperextension of the neck, drooling, respiratory distress

Location

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Table 19-5 Clinical Features of Peritonsillar, Retropharyngeal, and Pharyngeal Abscesses

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Etiology Most deep abscesses are caused by polymicrobial infections; the average number of isolates from such lesions is 5 (range 1-10) (52-58). Predominant anaerobic organisms recovered in peritonsillar (56-57), lateral pharyngeal (55,58), and retropharyngeal (54,58) abscesses are Prevotella, Porphyromonas, Fusobacterium, and Peptostreptococcus species; aerobic organisms are group A streptococci (e.g., S. pyogenes), S. aureus, and H. influenzae. Anaerobic bacteria can be isolated from most abscesses, whereas S. pyogenes is isolated in only approximately one third of cases (53-58). More than two thirds of deep neck abscesses contain BLPB (53-55). Fusobacterium necrophorum is especially associated with deep neck infections that cause septic thrombophlebitis of great vessels and metastatic abscesses (Lemierre syndrome) (59,60). Rarely, Mycobacterium tuberculosis (61), atypical mycobacteria, or Coccidioides immitis (62) is isolated. Specimens should be collected during surgical drainage and should be transported, inoculated, and incubated to optimize the recovery of aerobic and anaerobic organisms.

Antimicrobial Therapy The recovery of BLPB from most abscesses mandates the use of antimicrobial agents effective against these organisms. BLPB include Prevotella, Fusobacterium, Haemophilus, and Staphylococcus species. Antimicrobial agents with expected efficacy include cefoxitin, a carbapenem (e.g., imipenem, meropenem), the combination of penicillin (e.g., ticarcillin) and a β-lactamase inhibitor (e.g., clavulanate), chloramphenicol, or clindamycin (Table 19-6). The duration of therapy varies from 7 to 21 days and can be reduced in the presence of adequate drainage. Antimicrobial therapy can abort abscess formation if given at an early stage of infection. However,

Table 19-6 Antimicrobial Agents with Expected Efficacy in Treatment of Oropharyngeal Abscesses* Cefoxitin (from 1 g every 8 hours to 2 g every 4 hours IM or IV) Cefotetan (1–3 g every 12 hours IV) Clindamycin (0.30–0.45 g every 6 hours PO or 600–900 mg every 8 hours IV or IM) Metronidazole (7.5 mg/kg every 6 hours; maximum 4 g/d IV or PO) plus β-lactam–resistant penicillin (e.g., oxacillin 1–2 g every 4 hours IV or IM) A carbapenem (e.g., imipenem 0.5 g every 6 hours IV, meropenem 0.5–1.0 g every 8 hours IV) A combination of a penicillin (e.g., amoxicillin 875 mg every 12 hours PO, ampicillin 1.5–3.0 g every 6 hours IV, piperacillin 3.375 g every 6 hours IV) and a betalactamase inhibitor (e.g., clavulanate, sulbactam, tazobactam) Chloramphenicol (50 mg/kg IV) IM = intramuscularly; IV = intravenously; PO = orally. * Adult dosages.

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when pus has formed, antimicrobial therapy is effective only in conjunction with adequate surgical drainage.

Peritonsillar Abscess (Quinsy) Peritonsillar abscess is the most common deep head and neck infection. It generally occurs in adolescents and adults as a complication of repeated episodes of bacterial tonsillitis; it can occur infrequently as a secondary complication of viral infection, such as infectious mononucleosis. The most common location is the superior pole of the tonsil.

Clinical Manifestations A peritonsillar abscess is often preceded by acute PT; either an afebrile interval of a few days can occur or fever from the primary infection can persist. Quinsy is usually unilateral. The patient can be apprehensive and pale, and temperature and pulse rate may increase (often after a rigor). There is difficulty in swallowing and/or speaking. Pain increases in severity, radiates to the ear, and causes trismus resulting from spasm of the pterygoid muscle. The breath has a foul odor, and saliva may dribble from the mouth. The tonsil is swollen and inflamed, but the soft palate does not bulge. The uvula is edematous and pushed toward the opposite side. The involved tonsil is usually hidden by the swelling but can have some mucopurulent secretions on its surface. Ipsilateral cervical lymph nodes are enlarged and tender. When the peritonsillar abscess has developed, there is acute pain on 1 side of the throat and considerable constitutional disturbance. If not reversed by antibiotic therapy or surgical drainage, the abscess can leak slowly or burst, possibly leading to aspiration. Treatment The treatment of choice for a peritonsillar abscess is needle aspiration of the abscess under topical anesthesia combined with the administration of parenteral antimicrobial therapy. The antimicrobial agents used in this treatment are discussed in the Antimicrobial Therapy section earlier in this chapter and outlined in Table 19-6. Emergency tonsillectomy is also an option. Patients with peritonsillar abscess and a history of recurrent tonsillitis should be considered for tonsillectomy after the acute episode subsides (63).

Retropharyngeal Abscess A retropharyngeal abscess often follows bacterial pharyngitis or nasopharyngitis. Rarely is it an extension of vertebral osteomyelitis, the result of a wound infection after a penetrating injury of the posterior pharynx, or a complication of endoscopy, a dental procedure, or other medical or surgical trauma.

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Clinical Manifestations The patient with a retropharyngeal abscess generally suffers first from acute pharyngitis or nasopharyngitis with a high fever of sudden onset; difficulty in swallowing; and associated drooling, dysphagia, dyspnea, and neck pain and hyperextension. Usually, anterior bulging of the posterior pharyngeal wall is seen, often to 1 side of the midline. Nasal obstruction can follow, and signs of difficulty in breathing can dominate the clinical picture (Table 19-5). Cervical lymphadenopathy is often present (64). The oropharynx can be examined carefully only in a cooperative patient. Using indirect (mirror) hypopharyngeal inspection and digital palpation, the patient should be examined in the Trendelenburg position; adequate suction equipment should be available in the event that the abscess ruptures. A lateral radiograph of the nasopharynx and neck may reveal the retropharyngeal mass. Chest radiography can identify extension into the mediastinum. Computed tomography with contrast medium may distinguish neck cellulitis from deep neck abscess and may identify the extension of an abscess and any involvement of vascular structures. The differential diagnosis of retropharyngeal abscess includes cervical osteomyelitis, meningitis, Pott disease, and calcified tendonitis of the longus colli muscle. Treatment Drainage of a retropharyngeal abscess and the intravenous administration of antimicrobial agents are needed (65). The agents used in this therapy are discussed in the Antimicrobial Therapy section earlier in this chapter and are outlined in Table 19-6. Most abscesses can be evacuated by peroral incision and suction. External incision is rarely required but is often needed when the abscess is longitudinally extensive or when fever persists after peroral drainage. Tracheostomy may be needed when the risk of airway obstruction is great. Complications of a retropharyngeal abscess include aspiration, extension of infection to the side of the neck, and dissection into the posterior mediastinum. Death can occur from aspiration, obstruction of the airway, erosion into major blood vessels, or extension to the mediastinum.

Lateral Pharyngeal Abscess Involvement of the lateral pharyngeal (anterior and posterior pharyngomaxillary) space determines the clinical manifestations and complications of abscesses in these locations.

Clinical Manifestations Infection of the lateral pharyngeal space can be the result of tonsillitis, pharyngitis, otitis media, mastoiditis (Bezold abscess), parotitis, or dental infections (usually of the mastication space).

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Infection in the anterior compartment usually is accompanied by high fever, chills, tender swelling below the angle of the mandible, induration and erythema of the side of the neck, and trismus. Most patients are acutely ill and have odynophagia, dysphagia, and mild dyspnea. A bulge in the lateral pharyngeal wall can be seen, but the tonsil size is normal. Torticollis toward the side of the abscess (caused by muscle spasm) is often seen, as is cervical lymphadenitis. The classic triad of pharyngomaxillary abscess occurs only in anterior-compartment syndrome and consists of 1) prolapse of the tonsils and tonsillar fossa, 2) trismus, and 3) swelling of the parotid area. Signs of septicemia, with minimal pain or trismus, characterize infection in the posterior compartment. Swelling can be overlooked because it is deep behind the palatopharyngeal arch. Indirect laryngoscopy can reveal ipsilateral obliteration of the pyriform sinus. A tender, high cervical mass can be palpated. The most frequent complications of infection in the posterior compartment include the following (64,66): ● ● ● ● ● ●

●

●

Respiratory distress Laryngeal edema Airway obstruction Septicemia Pneumonia Septic thrombosis of the internal jugular vein with metastatic abscesses (Lemierre syndrome) Intracranial extension (causing meningitis, brain abscess, and cavernous and lateral sinus thrombosis) Erosion of the carotid artery

Carotid artery erosion can cause bleeding from the external auditory canal. Additionally, abscess dissection through the junction of the cartilaginous external canal and bone can cause suppurative otorrhea. Extension of infection inferiorly along the carotid sheath or posteriorly into the retropharyngeal space can lead to mediastinitis. Computed tomography or magnetic resonance imaging can delineate the affected structures and any vascular complications.

Treatment Drainage of the lateral neck in conjunction with appropriate high-dose intravenous antimicrobial therapy is needed for treating a lateral pharyngeal abscess. The antimicrobial agents used in this treatment are discussed in the Antimicrobial Therapy section earlier in this chapter and are outlined in Table 19-6. An external excision below the angle of the jaw is preferred because it provides access to the carotid artery, which should be ligated in case of arterial erosion. Surgical drainage is best done after the infection has been localized, unless a hemorrhage or respiratory obstruction necessitates

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earlier intervention. Tracheostomy may be required prophylactically. Airway obstruction caused by laryngeal edema can develop abruptly.

Epiglottitis Epiglottitis (or supraglottitis) is usually a bacterial infection of the supraglottic area that primarily affects the epiglottis but can also affect the arytenoids and the aryepiglottic areas. Swelling of the epiglottis can cause laryngeal obstruction. Epiglottitis is most common in children younger than 5 years of age and is characterized by several upper respiratory tract infections that may progress rapidly to fatal obstruction.

Etiology Viral infection can precede bacterial epiglottitis. Edema of the supraglottic structures, which can obstruct the airway, then progresses rapidly. Rarely, infection spreads to the paraglottic space. Infection can be associated with transient bacteremia (in up to 90% in patients with H. influenzae type B). Circulatory collapse is unusual and caused by hypoxia and dehydration. Pulmonary edema occurs in approximately one quarter of patients because of negative intrathoracic pressure generated with obstruction of the extrathoracic airway. Epiglottis is generally caused by encapsulated bacteria (67,68). It has been postulated that a viral respiratory tract infection permits local invasiveness of an organism that previously colonized the airway asymptomatically. H. influenzae type B was the predominant cause of epiglottitis before infants were universally immunized against it (67,68), and epiglottitis with bacteremia caused by other organisms was uncommon. The incidence of epiglottitis has decreased dramatically in the past decade (69). The main organisms now recovered in children are S. pneumoniae, S. aureus, nontypeable H. influenzae, H. parainfluenzae, and β-hemolytic streptococci (groups A, B, and C) (70). In adults H. influenzae type b is still the most common causative pathogen.

Clinical Manifestations The diagnosis of epiglottitis is suspected on the basis of signs of upper airway obstruction (e.g., inspiratory stridor, hoarseness, barking cough, retractions) (71). In the young child, acute epiglottitis is a fulminant illness characterized by high fever of acute onset, dyspnea, rapidly progressive respiratory obstruction (within hours), and prostration. Aphonia, drooling, and respiratory distress accompany stridor. In an older child, sore throat and dysphagia generally are followed rapidly by progressive respiratory distress and the sensation of suffocation. Cough and hoarseness usually are

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not present. The child seems toxic but sits still with chin up, neck hyperextended, hands extended behind the body in a tripod position, mouth open, and tongue protruding. Progression of epiglottitis to a shocklike condition characterized by cyanosis, pallor, and impaired consciousness can occur rapidly. The progression of symptoms in adults is usually slower and manifested as an increasing sore throat with muffled voice without dyspnea.

Diagnosis In a cooperative patient who willingly opens his or her mouth, epiglottitis can be diagnosed by visualizing a cherry-red, swollen epiglottis arising at the base of the tongue. If the diagnosis is suspected, indirect visualization by laryngoscopy should be done urgently in a controlled setting by skilled individuals who have the facility and intention to do intubation (or tracheostomy if necessary) (72,73). Differentiation among causes of infectious upper airway obstruction is facilitated by careful attention to the history of the patient’s illness, physical findings, and the context of the illness in the family and community. Life-saving management depends on accurate diagnosis. A lateral neck radiograph can be made before examination in cases of suspected epiglottitis if the child’s clinical state is favorable; this can be done rapidly and without agitating the child in the presence of individuals who are skilled and prepared for resuscitation. If the clinical presentation suggests epiglottitis, visualization of the epiglottitis and intubation should not be delayed by radiography. A lateral neck film shows a thickening of the epiglottis (thumb sign) and aryepiglottic folds in the presence of an apparently normal laryngeal ventricle and subglottic airway. Both blood and epiglottis swab cultures (taken at the time of intubation) usually yield positive results when H. influenzae type B is the etiologic organism. Gram stain and culture of an epiglottis swab specimen can confirm other bacterial causes. Blood cultures are variably positive.

Treatment Maintenance of adequate respiratory exchange is of primary importance in cases of epiglottitis and requires careful observation and monitoring of the patient for signs of increasing obstruction or fatigue. Complete airway obstruction is the major risk in acute epiglottitis. An artificial airway should be secured, preferably by nasotracheal intubation or, in extreme cases, by cricothyrotomy (74); tracheostomy is rarely required. Establishing an artificial airway is best done in the operating room under halothane anesthesia. Oxygen should be given until intubation is complete, and the child should be kept calm in a parent’s arms. In addition to establishing an airway, antimicrobial therapy is required. Cefuroxime 200 mg/kg/d or ceftriaxone 100 mg/kg/d are appropriate for initial therapy. Alleviated respiratory dis-

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tress is immediate after an artificial airway is secured. Fever and toxicity subside over 24 to 72 hours, and extubation is usually accomplished within 72 hours (75).

Prevention When H. influenzae type B is the agent responsible for epiglottitis, a 4-day course of rifampin (20 mg/kg/d in a single dose; 600 mg maximum) should be administered prophylactically to all household contacts of the patient if anyone in the household is younger than 4 years of age and has not been immunized completely (the patient also should receive a 4-day course of rifampin after completing the initial course of antimicrobial therapy). All contacts of the patient should be instructed about the signs and symptoms of H. influenzae infection, because it can occur, albeit rarely, in older individuals. Immunization of all children with conjugated H. influenzae type B polysaccharide vaccine reduces the incidences of H. influenzae epiglottitis.

REFERENCES 1. Bisno AL. Acute pharyngitis: etiology and diagnosis. Pediatrics. 1996;97:949-54. 2. Tsevat J, Kotagal UR. Management of sore throats in children: A cost-effectiveness analysis. J Postgrad Med. 1999;75:141-4. 3. Brook I, Deleyva F. Immune response to Fusobacterium nucleatum and Prevotella intermedia in patients with infectious mononucleosis. J Med Microbiol. 1996;44:131-4. 4. Brook I. Bacterial interference in upper respiratory tract infection. Reviews in Medical Microbiology. 1999;10:225-33. 5. Brook I. The role of beta-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Rev Infect Dis. 1984;6:601-7. 6. Cimolai N, Elford RW, Bryan L,Anand C, Berger P. Do the beta-hemolytic non-group A streptococci cause pharyngitis? Rev Infect Dis. 1988;10:587-601. 7. Turner JC, Hayden GF, Kiselica D, Lohr J, Fishburne CF, Murren D. Association of group C betahemolytic streptococci with endemic pharyngitis among college students. JAMA. 1990;264:2644-7. 8. Turner JC, Hayden FG, Lobo MC, Ramirez CE, Murren D. Epidemiologic evidence for Lancefield group C beta-hemolytic streptococci as a cause of exudative pharyngitis in college students. J Clin Microbiol. 1997;35:1-4. 9. Gerber MA, Randolph MF, Martin N J, Rizkallah MF, Cleary PP, Kaplan EL, et al. Community-wide outbreak of group G streptococcal pharyngitis. Pediatrics. 1991;87:598-603. 10. Davies HD, McGeer A, Schwartz B, Green K, Cann D, Simor AE, et al. Invasive group A streptococcal infections in Ontario, Canada. Ontario Group A Streptococcal Study Group. N Engl J Med. 1996;335:547-54. 11. Chowdhury MN, Kambal AM, al-Eissa YA, Khaliq MR, al-Ayed IH, al-Sanie AM. Non-group A streptococci: are they pathogens in the throat? J R Soc Health. 1997;117:160-3. 12. Mackenzie A, Fuite LA, Chan FT, King J,Allen U, MacDonald N, et al. Incidence and pathogenicity of Arcanobacterium haemolyticum during a 2-year study in Ottawa. Clin Infect Dis. 1995;21:177-81. 13. Brook I. The role of anaerobic bacteria in tonsillitis. Int J Pediatr Otorhinolaryngol. 2005;69:9-19. 14. Rosbery T. Microorganisms Indigenous to Man. New York, NY: McGraw-Hill; 1962. 15. Brook I, Frazier EH, Thompson DH. Aerobic and anaerobic microbiology of peritonsillar abscess. Laryngoscope. 1991;101:289-92. 16. Kaplan D. Acute necrotizing ulcerative tonsillitis and gingivitis (Vincent’s infections). Ann Emerg Med. 1981;10:593-5. 17. Brook I, Gober AE. Bacteroides melaninogenicus. Its recovery from tonsils of children with acute tonsillitis. Arch Otolaryngol. 1983;109:818-20.

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18. Brook I,Yocum P. Comparison of the microbiology of group A and non-group A streptococcal tonsillitis. Ann Otol Rhinol Laryngol. 1988;97:243-6. 18a. Brook I, Gober AE. Treatment of non-streptococcal tonsillitis with metronidazole. Int J Pediatr Otorhinolaryngol. 2005;69:65-8. 18b. Davidson S, Kaplinsky C, Frand M, Rotem J. Treatment of infectious mononucleosis with metronidazole in the pediatric age group. Scand J Infect Dis. 1982;14:103-4. 18c. Brook I, Foote PA Jr., Slots J, Jackson W. Immune response to Prevotella intermedia in patients with recurrent nonstreptococcal tonsillitis. Ann Otol Rhinol Laryngol. 1993; 102:113-6. 19. Brook I, Foote PA Jr., Slots J. Immune response to anaerobic bacteria in patients with peritonsillar cellulitis and abscess. Acta Otolaryngol. 1996;116:888-91. 20. Breese BB. A simple scorecard for the tentative diagnosis of streptococcal pharyngitis. Am J Dis Child. 1977;131:514-7. 21. Roddey OF Jr., Clegg HW, Martin ES, Swetenburg RL, Koonce EW. Comparison of throat culture methods for the recovery of group A streptococci in a pediatric office setting. JAMA. 1995;274:1863-5. 22. Pacifico L, Ranucci A, Ravagnan G, Chiesa C. Relative value of selective group A streptococcal agar incubated under different atmospheres. J Clin Microbiol. 1995;33:2480-2. 23. Kellogg JA. Suitability of throat culture procedures for detection of group A streptococci and as reference standards for evaluation of streptococcal antigen detection kits. J Clin Microbiol. 1990;28:165-9. 24. Brook I, Foote PA Jr. Microbiology of “normal” tonsils. Ann Otol Rhinol Laryngol. 1990;99:980-3. 25. Murray PR, Wold AD, Hall MM, Washington JA 2nd. Bacitracin differentiation for presumptive identification of group A beta-hemolytic streptococci: comparison of primary and purified plate testing. J Pediatr. 1976;89:576-9. 26. Pichichero ME. Group A beta-hemolytic streptococcal infections. Pediatr Rev. 1998; 19:291-302. 27. Randolph MF, Gerber MA, DeMeo KK, Wright L. Effect of antibiotic therapy on the clinical course of streptococcal pharyngitis. J Pediatr. 1985;106:870-5. 28. Krober MS, Bass JW, Michels GN. Streptococcal pharyngitis. Placebo-controlled double-blind evaluation of clinical response to penicillin therapy. JAMA. 1985;253:1271-4. 29. Holbrook T. Rapid strep tests in the pediatric clinical setting. J Pediatr Nurs. 1998;13:131-3. 30. Lieu TA, Fleisher GR, Schwartz JS. Clinical evaluation of a latex agglutination test for streptococcal pharyngitis: performance and impact on treatment rates. Pediatr Infect Dis J. 1988;7:847-54. 31. Gerber MA. Comparison of throat cultures and rapid strep tests for diagnosis of streptococcal pharyngitis. Pediatr Infect Dis. 1989;8:820-4. 32. Denny FW, Wannamaker LW, Brink WR, et al. Prevention of rheumatic fever: Treatment of the preceding streptococci infection. JAMA. 1950;143:151-3. 33. Seppälä H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. N Engl J Med. 1997;337:441-6. 33a. Richter SS, Heilmann KP, Beekmann SE, Miller NJ, Miller AL, Rice CL, et al. Macrolide-resistant Streptococcus pyogenes in the United States, 2002-2003. Clin Infect Dis. 2005;41:599-608. 33b. Martin JM, Green M, Barbadora KA, Wald ER. Erythromycin-resistant group A streptococci in schoolchildren in Pittsburgh. N Engl J Med. 2002;346:1200-6. 34. Pichichero ME, Margolis PA. A comparison of cephalosporins and penicillins in the treatment of group A beta-hemolytic streptococcal pharyngitis: a meta-analysis supporting the concept of microbial copathogenicity. Pediatr Infect Dis J. 1991;10:275-81. [PMID: 1829514] 35. Brook I, Gilmore JD. Evaluation of bacterial interference and beta-lactamase production in management of experimental infection with group A beta-hemolytic streptococci. Antimicrob Agents Chemother. 1993;37:1452-5. 36. Brook I, Gober AE. Role of bacterial interference and beta-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis. Arch Otolaryngol Head Neck Surg. 1995;121:1405-9. 36a. Brook I, Foote PA Jr. Effect of antimicrobial therapy with amoxicillin and cefprozil on bacterial interference and beta-lactamase production in the adenoids. Ann Otol Rhinol Laryngol. 2004;113:902-5. 37. Pichichero ME, Cohen R. Shortened course of antibiotic therapy for acute otitis media, sinusitis and tonsillopharyngitis. Pediatr Infect Dis J. 1997;16:680-95.

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38. Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group a streptococci from children with acute pharyngitis. Pediatrics. 2001;108:1180-6. 39. Tanz RR, Poncher JR, Corydon KE, Kabat K, Yogev R, Shulman ST. Clindamycin treatment of chronic pharyngeal carriage of group A streptococci. J Pediatr. 1991;119:123-8. 40. Kaplan EL, Gastanaduy AS, Huwe BB. The role of the carrier in treatment failures after antibiotic for group A streptococci in the upper respiratory tract. J Lab Clin Med. 1981;98:326-35. 41. Neeman R, Keller N, Barzilai A, Korenman Z, Sela S. Prevalence of internalisation-associated gene, prtF1, among persisting group-A streptococcus strains isolated from asymptomatic carriers. Lancet. 1998;352:1974-7. 42. Grahn E, Holm SE, Roos K. Penicillin tolerance in beta-streptococci isolated from patients with tonsillitis. Scand J Infect Dis. 1987;19:421-6. 42a. Lafontaine ER,Wall D,Vanlerberg SL, Donabedian H, Sledjeski DD. Moraxella catarrhalis coaggregates with Streptococcus pyogenes and modulates interactions of S. pyogenes with human epithelial cells. Infect Immun. 2004;72:6689-93. 43. Brook I, Gober AE. Emergence of beta-lactamase-producing aerobic and anaerobic bacteria in the oropharynx of children following penicillin chemotherapy. Clin Pediatr (Phila). 1984;23:338-41. 43a. Brook I. Emergence and persistence of beta-lactamase-producing bacteria in the oropharynx following penicillin treatment. Arch Otolaryngol Head Neck Surg. 1988; 114:667-70. 44. Brook I, Gober AE. Monthly changes in the rate of recovery of penicillin-resistant organisms from children. Pediatr Infect Dis J. 1997;16:255-7. 45. Brook I, Pazzaglia G, Coolbaugh JC, Walker RI. In-vivo protection of group A beta-haemolytic streptococci from penicillin by beta-lactamase-producing Bacteroides species. J Antimicrob Chemother. 1983;12:599-606. 46. Brook I. Role of beta-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococci. Pediatr Infect Dis. 1985;4:491-5. 47. Brook I, Yocum P, Friedman EM. Aerobic and anaerobic bacteria in tonsils of children with recurrent tonsillitis. Ann Otol Rhinol Laryngol. 1981;90:261-3. 48. Tunér K, Nord CE. beta-Lactamase-producing anaerobic bacteria in recurrent tonsillitis. J Antimicrob Chemother. 1982;10 Suppl A:153-6. 49. Rajasuo A, Jousimies-Somer H, Savolainen S, Leppänen J, Murtomaa H, Meurman JH. Bacteriologic findings in tonsillitis and pericoronitis. Clin Infect Dis. 1996;23:51-60. 50. Brook I, Yocum P. Quantitative measurement of β-lactamase level in tonsils of children with recurrent tonsillitis. Acta Otolaryngol Scand. 1984;98:446-60. 51. Brook I, Hirokawa R. Treatment of patients with a history of recurrent tonsillitis due to group A beta-hemolytic streptococci. A prospective randomized study comparing penicillin, erythromycin, and clindamycin. Clin Pediatr (Phila). 1985;24:331-6. 52. Finegold SM. Anaerobic Bacteria in Human Disease. New York, NY: Academic Press; 1977. 53. Brook I, Frazier EH, Thompson DH. Aerobic and anaerobic microbiology of peritonsillar abscess. Laryngoscope. 1991;101:289-92. 54. Brook I. Microbiology of retropharyngeal abscesses in children. Am J Dis Child. 1987;141:202-4. 55. Brook I. Microbiology of abscesses of the head and neck in children. Ann Otol Rhinol Laryngol. 1987;96:429-33. 56. Jokipii AM, Jokipii L, Sipilä P, Jokinen K. Semiquantitative culture results and pathogenic significance of obligate anaerobes in peritonsillar abscesses. J Clin Microbiol. 1988;26:957-61. 57. Mitchelmore I J, Prior A J, Montgomery PQ, Tabaqchali S. Microbiological features and pathogenesis of peritonsillar abscesses. Eur J Clin Microbiol Infect Dis. 1995;14:870-7. 58. Asmar BI. Bacteriology of retropharyngeal abscess in children. Pediatr Infect Dis J. 1990;9:595-7. 59. Hughes CE, Spear RK, Shinabarger CE, Tuna IC. Septic pulmonary emboli complicating mastoiditis: Lemierre’s syndrome revisited. Clin Infect Dis. 1994;18:633-5. 60. Brook I. Microbiology and management of deep facial infections and Lemierre syndrome. ORL J Otorhinolaryngol Relat Spec. 2003;65:117-20. 61. Mathur NN, Bais AS. Tubercular retropharyngeal abscess in early childhood. Indian J Pediatr. 1997;64:898-901. 62. Barratt GE, Koopmann CF Jr., Coulthard SW. Retropharyngeal abscess—a ten-year experience. Laryngoscope. 1984;94:455-63. 63. Friedman NR, Mitchell RB, Pereira KD,Younis RT, Lazar RH. Peritonsillar abscess in early childhood. Presentation and management. Arch Otolaryngol Head Neck Surg. 1997; 123:630-2.

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64. Blomquist IK, Bayer AS. Life-threatening deep fascial space infections of the head and neck. Infect Dis Clin North Am. 1988;2:237-64. 65. Gidley PW, Ghorayeb BY, Stiernberg CM. Contemporary management of deep neck space infections. Otolaryngol Head Neck Surg. 1997;116:16-22. 66. Chen MK,Wen YS, Chang CC, Huang MT, Hsiao HC. Predisposing factors of life-threatening deep neck infection: logistic regression analysis of 214 cases. J Otolaryngol. 1998;27:141-4. 67. Brilli R J, Benzing G 3rd, Cotcamp DH. Epiglottitis in infants less than two years of age. Pediatr Emerg Care. 1989;5:16-21. 68. Losek JD, Dewitz-Zink BA, Melzer-Lange M, et al. Epiglottitis: Comparison of signs and symptoms in children less than 2 years old and older. Ann Emerg Med. 1990;19:99-102. 69. Garpenholt O, Hugosson S, Fredlund H, Bodin L, Olcén P. Epiglottitis in Sweden before and after introduction of vaccination against Haemophilus influenzae type b. Pediatr Infect Dis J. 1999;18:490-3. 70. Solomon P,Weisbrod M, Irish JC, Gullane PJ. Adult epiglottitis: the Toronto Hospital experience. J Otolaryngol. 1998;27:332-6. 71. Skolnik NS. Treatment of croup. A critical review. Am J Dis Child. 1989;143:1045-9. 72. Baugh R, Gilmore BB Jr. Infectious croup: a critical review. Otolaryngol Head Neck Surg. 1986;95:40-6. 73. Custer JR. Croup and related disorders. Pediatr Rev. 1993;14:19-29. 74. Park KW, Darvish A, Lowenstein E. Airway management for adult patients with acute epiglottitis: a 12-year experience at an academic medical center (1984-1995). Anesthesiology. 1998;88:254-61. 75. Damm M, Eckel HE, Jungehülsing M, Roth B. Management of acute inflammatory childhood stridor. Otolaryngol Head Neck Surg. 1999;121:633-8.

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Chapter 20

Sinusitis and Otitis DAVID H. CANADAY, MD ROBERT A. SALATA, MD

Key Learning Points 1. In immunocompetent patients, acute sinusitis often has a viral etiology. In many cases it is prudent to withhold antibiotics for 7 days unless clinically indicated at the outset of infection. 2. Refer acute sinusitis patients to an Otolaryngologist if they have failed after one antibiotic switch or they have signs of locally invasive spread. 3. High does amoxicillin is still the drug of choice for non-newborn immunocompetent children with acute otitis who have not had recent antibiotics. 4. Removal of a child with frequent URI from large daycare settings may help decrease incidence of otitis. 5. Non-invasive otitis externa is best treated with topical antimicrobial eardrops that may also contain steroids.

Sinusitis Sinusitis, an inflammatory disorder of the mucosal lining of the paranasal sinuses, is a common infection in both children and adults. Most cases complicate the common cold or other upper respiratory infections (URIs), with occasional cases associated with dental infection (maxillary sinuses). An understanding of the epidemiology, pathophysiology, microbiology, and clinical manifestations of sinusitis is essential for its early diagnosis and effective treatment, as well as to prevent life-threatening complications or chronic sequelae. 387

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New Developments in the Management of Sinusitis and Otitis ●

●

There is increasing resistance to Streptococcus pneumoniae in the community. This should be taken into account when choosing antibiotics initially or adjusting a failing regimen for either otitis or sinusitis, particularly in pediatric populations. The release of new antibiotics continues, such as the ketolides that will have an effect on antibiotic choices in the future. However, the indication for the Keliotide telithromycin has recently been removed.

Etiology The paranasal sinuses are air-filled cavities lined with ciliated pseudocolumnar epithelial tissue. They are connected indirectly with the nasal cavity through small ostia that drain into this cavity. The frontal, anterior ethmoidal, and maxillary sinuses open into the middle meatus, whereas the posterior ethmoidal and sphenoid sinuses open into the superior meatus. The paranasal sinuses are generally considered sterile. Microorganisms frequently find access to the paranasal sinuses, because the upper respiratory tract, oropharynx, and certain parts of the ears and eyes are anatomically adjacent to these sinuses and are usually heavily populated with colonizing flora. Patent ostia and normal mucociliary function are the keys to maintaining aeration and mucosal defenses of the sinuses. The cilia of the epithelium of the paranasal sinuses, contiguous with the nasal cavity, beat toward the ostia and clear the sinuses. Secretory immunoglobulins and an intact epithelium serve as additional barriers to infection. Conditions that impair ostial patency, mucociliary function, epithelial integrity, or normal immune defenses are the major factors predisposing to sinusitis (Table 20-1).

Clinical Manifestations Most cases of acute, community-acquired sinusitis are superimposed on an existing viral URI, and their clinical features reflect a dual infection. Acute bacterial sinusitis complicates approximately 0.5% to 2% of viral rhinosinusitis (1). Of patients with the common cold, 87% have some sinus cavity disease. In children, the most common symptoms of acute sinusitis are cough (80%), nasal discharge (76%), and fever (63%). In adults, purulent nasal discharge and facial pain are the major manifestations, with fever occurring in less than 20% of cases. Uncomplicated viral rhinosinusitis usually resolves in 7 to 10 days. One of the most consistent features of acute bacterial sinusitis is the occurrence of cold symptoms persisting either for more than a week or longer than the usual course for the individual patient. Other reported symptoms are postnasal drainage, pain with mastication, hyposmia, nasal congestion, and worsening pain on leaning forward. From

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Table 20-1 Risk Factors Predisposing to Sinusitis Obstruction of the Sinus Ostia ● ● ● ●

Viral upper respiratory infection Allergic rhinitis Rhinitis medicamentosa Anatomic abnormalities (e.g., deviated nasal septum, polyps, tumors, and foreign body)

Impaired Mucociliary Function or Disrupted Epithelial Integrity ● ● ● ●

Viral upper respiratory infection Cold or dry air Chemicals, drugs, and smoke Cystic fibrosis or ciliary dysmotility syndromes

Immune Defects ● ● ● ● ●

IgA deficiency IgG2a or IgG4 subclass deficiency Neutropenia AIDS Corticosteroids or cytotoxic drugs

Increased Microbial Invasion ● ● ● ● ●

Odontogenic infections Nasotracheal intubation Head trauma Swimming or diving Cocaine sniffing

5% to 10% of cases of acute maxillary sinusitis have a dental origin. Acute bacterial sinusitis has a duration of 4 weeks or less. Headaches or a sensation of pressure are prominent features of frontal sinusitis, because a branch of the ophthalmic division of the trigeminal nerve supplies this area of the head. The superior alveolar nerves supply both the molar teeth and the mucosa of the maxillary sinus. Toothache can occur with maxillary sinusitis. Severe, intractable headache is seen with sphenoid sinusitis and can mimic ophthalmic migraine or trigeminal neuralgia. Depressed mental status; clinical signs of meningeal irritation; and palsies of structures served by the third, fourth, and fifth cranial nerves suggest the extension of infection to the cavernous sinus. Edema of the eyelids and excessive tearing are prominent features of ethmoidal sinusitis. Retro-orbital pain and proptosis indicate orbital extension of sinus infection. Subacute sinusitis (lasting from 1 to 3 months) and chronic sinusitis (lasting more than 3 months) generally present with symptoms that are less severe but more protracted than those of acute sinusitis. Fatigue and malaise are more prominent than local nasal or sinus symptoms. Frequently, patients with chronic sinusitis have a dental cause of infection. Fungal sinusitis is often a more chronic condition that more often presents with pressure-related symptoms. Nasal polyps are commonly encountered

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in chronic maxillary sinusitis. Chronic sinusitis may mimic asthma, allergic rhinitis, or chronic bronchitis.

Diagnosis The diagnosis of sinusitis is most often based on clinical presentation. It is often a challenge to distinguish infectious from allergic and other noninfectious sources of the condition. An allergic cause can usually be identified from a history of paroxysmal sneezing, allergen exposure, itching eyes, and similar previous occurrences. Sinus aspiration is the most accurate diagnostic method. The results of nasal swab cultures correlate with those of sinus aspirate cultures in less than 65% of cases. The microbiology of sinusitis depends on the chronicity of infection, whether the infection was acquired from the community or nosocomial, and the patient’s age and underlying status. Transillumination of the sinuses may be a helpful bedside diagnostic procedure for sinusitis. The finding of complete sinus opacity is highly suggestive of infection, whereas normal light transmission indicates the absence of infection. Radiologic evaluation is a common, noninvasive diagnostic method for sinusitis. Abnormal radiologic findings of complete sinus opacification, an air–fluid level, or mucosal thickening (>4 mm in children, >5 mm in adults) are indicative of infection as established by sinus aspiration in 75% of cases, whereas a normal radiograph correlates with a negative aspirate in 80% of cases (1). Radiology is less useful in cases of chronic sinusitis, because of persistent abnormalities, and in infants younger than 12 months of age, because of redundant sinus mucosa and asymmetry of sinus development. Limited-view computed tomography (CT), a very sensitive means of diagnosing sinus abnormalities, is recommended more than plain sinus radiography because of similar cost. CT scanning has a role in chronic sinusitis in helping to differentiate bacterial from fungal disease, with bone destruction sometimes seen in the latter. The predominant bacterial pathogens are Streptococcus pneumoniae and Haemophilus influenzae, which together are responsible for more than 50% of cases of acute maxillary sinusitis in both children and adults. In children, Moraxella catarrhalis is another common pathogen. Recovery of anaerobes in acute sinusitis should prompt an investigation for an odontogenic source of infection. Anaerobes are also more commonly encountered in cases of chronic sinusitis. Staphylococcus aureus, although a common nasal colonist, is an uncommon cause of community-acquired maxillary sinusitis. However, S. aureus and streptococci are major pathogens in sphenoid sinusitis. The sinuses also have been reported to serve as reservoirs of S. aureus in cases of toxic shock syndrome. Viruses can be isolated in approximately 15% of cases of sinusitis. The most common viral isolate is rhinovirus. Viruses are thought to be the major

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agents predisposing to bacterial sinusitis, but the temporal delay between URI and bacterial sinusitis may account for the low viral culture rate seen at the time of presentation with sinusitis. Nosocomial sinusitis is commonly polymicrobial and caused by gramnegative bacilli or S. aureus, and less frequently by anaerobes. Predisposing factors include the presence of nasopharyngeal or nasogastric tubes, nasal packing, nasal cranial fractures, previous antibiotic use, corticosteroid therapy, and mechanical ventilation. Fungal sinusitis is rare among cases of community-acquired disease. It is usually seen in debilitated patients. Aspergillus is the most common fungal pathogen, and it can infect in a noninvasive or invasive manner. The noninvasive infection, more often seen in immunocompetent individuals, includes allergic aspergillosis and rarely mycetoma. Invasive Aspergillus occurs primarily in immunocompromised or HIV-infected patients. Rhinocerebral mucormycosis is a fulminant fungal infection occurring in debilitated and immunocompromised patients. It is often seen in individuals with uncontrolled diabetes with ketoacidosis, profoundly dehydrated children, and persistently neutropenic patients (especially those with lymphoreticular malignancy). Mucormycosis begins in the nose and can rapidly spread by way of the sinuses to the orbits or central nervous system (CNS). The diagnosis is suspected in acutely febrile patients with a blackened nasal discharge and eschar on the palate and nasal mucosa, cranial nerve findings, or altered mental status. Certain patients are predisposed to sinus infection with specific organisms. Patients with cystic fibrosis, for example, are predisposed to sinus infection with Pseudomonas aeruginosa and S. aureus. Immunocompromised patients with nosocomial sinusitis have a higher rate of polymicrobial infection with gram-negative bacteria such as Escherichia coli, Pseudomonas species, and Serratia species.

Treatment The goals of therapy for sinus infection are to eradicate infection, restore or alleviate sinus function, provide symptomatic relief, and prevent suppurative complications. Empiric treatment of sinus infection should target the most common infections in the patient’s age and cultural/environmental group, while also taking into consideration the duration of the infection. The specific bacterial resistance patterns in each community and hospital should also be taken into account. Until recently, amoxicillin was the mainstay of treatment of sinus infection. With the increase in beta-lactamase–producing strains of Haemophilus and Moraxella, other agents can be considered. Increasing emergence of resistant S. pneumoniae is also of concern. Antibiotics to consider include amoxicillin–clavulanate, cefuroxime axetil, new macrolides (telithromycin, azithromycin, or clarithromycin), and fluoroquinolones that have enhanced pneumococcal activity (levofloxacin and

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Table 20-2 Treatment of Acute Sinusitis or Otitis Media Penicillins

High-dose Amoxicillin Amoxicillin/ Clavulanate-ER

Adult

Pediatrics

1000 mg tid

90 mg/kg/d div q8 or q12h extra strength 90 mg/kg/d div q8 or q12h

2000 mg bid

Cephalosporins

Cefuroxime axetil Cefpodoxime

250 mg bid 200 mg bid

Cefixime Cefdinir Cefprozil

500 mg qd 600 mg qd 250-500 mg qd

30 mg/kg/d div q12h 10 mg/kg/d qd (max 400 mg) 8 mg/kg/d 14 mg/kg/d 30 mg/kg/d div q12h

250-500 mg bid 500 mg once, then 250 mg qd×4d

15 mg/kg/d div q12h 10 mg/kg once, then 5 mg/kg qd×4d

750 mg qd 400 mg qd

do not use do not use

1 DS bid

8-12 mg TMP kg/d/ 40-60 mg SMX kg/d div q12

Macrolides

Clarithromycin Azithromycin Fluoroquinolones

Levofloxacin Moxifloxacin Sulfa

TMP-SMX

* All treatments listed by mouth. Abbreviations: bid = twice a day; d = day; div = divide; DS = double strength; max = maximum; q = every; tid = three times a day; TMP-SMX = trimethoprim-sulfamethoxazole.

moxifloxacin) (Table 20-2). The local incidence of resistant S. pneumoniae should be taken into consideration when selecting a first-line antimicrobial agent for treating sinus infection. The recommended duration of initial treatment is for a 7- to 10-day course of antibiotics. A general treatment algorithm for primary management of acute sinusitis is given in Figure 20-1 (2-4). In general, bacterial sinusitis should be considered when symptoms have been present or worsened over at least 7 days. At this point an antibiotic can be given. If there is not significant resolution in 3 to 5 days or a relapse, resistant flora might be present; and a switch in antibiotics to a more broad spectrum agent is indicated. If there is no resolution of the symptoms after a switch of antibiotics, the primary care physician should consider referral for otolaryngology consultation. The patient should also be carefully questioned to assess for development of extension of disease or more serious complications. Complications include local extension causing sinus osteomyelitis, orbital cellulitis, or infection to the CNS including meningitis, brain abscess, or infection of the intracranial venous sinuses. Fortunately, these complications are rare with treatment. If

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Signs and symptoms of URI

Symptoms for <7 days or no recent abx? Likely Viral

Symptoms no better or worse in 7-10 days. Suspect bacterial infection

Symptomatic treatment Antibiotic No resolution or worsening of symptoms. Suspect bacterial infection No resolution of symptoms within 3-5 days or symptoms return within 2 weeks. Suspect resistant pathogens

No resolution or worsening of signs and symptoms Sinus CT and ENT consult Sinus aspirate and sinus lavage Antibiotic

Use antibiotic with different coverage for pathogens not covered with first course of therapy

Figure 20-1 Algorithm for the treatment of acute sinusitis.

at any time there is a suggestion of local or CNS spread, the patient should be referred for emergent consultation and possible inpatient treatment. Antibiotic therapy for nosocomial sinusitis should be guided by the results of Gram stain and culture of sinus aspirates. Empiric therapy should include broad-spectrum coverage of aerobic gram-negative bacilli, S. aureus, and anaerobes such as Bacteroides or Fusobacterium until microbiological data are available. Chronic sinusitis may require surgical intervention in up to half of cases (5). A course of antibiotic therapy and sinus irrigation can be attempted with

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success in up to 58% of cases. Acute exacerbation of infection in patients with chronic sinusitis is treated as described previously for acute sinusitis. In a case series, functional endoscopic sinus surgery was shown to provide moderate to complete relief of symptoms in 80% to 90% of patients (6). Other supportive therapy that may be particularly useful in allergic rhinitis patients includes the use of antihistamines, decongestants, irrigation, and inhaled glucocorticoids (7). They may be useful in conjunction with antibiotic therapy for acute disease. It has been shown that nose blowing may propel fluid into the sinuses during URI (8). By reducing nasal secretions, antihistamines may reduce the frequency of viral and bacterial dissemination from the nasal to the sinuses passages. Irrigation of the nasal cavity has been shown to provide symptomatic relief.

Prevention There are no effective methods for specifically preventing sinusitis. However, prevention of URI is helpful. Prophylactic use of antimicrobial agents to prevent recurrence promotes the emergence of resistant flora. Treatment should be undertaken on an early and aggressive basis to avoid complications or chronic disease. Surgical correction of anatomic sinus ostial abnormalities, promotion of good dental hygiene, and control of allergic manifestations are several important preventive measures.

Otitis Media Otitis media is an inflammatory disorder of the middle ear. The presence of fluid in the middle ear accompanied by signs or symptoms of illness define acute otitis media. Otitis media can also be recurrent or occur with chronic effusion. Chronic suppurative otitis media is a chronic middle ear infection with perforation of the tympanic membrane and mastoid involvement.

Etiology Otitis media in children seems related to dysfunction of the eustachian tubes. Infants are more predisposed to ear infections because their eustachian tubes are shorter, wider, lie more horizontally, and have a less developed musculature than those of older children (9). The usual sequence of infection in otitis media in children and adults begins with an antecedent viral infection or allergic episode that causes increased secretion. The eustachian tube becomes blocked and the middle ear accumulates fluid, which becomes secondarily infected with flora that normally colonize the nasopharynx. Risk factors that have been associated with a greater rate of middle ear infection in children include attendance at large-group day care facilities, a

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genetic familial predisposition, living in developing countries, hostile climatic environments (e.g., Inuits), AIDS, and anatomic abnormalities such as cleft palate. The highest incidence of otitis media occurs in children ages 6 to 24 months (10). Only 23% of children have not had an episode of otitis media by 2 years of age.

Clinical Manifestations Otitis media occurs primarily in children; but it occasionally occurs in adults, with a clinical presentation and microbiology similar to that which occurs in children. The treatment is also very similar (11,12). Acute otitis media is characterized by signs and symptoms of rapid onset. These include, fever, otalgia (indicated by pulling of the ear by young children), irritability of recent onset, hearing loss, headache, lethargy, anorexia, or vomiting. Other, less common symptoms include vertigo, tinnitus, and nystagmus (13). Chronic otitis media can occur with persistent effusion or perforation. Persistent effusion can lead to a hearing loss of up to 25 dB when fluid is present in the middle ear (14). This may be a significant problem when a child is in the critical period of language development. If there is perforation, it is usually associated with some degree of mastoid infection. Mastoiditis begins with acute otitis media leading to localized erythema, swelling, and tenderness.

Diagnosis Physical examination is the most important means of establishing the diagnosis of acute otitis media. The normal tympanic membrane is in a neutral position and is gray, mobile, and translucent. Evidence of a fluid-filled, acutely inflamed middle ear includes bulging, redness, and lack of mobility of the tympanic membrane. Otorrhea—a purulent discharge either through perforation or a tympanostomy tube—is also diagnostic of acute otitis media. Consider diagnosis of acute otitis media by sampling middle ear fluid for patients who are severely ill or toxic on presentation, for newborn infants, in association with a potential or confirmed suppurative complication, in cases of a known immunologic defect, and in cases of continued toxicity with failure of many days of appropriate antibiotic therapy. Sampling fluid is a simple and safe procedure but should be reserved for otolaryngologists, pediatricians, or other clinicians with experience in this procedure. The microbiology of acute otitis media most commonly includes S. pneumoniae (29%), H. influenzae (23%), M. catarrhalis (13%), and others (17%), with the balance (18%) consisting of cases of culture negative disease (15). In chronic otitis, cultures are commonly negative (24%) or grow other organisms such as S. aureus, P. aeruginosa, Streptococcus pyogenes, or

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fungi (44%). In acute otitis media, at least 30% of isolates of H. influenzae and 80% of isolates of M. catarrhalis are beta-lactamase producers. When appropriate cultures are done, viruses can be isolated in up to one quarter of cases of acute otitis media.

Treatment Most experts agree that patients with signs and symptoms of otitis media should be given antibiotic therapy (see Table 20-2). This is especially true of children less than 2 years of age. Consideration for observation option can be made in patients older than age 2 years in nonsevere illness. A recent practice guideline was published by the American Academy of Pediatrics and American Academy of Family Physicians that discusses the use of antibiotics, symptomatic relief, and the observation option (16). High-dose amoxicillin is the initial drug of choice for healthy, non-newborn and immunocompetent patients who have not had recent antibiotics. Azithromycin, clarithromycin, or trimethoprim-sulfamethoxazole are choices for penicillin-allergic patients. There is no definitive standard length of treatment, but most patients are treated for 10 days; however, a 5-day course of azithromycin should be adequate because of its long half-life. If the patient is known to be infected with H. influenzae or M. catarrhalis, both of which may be associated with higher levels of beta-lactamase production, amoxicillin–clavulanate or oral cephalosporins such as cefuroxime or cefixime could be given. The local incidence of resistant S. pneumoniae should be taken into consideration when selecting a first-line antimicrobial agent. If the patient fails to respond to the initial management option within 48 to 72 hours, the patient must be reassessed to confirm the diagnosis of otitis media or exclude other illnesses. Consideration should be given to a diagnostic tympanocentesis. Existing antibiotic therapy should be changed to another more broad-spectrum agent such as a cephalosporin or amoxicillin/clavulanate in children. A fluoroquinolone is an additional choice in adults. Use of decongestants or antihistamines for treating otitis media with effusion has theoretical benefits, but these have not been borne out in clinical trials. Chemoprophylaxis is an option considered for patients with 3 documented episodes of otitis media in a 6-month period; 2 infections in the first year of life; or 1 infection in the first 6 months of life, accompanied by a family history of frequent ear infections. Amoxicillin or sulfonamide at half standard therapeutic dosage (once per day) is commonly chosen for prophylaxis. The most important times for providing chemoprophylaxis are during the peak periods of URI in the fall, winter, and early spring. Another approach is to begin prophylaxis at the onset of symptoms of URI. Antibiotic prophylaxis has been shown to be at least as effective at preventing new infections as ventilating tubes.

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Placement of ventilating tubes (tympanostomy tubes) is another option, especially for patients with persistent effusion or chronic infection. Such tube placement is 1 of the most common surgical procedures done in children. The hearing attenuation that often accompanies middle ear effusion is relieved after ventilating tubes are placed. Other indications for tube placement include effusion for at least 3 months with signs of hearing loss, unresponsiveness to medical therapy, and recurrent otitis media for which chemoprophylaxis fails. Adenoidectomy can also be considered for children whose adenoids are thought to cause significant eustachian tube dysfunction.

Prevention In children with recurrent otitis media, vaccination with pneumococcal and influenza vaccines may be reasonable. Use of influenza vaccines has more than 30% efficacy in prevention of otitis media during the influenza season in children older than 2 years old (17,18). Pneumococcal conjugate vaccines are effective at preventing vaccine-serospecific pneumococcal otitis media. They have a modest benefit overall in prevention of disease and need for tube procedures (19-21). Removal of a child with frequent URI from a large day care setting may help decrease the incidence of predisposing infection and therefore of otitis media. It has been shown that day care settings with 6 or fewer children have a lower incidence of URI. Parents should also be counseled about measures that may reduce otitis, such as breast feeding and limiting exposure to tobacco smoke. Feeding infants by bottle-propping is associated with an increased incidence of otitis and should be avoided.

Otitis Externa Otitis externa represents infection of the external auditory canal. The disease can be subdivided into the 4 categories: acute localized, acute diffuse, chronic, and invasive otitis externa.

Etiology Otitis externa is a soft tissue infection resembling this type of infection at other sites. The major difference is the anatomic limitation on the swelling of inflamed tissues in the external auditory canal. The ear canal is also a site where desquamating skin can build up. Combined with a warm, moist environment, this can constitute a favorable milieu for bacterial invasion if macerated skin is present. Humid climates, warm weather, and use of a hearing aid are several factors predisposing to otitis externa. Interestingly, overaggressive cleansing of the ear canal also can predispose to infection.

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Otitis externa usually results from infection by the flora that colonize the skin of the auditory canal (as at other skin sites), with a predominance of Staphylococcus epidermidis, S. aureus, Corynebacterium species, and occasionally of anaerobes. The pathogens that cause otitis media are not normally part of the flora of the external canal when the tympanic membrane is intact.

Clinical Manifestations and Diagnosis There are 4 major clinical manifestations of otitis externa. Acute localized otitis externa is caused primarily by S. aureus infection at a hair follicle in the ear canal. Group A Streptococcus can cause erysipelas in the ear canal. In this localized infection, pain is often severe, and hemorrhagic bullae may be present in the canal and even over the tympanic membrane. Adenopathy of the draining lymph nodes may be present. The diagnosis is established by physical examination, and the drainage fluid should be cultured if resistant flora are considered likely to be present. Swimmer’s ear is the classic presentation of acute diffuse otitis externa. It usually occurs in hot and humid weather. The major clinical symptoms include a painful, pruritic ear and tenderness to palpation. Fullness and hearing loss are common with edema of the canal. Physical examination shows the lining of the auditory canal to be diffusely erythematous. Gramnegative bacilli, mainly P. aeruginosa, are the major pathogens of swimmer’s ear, with S. aureus also encountered. Fungal otitis externa can be responsible for up to 10% of cases of the disease. It occurs most commonly in patients with chronic ear canal moisture or those receiving long-term topical antibiotic therapy. A past medical history of diabetes mellitus or immunocompromise may be present. The patient usually has pruritus and thick otorrhea. The physical examination commonly shows growth of fungal appearance of various colors, which may look like a mold. Aspergillus causes 80% to 90% of fungal otitis externa, with Candida species the next most common pathogens. Fungal cultures should be obtained. Chronic otitis externa is most often caused by chronic drainage from the middle ear in patients with draining suppurative otitis media. Clinically, patients with chronic otitis externa will report of pruritus as well as middle ear manifestations. Malignant or invasive otitis externa is a severe local infection that spreads into the adjacent tissues, including blood vessels and bone. There is usually drainage from the ear canal accompanied by severe pain and tenderness to palpation. Diabetic individuals, immunocompromised hosts including AIDS patients, and the debilitated elderly are groups at risk. Malignant otitis externa can be life threatening if there is spread into the temporal bone and subsequent involvement of the sphenoid sinus,

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meninges, and brain. Facial paralysis and cranial nerves IX, X, and XII can be affected. CT scanning or magnetic resonance imaging are useful for evaluating the extent of infection. P. aeruginosa is the most likely pathogen.

Treatment The treatment of acute localized otitis externa includes local application of heat and systemic antibiotic therapy (22). Incision and drainage may be needed to relieve severe pain. An ear wick can be inserted if the ear canal is occluded. For acute diffuse otitis externa, local care is paramount (23). Gentle removal of debris with hypertonic saline (3%) and cleansing with alcohol (70%-95%), hydrogen peroxide, or dilute acetic acid can be undertaken. Inflammation can be reduced through the administration of steroid-containing ear drops or irrigation with Burrow solution for several days. A 10-day course of antibacterial topical eardrops containing neomycin and polymyxin are the mainstays of treatment. Newer alternatives are fluoroquinolone otic solutions such as ofloxacillin otic or ciprofloxacin-dexamethasone otic. The otic antibiotics are fairly acidic. For some patients, the use of otic antibiotics will be so painful that compliance decreases. Ophthalmic antibiotics or steroid and antibiotic preparations can be used. The ophthalmic solutions have a more favorable pH. Adequate analgesic medication is important for patient comfort and to promote adherence to medical treatment. Nonsteroidal antiinflammatory drugs or even opioids are often necessary for analgesia. Systemic antibiotic therapy can be included if there are signs of significant tissue involvement. Fungal otitis externa is most commonly treated with topical antifungal ear drops, local cleansing, and acidifying local agents. If chronic otitis is caused by a draining middle ear infection, treatment should be targeted at the middle ear infection. Other cases of chronic otitis will probably require frequent cleansing and debridement, and should be referred to an otolaryngologist. Malignant otitis externa is a potentially life-threatening condition that in most cases initially requires inpatient treatment. Systemic intravenous therapy should include the combination of an antipseudomonal antibiotic such as piperacillin or ceftazidime with an aminoglycoside for 4 to 6 weeks or ciprofloxacin orally for early disease. Local care should include cleansing of the ear canal and instillation of a topical steroid as well as an antipseudomonal antibiotic. Many reasons exist for referring a patient with otitis externa to an otolaryngologist. These include unresponsiveness to medical treatment, signs or symptoms suggesting a necrotizing infection (malignant otitis externa), or for help in ruling out a neoplasm.

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Prevention Water-impermeable ear plugs may be effective for people who are prone to frequent infections after water sports. Drying of the ear canals with a blow dryer after exposure to water, followed by swabbing with 70% alcohol, can help prevent infection. Other possibilities for nonswimmers include prophylactic use of 3% boric acid in 70% alcohol every other day. Regular care and evaluation by an otolaryngologist are sometimes necessary.

REFERENCES 1. Gwaltney JM Jr., Sydnor A Jr., Sande MA. Etiology and antimicrobial treatment of acute sinusitis. Ann Otol Rhinol Laryngol Suppl. 1981;90:68-71. 2. Sande MA, Gwaltney JM. Acute community-acquired bacterial sinusitis: continuing challenges and current management. Clin Infect Dis. 2004;39 Suppl 3:S151-8. 3. Brooks I, Gooch WM 3rd, Jenkins SG, Pichichero ME, Reiner SA, Sher L, et al. Medical management of acute bacterial sinusitis. Recommendations of a clinical advisory committee on pediatric and adult sinusitis. Ann Otol Rhinol Laryngol Suppl. 2000;182:2-20. 4. Sinus and Allergy Health Partnership. Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg. 2004;130:1-45. 5. Kennedy DW, Senior BA. Endoscopic sinus surgery: A review. Prim Care. 1998;25:703-20. 6. Hartog B, van Benthem PP, Prins LC, Hordijk G J. Efficacy of sinus irrigation versus sinus irrigation followed by functional endoscopic sinus surgery. Ann Otol Rhinol Laryngol. 1997;106:759-66. 7. Low DE, et al. A practical guide for the diagnosis and treatment of acute sinusitis [see comments]. CMAJ. 1997;15(156):S1-14. 8. Gwaltney JM Jr., Hendley JO, Phillips CD, Bass CR, Mygind N,Winther B. Nose blowing propels nasal fluid into the paranasal sinuses. Clin Infect Dis. 2000;30:387-91. 9. Klein JO. Otitis media. Clin Infect Dis. 1994;19:823-33. 10. Teele DW, Klein JO, Rosner B. Epidemiology of otitis media during the first seven years of life in children in greater Boston: a prospective, cohort study. J Infect Dis. 1989;160:83-94. 11. Schwartz LE, Brown RB. Purulent otitis media in adults. Arch Intern Med. 1992;152:2301-4. 12. Celin SE, Bluestone CD, Stephenson J,Yilmaz HM, Collins J J. Bacteriology of acute otitis media in adults. JAMA. 1991;266:2249-52. 13. Berman S. Otitis media in children. N Engl J Med. 1995;332:1560-5. 14. Fria T J, Cantekin EI, Eichler JA. Hearing acuity of children with otitis media with effusion. Arch Otolaryngol. 1985;111:10-6. 15. Bluestone CD. The ear and mastoid infections. Mandel G, Bennett J, eds. New York, NY: Churchill Livingstone; 1995:441-8. 16. American Academy of Pediatrics Subcommittee on Management of Acute Otitis Media. Diagnosis and management of acute otitis media. Pediatrics. 2004;113:1451-65. 17. Clements DA, Langdon L, Bland C,Walter E. Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med. 1995;149:1113-7. 18. Belshe RB, Gruber WC. Prevention of otitis media in children with live attenuated influenza vaccine given intranasally. Pediatr Infect Dis J. 2000;19:S66-71. 19. Fireman B, Black SB, Shinefield HR, Lee J, Lewis E, Ray P. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. 2003;22:10-6. 20. Finnish Otitis Media Study Group. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403-9. 21. Finnish Otitis Media Study Group. Protective efficacy of a second pneumococcal conjugate vaccine against pneumococcal acute otitis media in infants and children: randomized, controlled trial of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine in 1666 children. Clin Infect Dis. 2003;37:1155-64. 22. el-Silimy O, Sharnuby M. Malignant external otitis: management policy. J Laryngol Otol. 1992;106:5-6. 23. Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhoea. Clin Otolaryngol Allied Sci. 1990;15:7-10.

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Chapter 21

Acute Bronchitis and Exacerbations of Chronic Bronchitis RICHARD B. KOHLER, MD JAMES S. TAN, MD

Key Learning Points ●

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Bacteria play a minor role, if any, in the pathogenesis of acute bronchitis in adults. Management of patients with suspected acute bronchitis should focus on ruling out serious illness, particularly pneumonia. Adults with acute bronchitis benefit little from, and should not be treated with, antibiotics. Bacteria, particularly Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, cause a substantial proportion of exacerbations of chronic bronchitis. Antibiotics chosen on the basis of a risk classification assignment should be used to treat exacerbations of chronic bronchitis. Daily use of inhaled bronchodilators and corticosteroids decrease the frequency of exacerbations of chronic bronchitis.

Acute Bronchitis Acute respiratory infections account for more visits to primary care physicians than any other single diagnosis. They often lead to an antibiotic prescription and account for approximately 75% of annual antibiotic prescriptions in the United States. (1). Acute bronchitis accounts for a sizeable proportion of these visits and prescriptions despite the recognition that antibiotics provide marginal, if any, benefits to these patients. In practice, physicians usually define acute bronchitis as a respiratory infection of less than 2 weeks of duration that is dominated by a cough, 401

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New Developments • In a recent trial of acellular pertussis vaccine, 63% of individuals developed

prolonged illness with cough each year with an average duration of 24.5 days. For illnesses that last more than 28 days, 1.9% were callused by B. pertussis. • A recent review of all placebo-controlled trials of β2-agonists in acute bronchitis did not reveal any significant benefit of oral or inhaled drug. • New data suggest that exacerbations of COPD are often caused by a new strain of Haemophilus influenzae, Sterptococcus pneumoniae, or Moraxella catarrhalis, which bear new cell surface antigens.

often but not always productive (2). Patients with pneumonia often have associated inflammation of the bronchial mucous membranes, but most physicians who choose the term acute bronchitis intend to infer the absence of pneumonia. Patients with chronic pulmonary diseases are excluded from most studies of acute bronchitis. In this chapter, findings from many studies are cited, with no uniform definition of acute bronchitis used by all. Generally, however, patients had an illness that was acute, usually 14 days or less at the time of presentation for study, with cough as the dominant symptom, often but not always productive. Upper respiratory symptoms such as sore throat were often present but did not dominate the clinical picture. Pneumonia was generally assumed absent, but radiological proof was not always provided. Chronic pulmonary disease was excluded to prevent confounding from chronic inflammation of the bronchial mucous membranes. Nearly always, the authors inferred that the cause of the bronchial symptoms were infectious agents. The discussion that follows focuses on the illness that occurs in adults.

Epidemiology In a multicenter U.S. trial of an acellular pertussis vaccine that involved adolescents and adults aged 15 to 65 years, 63% of individuals developed a prolonged illness with cough each year with an average duration of 24.5 days (3). Had they not been in the trial, however, many may not have sought medical care. In this trial, the seasonal peak incidence of acute cough illnesses was between December and March. Longer-term observations from the United Kingdom demonstrated a consistent seasonal variation in the acute bronchitis attack rate, ranging from highs of 70 to 140 per 100,000 persons in January and February to lows of 25 to 40 in late August (4). Attack rates were highest in people aged 0 to 4 years and older than age 64 years. Those aged 15 to 44 years were least likely to present with illness. Patients with asthma may be at increased risk for presenting to physicians with acute bronchitis (5).

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Etiology Noninfectious insults can inflame the bronchial mucosa and produce symptoms that resemble those in infectious acute bronchitis. These include thermal and chemical injury, environmental pollutants, medicines, and other systemic conditions. This section will focus on infectious causes of acute bronchitis. Despite careful study, a microbiologic cause of acute cough illnesses cannot be delineated in most cases (6,7). Thus, we do not know what causes most cases of acute bronchitis. Viruses cause many of the cases for which a cause can be delineated, including the influenza virus, respiratory syncytial virus, rhinoviruses, adenoviruses, and parainfluenza viruses. The severe acute respiratory syndrome–associated coronavirus can apparently cause a mild febrile respiratory illness associated with a chronic impracticable cough (8), but evidence linking other coronaviruses with acute bronchitis is tenuous. Mycoplasma pneumoniae and Chlamydophila pneumoniae in all likelihood cause some cases of acute bronchitis, but their presence in the respiratory secretions of healthy controls confounds interpretation of their presence in patients with acute cough illness. Some investigators (6,7) have attributed cases of acute bronchitis to Streptococcus pneumoniae, Haemophilus influenzae, and other bacteria. However, all these species are commonly carried by healthy humans (9,10), so the association with acute bronchitis is probably coincidental. Bordetella pertussis accounts for occasional cases of adult acute bronchitis. In an adult acellular pertussis vaccine trial in which 73% of participants recalled childhood pertussis immunization, 0.7% of 1284 acute cough illnesses of more than 5 days of duration were caused by B. pertussis. For illnesses that lasted more than 28 days, 1.9% of 208 were caused by B. pertussis (3).

Clinical Manifestations Coughing, essentially by definition, is present in all patients with acute bronchitis. Cough was productive, ranging from 70% to 90% of cases, in 3 series (2,7,11). Patients sought care primarily for cough, 90%; trouble sleeping (primarily caused by the cough), 61%; general feeling of illness, 56%; worry about a more serious illness (particularly pneumonia) either by the patient, 56%, or someone else, 47%; shortness of breath, 47%; inability to work, 38%; and others, 19% (Table 21-1) (11). On average, patients waited 10 days with their symptoms before presenting to a physician (range: 2-35 days) (7). Patients in the 20- to 60-year age group tended to wait longer than their younger and older counterparts. Patients often reported other respiratory symptoms such as nasal congestion (approximately half), rhinorrhea (half or more), sore throat (approximately half), headache (approximately half), and feverishness (approximately one third) (2,7,11). Verheij (11) found that at baseline, 35% of patients felt sick enough to have stopped daily work activities, and 33% were spending extra time in

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Table 21-1 Clinical Manifestations of Acute Bronchitis Manifestation

Frequency (%)*

Cough Trouble sleeping Dyspnea Nasal congestion Rhinorrhea Sore throat Inability to work Feverishness Fever

Nearly always 60 50 50 50 50 40 33 10-20

Data from: Verheij T, Hermans J, Kaptein A, Julder J. Acute bronchitis: Course of symptoms and restrictions in patients’ daily activities. Scand J Prim Health Care. 1995;13:8-12. * Frequency values are approximate.

bed; 69% reported at least some limitation in their normal physical activities. On physical examination, the lungs were abnormal 40% to 70% of the time. Rhonchi were found in 68% of patients in 1 study (11) and wheezes in 18% to 43% (7,11). Crackles were reported in 24% to 33%. Although feverishness was reported by approximately one third of patients, fever was documented on examination in only 20% (2). At 1 and 2 weeks, 30% and 13% of patients in 1 study reported continued frequent coughing; and 53% and 28% reported continued productive coughing (Table 21-2) (11). At 2 weeks, 34% continued to report dyspnea, 27% nasal congestion, 13% sore throat, and 5% feverishness. In a trial of oral albuterol for acute cough syndrome (12), the mean duration of cough was 10 days, and the range was 1 to 28 days. In the acellular pertussis vaccine trial, of 1284 acute cough illnesses, cough persisted for more than 2 weeks in 62%, more than 4 weeks in 24%, and more than 6 weeks in 11% (3). Thus, many patients with acute bronchitis continue to report of cough for 2 weeks after presentation, and coughing at 28 days is fairly common. Leukocytosis was documented in only 22% of patients in whom the leukocyte count was examined (7). Pulmonary function testing shows

Table 21-2 Percentage of Patients with Acute Bronchitis Still Coughing After Presentation for Care Days after Presenting for Care

7 14 21 28

Still Coughing (%)

80 40 20 10

Republished with permission from: Williamson HA. A randomized, controlled trial of doxycycline in the treatment of acute bronchitis. J Fam Pract. 1984;19:481-6. Note: Percentages are approximate.

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diminished airflow in some patients with acute bronchitis. In a study that excluded asthma patients, 11 of 33 at presentation had an FEV1 of less than 80% of predicted (5). Those with lower FEV1 at study entry missed more days of work on average than those with normal findings; but their cough duration, likelihood of smoking, and overall health ratings during the 14 days of observation did not differ. Hallett (13) suggests that a history of recurrent acute bronchitis may be a marker for underlying asthma. Of 46 consecutive patients with at least 2 physician-diagnosed episodes of acute bronchitis within the previous 5 years, 15 (33%) met American Thoracic Society spirometric criteria for asthma, and 15 of the remaining 31 had an abnormal methacholine challenge test. Documented progression of acute bronchitis to pneumonia is apparently rare. Only 1 instance is noted in the aforementioned studies (7).

Diagnosis The major diagnostic task for a clinician entertaining a diagnosis of acute bronchitis is to differentiate it from pneumonia, preferably quickly and inexpensively. As noted later, therapies for acute bronchitis, as opposed to pneumonia, have little or no beneficial effect. Most patients who present to physicians with acute cough illnesses do not have pneumonia. Using the chest radiograph as the gold standard, the likelihood of pneumonia in all patients presenting to physicians’ offices with acute cough in 1 study was 2.6% (14). In an emergency room study confined only to patients whose physicians ordered a chest radiograph to rule out pneumonia, it was present in 38% (15). Metlay and colleagues (16) found that there are no individual historical findings whose presence or absence reduce or raise the odds of pneumonia sufficiently to exclude the diagnosis without a chest film. In another study (14), a history of fever raised the likelihood of pneumonia in that office population from 2.5% to 5.5% (5.5%). Rhinorrhea reduced the likelihood to 0.4%. Regarding the examination, examiners often disagree about their chest findings. Spiteri (17) compared the chest examination findings of groups of certified physicians and determined that they were in complete agreement only 55% of the time. Agreement was greatest on percussion note, wheezing, and pleural rub; whereas it was in least agreement for whispering pectoriloquy, tactile vocal fremitus, and tracheal displacement, and intermediate for crackles and bronchial breathing. Gennis (15) found in an emergency room study that the combined findings of a temperature at least 37.8ºC, heart rate at least 100 beats/min, and respiratory rate at least 30 breaths/min reduced the likelihood of pneumonia from 38% in the entire study population to 6.8%. When asymmetric respiration was noted, pneumonia was always present, but asymmetric respiration was present in only 4% of patients with pneumonia. Other findings

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revealed that egophony and dullness to percussion increased the likelihood of pneumonia by a factor of 2.2 from its prevalence in the reference population. However, given the low prevalence of pneumonia in the overall study populations, the effect of observing these findings on estimating the probability of pneumonia was only modest. All 4 studies reviewed by Metlay and colleagues (16) supported the conclusion that the presence or absence of crackles on examination are insufficient to rule in or out the diagnosis of pneumonia. For example, with a prevalence of pneumonia of 5% in the target population, the absence of crackles reduced the probability of pneumonia only to 3%, and the presence of crackles raised the probability only to 10%. Metlay and colleagues (16) also examined the value of prediction algorithms. In 1 study in which the prevalence of pneumonia was 7%, physicians’ judgments that their patients did not need chest radiography reduced the probability of pneumonia to 2%. The physicians’ judgments surpassed all prediction rules produced by earlier studies. Even so, when the physician judged that the patient needed a chest radiograph, pneumonia was present in only 13%. Metlay and coworkers (16) concluded that there no are no combinations of history and physical examination findings that confirm the diagnosis of pneumonia. Thus, if diagnostic certainty is needed to differentiate acute bronchitis from pneumonia, within the limits of the chest radiograph itself, chest radiography should be done to rule pneumonia in or out.

Treatment Antibiotics Although evidence directs otherwise, most physicians prescribe antibiotics to treat adults with acute bronchitis (2,7,18). In 1 analysis, bronchitis accounted for 11% of all antibiotics prescribed and was the second-ranked reason for prescribing antibiotics in the ambulatory setting (19). Antibiotics were prescribed for acute bronchitis more often in 1994 (70% likelihood) than in 1980 (59% likelihood) (18). Physicians in a staff model health maintenance organization (HMO) prescribed antibiotics at the same rate as fee for service caregivers (20), but the antibiotics prescribed in the HMO were more likely narrow-spectrum, low-cost choices than in the fee-for-service practice. Many small trials over the years have compared an antibiotic to placebo for acute bronchitis. None alone has powered sufficiently to instill confidence in their outcomes. Smucny and colleagues (21) are the most recent investigators to attempt to combine data from these trials to enhance statistical power. They analyzed 11 outcomes: 1) cough at follow-up visit, 2) night cough at follow-up visit, 3) productive cough at follow-up visit, 4) limitation in work or activities at follow-up visit, 5) not alleviated by physician global assessment, 6) abnormal lung exam, 7) adverse effects, 8) number of days of cough, 9) number of days of productive cough,

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10) number of days of impaired activities, and 11) mean number of days of feeling ill. Because of variability in study design, the combined numbers of patients analyzed for measurement ranged from 275 to 1175. Antibiotic recipients were 64% (95%, CI 40%-85%) as likely as placebo recipients to have cough at follow-up visit, 67% (54%-83%) as likely to have night cough, 61% (48%-79%) as likely to be not alleviated, and 54% (41%-70%) as likely to have an abnormal lung exam. But these benefits were small in degree. Antibiotic recipients had a shorter duration of cough, on average 0.58 days (0.01-1.16), and productive cough, on average 0.52 days (0.01-1.03). The differences in the other measurements did not reach statistical significance. Most studies showed more adverse effects in the antibiotic group with a combined but nonsignificant relative risk of 1.22 (0.94-1.58). Most trials did not require chest radiographs for inclusion, so some participants may have had pneumonia. However, as cited earlier in this chapter, the incidence of pneumonia in these patients in office practices is low. There may have been publication bias, because small positive trials are more likely to be published than small negative trials. Nonetheless, the current accumulated evidence suggests small benefits to antibiotics in adults with acute bronchitis. Weighing against these small benefits are antibiotic side effects and the effect of widespread population antibiotic exposure on bacterial resistance patterns. A panel of physicians convened by the Centers for Disease Control and Prevention (CDC) (22) representing the disciplines of internal medicine, family medicine, emergency medicine, and infectious diseases developed and published a set of principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis (23). They recommended that the evaluation of adults with an acute cough illness or a presumptive diagnosis of uncomplicated acute bronchitis (prominent acute cough for less than 3 weeks of duration) should focus on ruling out serious illness, particularly pneumonia. Except in the unusual situation of a pertussis outbreak or known recent exposure, routine antibiotic treatment of uncomplicated acute bronchitis is not recommended regardless of cough duration or presence of purulent sputum. CDC cited evidence that supports the principle that patient satisfaction with care for acute bronchitis depends most on physician–patient communication and not on whether an antibiotic is prescribed. Furthermore, the CDC recommended that physicians provide realistic expectations for the duration of the patient’s cough, which will typically last 10 to 14 days after the office visit; refer to the cough as a chest cold rather than bronchitis; personalize the risk of unnecessary antibiotic use; and explain why, in public health terms, we must be more selective in treating only those conditions for which a major clinical benefit of antibiotics is proven. Summarizing, antibiotics probably produce small benefits in acute bronchitis. These small benefits are offset by side effects and selection of resistant organisms. Physicians who decide, as recommended by the guidelines, not to use antibiotics to treat acute bronchitis still sometimes face the problem of

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knowing whether their patients have acute bronchitis or pneumonia. The history and physical examination are imperfect in distinguishing acute bronchitis and pneumonia. The following process might be considered, but it, too, should be subject to prospective study. Patients suspected of having acute bronchitis, without fever, tachycardia, or hypotension, or some overt sign of more significant intrathoracic disease (definite dullness to percussion, markedly decreased breath sounds, unequal expansion of the 2 sides of the chest, etc.) should not receive antibiotics. All others should undergo chest radiograph exam. Those thought to have acute bronchitis should receive counseling and reassurance, but they should not receive antibiotics.

Bronchodilators and Antitussives Smucny and coworkers (24) reviewed all placebo-controlled trials of β2-agonists in acute bronchitis. They found that overall summary statistics did not reveal any significant benefits from oral or inhaled drug. There may have been benefits in subgroups with airflow limitation; but tremor, shakiness, and nervousness were more common in the drug recipients. They concluded that there is little evidence that routine use of β2-agonists is helpful in adults with acute cough and that any benefits may be offset by side effects. Guaifenesin seems ineffective as an antitussive (25). Although codeine and dextromethorphan seem effective antitussives (25), a subsequent study of codeine (26) showed no benefit.

Prevention Immunization with the influenza vaccine reduces the frequency and severity of influenza infections. The acellular pertussis vaccine reduced the frequency of pertussis in adults by approximately 90% over a 1-year period of observation, but many needed to be immunized to prevent a case (3).

Summary Acute bronchitis accounts for many visits to primary care physicians annually. Primary care physicians manage most patients with this problem. These illnesses can last for weeks at a time. The infecting pathogen cannot be delineated in most cases, but viruses account for most with a defined microbial cause. If antibiotics produce any benefits in acute bronchitis, they are small and difficult to measure. Pneumonia must be reasonably excluded on clinical or radiological grounds. Normal vital signs make pneumonia unlikely. Chest radiographs to exclude pneumonia may be warranted to minimize antibiotic use in this era of selection of resistant pathogens. Antitussives and β2-agonists are controversial and seem to be of marginal or no benefit. Counseling and observation seem to be warranted for most patients with acute bronchitis. An overall strategy for managing suspected acute bronchitis is outlined in Figure 21-1.

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Strategies for Managing Suspected Acute Bronchitis

Acute bronchitis suspected Acute respiratory infections suspected

Temperature ≤ 37.8⬚C Heart rate ≤ 100 Resp rate ≤ 30 No asymmetric respiration or signs of consolidation

No

Pneumonia possible; Strategy B: chest radiograph Strategy C: empiric antibiotics

Yes

Acute bronchitis suspected. Pneumonia unlikely Strategy A: No antibiotics

Figure 21-1 Strategies for managing suspected acute bronchitis. Strategy A: Patient unlikely to have pneumonia. Minimal expected benefits from antibiotics in acute bronchitis. Minimize selective pressure for antibiotic resistance. Avoid antibiotic side effects. Strategy B: Preferred strategy. Trades increased radiation exposure and cost for studies versus decreased need to use antibiotics. Strategy C: Optional strategy. Probably less expensive in short run. Less radiation exposure. More time-efficient for patient. Increase public risk for selection antibiotic-resistant bacteria. Note: This algorithm has not been studied prospectively or subjected to cost-effectiveness analysis. It represents the authors’ proposal based on the data available.

Acute Exacerbations of Chronic Bronchitis In practical terms, chronic bronchitis may be defined as chronic productive cough without a medically discernible cause that is present for more than half the time for at least 2 years (27). When these individuals develop increased cough and sputum production, increased sputum purulence, and increased dyspnea, they are said to have an acute exacerbation of chronic bronchitis (28). Often, a more formal definition is used in which 2 of these 3 elements are present (29). Also implied in this definition is that no easily documented cause of these symptoms, particularly pneumonia, is present (30).

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Epidemiology Chronic bronchitis occurs in 3% to 7% of the middle-aged to elderly population in most parts of the world (31). Approximately 5% of U.S. adults suffer from chronic bronchitis (32). Between them, acute bronchitis and acute exacerbations of chronic bronchitis account for approximately 14 million physician visits per year in the United States (30).

Pathogenesis and Etiology There is increased airway inflammation in patients with chronic obstructive pulmonary disease (COPD), and this inflammation increases further during exacerbations (33). Factors proposed as possible causes of exacerbations of chronic bronchitis include infection and irritant or allergic reaction to environmental pollutants or allergens (34). Viruses such as influenza, parainfluenza, rhinovirus, coronavirus, adenovirus, and respiratory syncytial virus or their DNA or RNA, are present more often during COPD exacerbations than at baseline (33). Bacteria, particularly Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, also cause exacerbations. This is often associated with replacement of old strains by a new strain bearing new cell surface antigens (33). In the face of recurrent treatment, other gramnegative rods may also play a role.

Clinical Manifestations The reported clinical manifestations in exacerbations of chronic bronchitis depend on how exacerbation is defined. Ball (34) described findings in 471 patients who were diagnosed by 127 British practitioners with acute exacerbations of chronic bronchitis using no predefined criteria for the diagnosis. The most common symptom was increased sputum production, seen in 77%. Other symptoms were mucopurulent or purulent sputum in 66%, moderate to severe increase in breathlessness in 45%, and fever in 12%. Sixty-nine percent met the definition for acute exacerbation of chronic bronchitis that requires having 2 of the following 3 elements: 1) increased dyspnea, 2) increased sputum production, and 3) sputum purulence. The reported number of previous exacerbations in the preceding year was less than 3 in 37%, 3 or 4 in 31%, and more than 4 in 32%. Most patients received antibiotic therapy. Thirteen percent returned with the same symptoms within 4 weeks, 2% requiring hospitalization. Having a history of cardiopulmonary disease plus more than 4 exacerbations in the previous year predicted return within 4 weeks with a specificity of 47% and sensitivity of 75%. Receiving antibiotics did not decrease the likelihood of return within 4 weeks. In a 1-year longitudinal study of patients with chronic bronchitis, exacerbations lasted on average approximately 14 days (28). In 10% the exacerbation lasted at least 25 days.

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Diagnosis Exacerbations of chronic bronchitis are diagnosed on the basis of the history. Corroboration of the history of sputum purulence involves gross inspection of sputum. Deteriorating arterial blood gas findings can substantiate a history of worsening dyspnea. A chest radiograph can exclude pneumonia or pneumothorax if either is suspected.

Treatment Because each infective acute exacerbation may result in a sustained effect on the patient’s health status, such as a decline in FEV1, therapy that can reduce the frequency and duration of attacks may have a clinically significant effect on the patient’s health status. Antibiotics seem to shorten the duration of exacerbations. Saint and coworkers (35) showed in a metaanalysis that antibiotic therapy had done better than placebo. A meta-analysis by Bach and colleagues (36) found that patients with more severe exacerbations are more likely to benefit from antibiotic treatment than those with less severe attack. The potential short-term benefits of antibiotics include decrease in the duration of symptoms, reduced hospitalization, reduced number of work days lost, and prevention of pneumonia. The long-term benefits are prevention of progressive airway damage and prolongation of time between exacerbations. Table 21-3 shows a risk classification and antimicrobial therapy suggested by recent guidelines from the Canadian Thoracic Society and Canadian Infectious Diseases Society (37). The patients are classified into 4 categories namely, groups 0, I II, and III based on the clinical status. The diagnostic criteria of each are listed with their corresponding probable pathogens and recommended treatment. The classification scheme and associated treatment recommendations (Table 21-4) have not been subjected to prospective testing but take into account the evidence available and the derived opinions of a panel of experts. Figure 21-2 shows a modified algorithm from the aforementioned publication. Although the focus of this book is on infections, the optimal treatment of exacerbations of chronic bronchitis includes appropriate oxygen supplementation, inhaled bronchodilators, and short course systemic corticosteroids (36,37). Selected patients may benefit from noninvasive positive-pressure ventilation, and some require invasive mechanical ventilatory support.

Prevention Daily use of inhaled bronchodilators and corticosteroids reduces the frequency of acute exacerbations of chronic obstructive lung disease. For example, combined treatment with inhaled salmeterol and fluticasone reduced the frequency of any exacerbation by 25% and reduced oral

Probable Pathogens

Antimicrobial First Choice

Antimicrobial Alternatives for Treatment Failures

Republished from: Balter M, La Forge J, Low D, et al. Canadian guidelines for the management of acute exacerbations of chronic bronchitis: Executive summary. Can Respir J. 2003;10:248-58. Abbreviations: d = day; mo = month; TMP-SMX = trimethoprim-sulfamethoxazole; y = year.

III

II

I

Acute tracheobronchitis

0

Symptoms and Risk Factors

Cough and sputum without Usually viral None unless symptoms Macrolide or tetracycline previous pulmonary disease last >10-14 d ● New macrolide ● Fluoroquinolone Chronic bronchitis Increased cough and sputum ● Haemophilus ● Ketolides (respiratory) without risk factors volume, sputum purulence, influenzae ● Haemophilus spp ● 2nd or 3rd generation ● Beta-lactam/beta(simple) and increased dyspnea ● No comorbid illness ● Moraxella cephalosporin lactamase inhibitor ● <4 exacerbations per year ● Amoxicillin catarrhalis ● FEV ≥ 50% predicted ● Streptococcus ● Doxycycline 1 ● TMP-SMX pneumoniae ● Fluoroquinolone May require parenteral Chronic bronchitis with As in group I plus at least 1 As in group I, plus ● Klebsiella species (respiratory) therapy; consider referral to risk factors (complicated) of the following: ● Cardiac disease ● Beta-lactam/betaand other gram a specialist or hospital ● ≥4 exacerbations/y negatives lactamase inhibitor ● FEV < 50% predicted ● Increased 1 ● Home oxygen probability of ● Chronic oral steroids β-lactam resistance ● Antibiotic use within the past 3 mo Chronic suppurative As in group II with constant ● As in group II plus ● Ambulatory patients: bronchitis purulent sputum Pseudomonas Tailor treatment to airway ● Some have bronchiectasis aeruginosa and pathogens. P. aeruginosa ● FEV usually <35% multiresistant common (ciprofloxacin) 1 predicted Enterobacteriaceae ● Hospitalized patients: ● Multiple risk factors family parenteral therapy usually required.

Basic Clinical State

412

Group

Table 21-3 Risk Classification and Suggested Antimicrobial Therapy

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Table 21-4 Recommended Antimicrobial Treatment Regimen for Acute Exacerbation of Chronic Bronchitis Group*

Antimicrobial Agent

Dose and Duration of Therapy

I

Azithromycin (Zithromax)

I I I I I I I II

Clarithromycin (Biaxin) Cefuroxime axetil (Ceftin) Cefprozil (Cefzil) Cefpodoxime (Vantin) Amoxicillin Doxycycline TMP-SMX Levofloxacin (Levaquin)

II II II

Gatifloxacin (Tequin) Moxifloxacin (Avelox) Amoxicillin/clavulanate (Augmentin)

500 mg PO initially, followed by 250 mg PO qd × 4d 500 mg PO bid or 1 g PO qd × 10-14d 500 mg PO bid × 10-14d 500 mg PO bid × 10-14d 200-400 mg PO bid × 10-14d 500 mg PO bid or 875 mg bid × 10-14d 100 mg PO bid × 10-14d 1 DS tablet PO bid × 10-14d 500 mg IV or PO qd × 7d 750 mg IV or PO qd × 5d 400 mg IV or PO qd × 5d 400 mg IV or PO qd × 5d 875 mg PO bid × 10-14d

Modified from: Balter M, La Forge J, Low D, et al. Canadian guidelines for the management of acute exacerbations of chronic bronchitis: Executive summary. Can Respir J. 2003;10:248-58. * Group I: patients with chronic bronchitis without risk factors (simple). Group II: patients with chronic bronchitis with risk factors (complicated). Group III: patients with chronic suppurative bronchitis. No antimicrobial recommendations are given. The choice of antimicrobial agents should be based on culture and susceptibility. Abbreviations: bid = twice a day; d = day; IV = intravenously; PO = by mouth; q = every; TMP-SMX = trimethoprim-sulfamethoxazole.

corticosteroid-requiring exacerbations by 39% compared to placebo in a recent large multticenter trial (38). Monotherapy with either drug was nearly as effective as the combination for the end point of frequency of exacerbations, but the combination had statistically significant advantages over monotherapy for other end points, such as flow rate improvement. Several meta-analyses have suggested that orally administered N-acetylcysteine (NAC) may decrease the frequency of exacerbations of COPD, but a subsequent multicenter trial showed no such benefit in the overall trial population (39). A subgroup analysis, however, showed a statistically significant 20% reduction in the frequency of exacerbations in patients not treated with concurrent inhaled corticosteroids. The tablet form of the drug used in the reported trials is not available in the United States, nor is NAC approved for this use by the Food and Drug Administration. Annual influenza immunization and 1 pneumococcal polysaccharide immunization repeated every 5 to 10 years are recommended to all patients with chronic lung disease (37). Smoking cessation diminishes the decline with time of the FEV1. It also decreases the frequency of self-reported lower respiratory illness in patients with mild chronic obstructive lung disease (40,41).

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Risk Factors: FEV1 <50% predicted >4 exacerbations/y heart disease use of home oxygen chronic oral steroid use antibiotics in past 3 mo.

· · · · · ·

Patient with chronic bronchitis with symptoms ? Increased sputum ? Increased sputum purulence ? Increased dyspnea

· · ·

Focal chest findings on examination

No

Yes

Yes

Chest x-ray new infiltrates suggestive of pneumonia

Yes

Pneumonia present

No

Poor response to Group I* antimicrobial recommendations

Two or more symptoms

No

Group 0 No antibiotics

Treat according to CAP guidelines

No

Pneumonia not present. Two or more symptoms

One or more risk factors present

Yes

Chronic suppurative bronchitis suspected***

No

Deterioraation Fluoroquinolone Amoxicillin/clavulanate

Yes

No

Poor response to Group II** antimicrobial recommendations

Improvement No further therapy

No

Improvement No further therapy

Yes Yes Treat empirically for Pseudomonas and resistant enteric organisms. Target therapy when susceptibilities are known

Gram stain and culture

*Group I: new macrolides, 2nd and 3rd generation cephalosporins, amoxicillin, Sulfamethoxazole-trimethoprim, doxycycliine

**Fluoroquinolone, β-lactam/βlactamase inhibitor

Figure 21-2 Algorithm for choosing antimicrobial therapy in acute exacerbation of chronic bronchitis. (Republished with permission from Balter M, La Forge J, Low D, et al. Canadian guidelines for the management of acute exacerbations of chronic bronchitis: Executive summary. Can Respir J. 2003;248-58.

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Summary Acute exacerbations of chronic bronchitis precipitate many visits to primary care physicians, who make the diagnosis primarily on the basis of the history. Antibiotics provide sufficient benefit in exacerbations of chronic bronchitis to warrant their use, with choices to be made on the basis of the patient’s disease severity and other risk factors. Exacerbation frequency can be diminished through smoking cessation and the regular use of inhaled corticosteroids and β2-agonists. Influenza and pneumococcal immunization are recommended as well to reduce the frequency of exacerbations. REFERENCES 1. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA. 1995;273:214-9. 2. Dunlay J, Reinhardt R. Clinical features and treatment of acute bronchitis. J Fam Pract. 1984;18:719-22. 3. APERT Study Group. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med. 2005;353:1555-63. 4. Ayres JG. Seasonal pattern of acute bronchitis in general practice in the United Kingdom 197683. Thorax. 1986;41:106-10. 5. Williamson HA Jr., Schultz P. An association between acute bronchitis and asthma. J Fam Pract. 1987;24:35-8. 6. Macfarlane JT, Colville A, Guion A, Macfarlane RM, Rose DH. Prospective study of aetiology and outcome of adult lower-respiratory-tract infections in the community. Lancet. 1993;341:511-4. 7. Boldy DA, Skidmore SJ,Ayres J G. Acute bronchitis in the community: clinical features, infective factors, changes in pulmonary function and bronchial reactivity to histamine. Respir Med. 1990;84:377-85. 8. Skowronski DM, Astell C, Brunham RC, Low DE, Petric M, Roper RL, et al. Severe acute respiratory syndrome (SARS): a year in review. Annu Rev Med. 2005;56:357-81. 9. Hendley JO, Sande MA, Stewart PM, Gwaltney JM Jr. Spread of Streptococcus pneumoniae in families. I. Carriage rates and distribution of types. J Infect Dis. 1975;132:55-61. 10. Hirschmann JV, Everett ED. Haemophilus influenzae infections in adults: Report of nine cases and a review of the literature. Medicine (Baltimore). 1979;58:80-94. 11. Verheij T, Hermans J, Kaptein A, Mulder J. Acute bronchitis: course of symptoms and restrictions in patients’ daily activities. Scand J Prim Health Care. 1995;13:8-12. 12. Littenberg B, Wheeler M, Smith DS. A randomized controlled trial of oral albuterol in acute cough. J Fam Pract. 1996;42:49-53. 13. Hallett JS, Jacobs RL. Recurrent acute bronchitis: the association with undiagnosed bronchial asthma. Ann Allergy. 1985;55:568-70. 14. Diehr P,Wood RW, Bushyhead J, Krueger L,Wolcott B,Tompkins RK. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis. 1984; 37:215-25. 15. Gennis P, Gallagher J, Falvo C, Baker S,Than W. Clinical criteria for the detection of pneumonia in adults: guidelines for ordering chest roentgenograms in the emergency department. J Emerg Med. 1989;7:263-8. 16. Metlay JP, Kapoor WN, Fine M J. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA. 1997;278:1440-5. 17. Spiteri MA, Cook DG, Clarke SW. Reliability of eliciting physical signs in examination of the chest. Lancet. 1988;1:873-5. 18. Metlay JP, Stafford RS, Singer DE. National trends in the use of antibiotics by primary care physicians for adult patients with cough. Arch Intern Med. 1998;158:1813-8. 19. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA. 1997;278:901-4. 20. Hueston WJ, Mainous AG 3rd, Brauer N, Mercuri J. Evaluation and treatment of respiratory infections: does managed care make a difference? J Fam Pract. 1997;44:572-7. 21. Smucny J, Fahey T, Becker L, Glazier R. Antibiotics for acute bronchitis. Cochrane Database of Syst Rev. 2005;1.

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22. Gonzales R, Bartlett JG, Besser RE, Cooper RJ, Hickner JM, Hoffman JR, et al. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods. Ann Emerg Med. 2001;37:690-7. 23. American Academy of Family Physicians. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Intern Med. 2001;134:521-9. 24. Smucny J, Flynn C, Becker L, Glazier R. Beta2-agonists for acute bronchitis. Cochrane Database of Syst Rev. 2005;1. 25. Irwin RS, Curley FJ. The treatment of cough. A comprehensive review. Chest. 1991; 99:1477-84. 26. Eccles R, Morris S, Jawad M. Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther. 1992;17:175-80. 27. Snider GL, Faling J, Rennard SI. Chronic bronchitis and emphysema. In: Murray JF, Nadel JA, eds. Textbook of Respiratory Medicine. 2nd ed. Philadelphia, PA: WB Saunders; 1994:1331-97. 28. Grossman R, Mukherjee J,Vaughan D, Eastwood C, Cook R, LaForge J, et al. A 1-year communitybased health economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbations of chronic bronchitis: the Canadian Ciprofloxacin Health Economic Study Group. Chest. 1998;113:131-41. 29. Anthonisen NR, Manfreda J,Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106:196-204. 30. Grossman RF. Guidelines for the treatment of acute exacerbations of chronic bronchitis. Chest. 1997;112(6S):310-3S. 31. Ball P, Make B. Acute exacerbations of chronic bronchitis: An international comparison. Chest. 1998;113(3 suppl):199-204S. 32. Centers for Disease Control and Prevention. Current estimates from the national health interview survey, 1995. Natl Vital Stat Rep. 1998;10:199. 33. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: new developments concerning microbiology and pathophysiology—impact on approaches to risk stratification and therapy. Infect Dis Clin North Am. 2004;18:861-82, ix. 34. Ball P, Harris JM, Lowson D. Acute infective exacerbations of chronic bronchitis. Q J Med. 1995;88:61-8. 35. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA. 1995;273:957-60. 36. American College of Physicians-American Society of Internal Medicine. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med. 2001;134:600-20. 37. Chronic Bronchitis Working Group. Canadian guidelines for the management of acute exacerbations of chronic bronchitis: executive summary. Can Respir J. 2003;10:248-58. 38. Trial of Inhaled Steroids and long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003;361:449-56. 39. Decramer M, Rutten-van Mölken M, Dekhuijzen PN,Troosters T, van Herwaarden C, Pellegrino R, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365:1552-60. 40. Lung Health Study Research Group. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164:358-64. 41. Williamson HA Jr. A randomized, controlled trial of doxycycline in the treatment of acute bronchitis. J Fam Pract. 1984;19:481-6.

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Chapter 22

Influenza and Other Viral Respiratory Tract Infections JASON W. CHIEN, MD, MS JOHN L. JOHNSON, MD

Key Learning Points 1. Clinical manifestations of viral respiratory infections are nonspecific 2. Diagnostic procedures should be pursued if a viral infection is considered, particularly among immunocompromised hosts. 3. Vaccination, when available, is the most effective method of avoiding respiratory viral infections. 4. Resistance to existing antiviral therapy is on the rise and resistance patterns should be considered before an antiviral is prescribed. 5. Preemptive therapy is important for preventing opportunistic viral infections in immunocompromised hosts.

V

iruses are important causes of community-acquired pneumonia in children and adults (Table 22-1). Although influenza and respiratory syncytial viruses (RSVs) are the most common causes of serious viral respiratory illness; parainfluenza, adenoviruses, and other agents are also significant pathogens (1). In adults, severe viral pneumonia is more frequent in elderly patients, persons with chronic lung disease such as chronic obstructive pulmonary disease (COPD), and other chronic medical illnesses and immunosuppressive conditions. The true proportion of community-acquired pneumonia in adults caused by viruses is difficult to determine because of the limited testing for viral pathogens in many settings and the limited sensitivity of some diagnostic tests. However, viral infections have been identified in approximately 10% (range 4% to 39%) of relatively immunocompetent adults hospitalized with community-acquired pneumonia (2). In a recent well-done prospective study 417

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New Developments • There has been an increased recognition of new viral respiratory infections

including avian influenza, human metapneumovirus and SARS. • The appearance of severe acute respiratory syndrome (SARS) was dramatic and

short lived but there was rapid recognition of the epidemiology, pathogenesis and etiology through worldwide efforts by public health agencies. • There is increasing resistance of seasonal influenza strains to amantadine and rimantadine globally.

Table 22-1 Common Causes of Viral Pneumonia in Adults and Children Children

Adults

Respiratory syncytial virus Parainfluenza virus, types 1-3 Adenovirus Influenza A and B Varicella-zoster virus Herpes simplex virus type 1 Human metapneumovirus

Influenza A and B Herpes simplex virus type 1 Varicella-zoster virus Adenovirus Cytomegalovirus Hantavirus

from the United Kingdom, of 267 adults with community-acquired pneumonia, viruses were suspected to be the cause of pneumonia in 23% (3). The frequency of reported viral pneumonias has increased during the past decade, most likely caused by a combination of better diagnostic techniques and an increasing risk for viral pneumonias among the growing immunocompromised population. This chapter will focus on modern diagnostic techniques and the most frequent viral pathogens causing severe lower respiratory disease in adults. The clinical and public health challenges imposed by new respiratory pathogens such as avian influenza, severe acute respiratory syndrome (SARS), and human metapneumovirus will also be discussed.

Diagnosis: General Principles Diagnosing viral lower respiratory tract infections can be challenging. The clinical presentation of viral pneumonia varies, is often nonspecific, and can be mimicked by other processes such as severe community-acquired or atypical pneumonias, acute lung injury from a systemic inflammatory syndrome, or noninfectious diffuse lung processes such as hypersensitivity pneumonitis. Clinical suspicion should be based on the combination of epidemiologic characteristics such as characteristic seasonal patterns, and constitutional symptoms such as fever, chills, nonproductive cough, rhinitis, myalgias, headaches, and fatigue. Although physical examination findings such as

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wheezing, rales, increased fremitus, and signs of wide spread bronchial inflammation frequently accompany viral processes, they are also seen in pyogenic pneumonia. However, viral respiratory tract infections are more likely to be associated with extrapulmonary manifestations, especially conjunctivitis, gastroenteritis, lymphadenopathy, and exanthems. Unfortunately, the radiological features of viral pneumonias are also nonspecific. Findings can mimic bacterial pneumonia and range from patchy bronchopneumonia to fleeting infiltrates to more characteristic diffuse interstitial or nodular infiltrates. Cavitation and pleural effusions, although possible, are rare. Because severe leukocytosis is uncommon in viral pneumonia, a total leukocyte count of less than 15,000 cells/mm3 in the setting of severe pneumonia should also suggest a viral cause.

Laboratory Testing Viral Culture and Antigen Detection An etiologic diagnosis of viral pneumonia can be made by isolation and identification of the viral pathogen through viral culture or by isolating its DNA or antigens in lower respiratory tract secretions or lung tissue (Table 22-2) (4). Most respiratory viruses can be isolated by cell culture of specimens from the upper and lower respiratory tract, which include nasopharyngeal swabs, sputum, and bronchoalveolar lavage (BAL) and biopsy specimens. Nasopharyngeal swabs or washings are useful for RSV, influenza, parainfluenza, and adenovirus culture. For best results viral cultures should be obtained early during the course of the illness. Cell cultures can be used to detect changes in appearance called viral cytopathic effect (CPE) as evidence of viral growth, or for hemadsorption testing by adding guinea pig erythrocytes to cultured cell monolayers and noting adherence of erythrocytes to the monolayer in the presence of viral growth. Once CPE is seen or hemadsorption tests are positive, the responsible virus can be further identified using immunofluorescent enzyme-linked immunosorbent assays (ELISA) and nucleic acid probes. Because of the slow growing nature of conventional fibroblast cell cultures, shell vial culture systems are now widely used to speed the detection of cytomegalovirus (CMV), RSV, herpes simplex virus (HSV), adenovirus, influenza, parainfluenza virus, and other pathogens. Rapid antigen detection tests based on ELISA methods are available for HSV, RSV, influenza A and B, parainfluenza types 1 through 4, CMV, and other respiratory viruses (4). Although the sensitivity of antigen detection tests is lower than viral cultures, many laboratories use panels of antibodies to common respiratory viruses for screening clinical specimens because this approach is faster. A recently developed molecular diagnostic technique, the multiplex reverse transcriptionpolymerase chain reaction (RT-PCR) assay, overcomes the low sensitivity of antigen detection assays, the delay of viral cultures, and the limitation of

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Table 22-2 Diagnostic Techniques for Viral Infections Virus

Method of Diagnosis

Herpesviruses

HSV

●

VZV

●

●

CMV

● ●

Tracheal aspirate or BAL for viral cultures and antigen testing by ELISA, immunoabsorbent assays Samples from lesions for Tzanck smears, viral culture, and immunofluorescent assays Serum for immunofluorescent assays, complement fixation, neutralizing antibody test, and enzyme immunoassay BAL specimens for cytology, viral culture, DNA PCR Serum for DNA PCR and antigen testing

Paramyxoviruses

RSV

●

Parainfluenza

●

●

Measles

● ●

Influenza

●

Adenovirus

●

Hantavirus

●

●

Tracheal aspirate or BAL for viral culture, antigen testing by ELISA and fluorescein conjugate monoclonal or polyclonal antibody, RTPCR Nasal and bronchial secretions for viral culture and immunofluorescent assays (serotypes 1, 2, and 3), RT-PCR Serum for complement fixation and hemagglutination BAL specimens for cytology Tracheal, respiratory secretions, or BAL samples for viral culture and immunofluorescent assays Respiratory secretions for viral cultures and immunofluorescent and ELISA assays, RT-PCR Respiratory secretions for viral culture, complement fixation, hemagglutinate inhibition, and neutralization Serum for hantavirus IgM antibodies or acute and convalescent IgG antibody Tissue for immunohistochemistry and RT-PCR

Abbreviations: BAL, bronchoalveolar lavage; CMV, cytomegalovirus; HSV, herpes simplex virus; ELISA, enzyme-linked immunoabsorbent assay; PCR, polymerase chain reaction; RSV, respiratory syncytial virus; RT-PCR, reverse transcriptase polymerase chain reaction; VZV, varicella-zoster virus.

assaying for only one virus per specimen by traditional PCR (5). An example is the Hexaplex assay (Prodesse, Inc., Milwaukee, Wis.), a multiplex RT-PCR assay for the detection of parainfluenza virus types 1, 2, and 3, respiratory syncytial virus (RSV) types A and B, and influenza virus types A and B in a single-step multiplex RT-PCR with much higher sensitivity and specificity than conventional viral culture and immunofluorescence methods (6,7). An extension of this method, real-time RT-PCR, has also been useful for detection of all four genetic lineages of human metapneumovirus (8). Test results should be interpreted with caution. Although recovery of influenza, parainfluenza, and RSV confirms the diagnosis of viral pneumonia caused by these pathogens, the significance of positive respiratory secretion and tissue cultures for herpes viruses such as CMV and HSV must be established by correlation with clinical and histologic findings. This is because herpes viruses can establish latency and are often shed intermittently in the absence of invasive disease. A positive culture of for herpes viruses alone is not diagnostic of active disease.

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Cytology and Histology Respiratory secretions, BAL samples, and tissue specimens can be examined using cytologic and histologic methods (4). Although intranuclear inclusions are often seen in cells infected with DNA viruses, cytoplasmic inclusions are usually present in RNA virus infected cells. For example, CMV infection is associated with the presence of characteristic “owl’s eye” cells, which appear as large cells with basophilic intranuclear inclusions with a surrounding clear zone. Although the presence of viral inclusions is diagnostic of a viral infection, cytologic methods have low sensitivity and the absence of inclusions does not reliably exclude infection or active disease.

Treatment: General Principles A decision to empirically treat for viral pneumonias should be made only after considering common etiologies of pulmonary infection. A suggested algorithm for assessment and treatment of the immunocompetent and immunocompromised host is summarized in Figure 22-1. Empiric therapy for community-acquired pneumonia, and especially atypical pneumonia, should be instituted until their absence is confirmed. An aggressive diagnostic approach with the aid of fiberoptic bronchoscopy is useful for ruling out pyogenic as well as noninfectious etiologies of diffuse pulmonary disease. As will be discussed next, there are few options available for treatment of viral pneumonias that have proven efficacy. However, because acyclovir and ganciclovir have relatively benign side-effect profiles, these antivirals should be considered for empiric therapy whenever herpes viruses such as varicella-zoster virus (VZV), HSV, and CMV are possible culprits. If a noninfectious cause such as hypersensitivity pneumonitis is a serious consideration and corticosteroid treatment can be indicated, one should make every effort to rule out an infectious process before initiating corticosteroid therapy.

Influenza Influenza viruses are enveloped, single-stranded RNA viruses of the family, Orthomyxoviridae. Influenza viruses are classified as type A, B, or C based on antigenic differences in internal matrix and nuclear proteins and subtyped based on differences in surface hemagglutinin (H) and neuraminidase (N) glycoproteins (9). Influenza A, the leading cause of influenza in adults in the United States, is responsible for up to 90% of cases of epidemic influenza. Influenza epidemics occur almost annually during the winter months and are associated with 10,000 to 40,000 excess deaths in the United States during severe outbreaks. Eighty percent of these deaths

Symptoms persist, repeat chest radiograph, consider bronchoscopy with BAL if etiology not known

Abnormal

Initiate medical therapy

Normal

Stop

Screen for respiratory viruses, serologic studies

Normal

Adjust medical therapy according to BAL results

Initiate empirical medical treatment for bacterial pathogens

Bronchoscopy with BAL, for bacterial, atypical, opportunistic, and viral pathogens, serologic studies

Abnormal

Figure 22-1 Algorithm for the evaluation and treatment of immunocompetent and immunocompromised patients with viral respiratory tract infections.

Symptoms resolve. Stop

Screen for community acquired bacterial, atypical, and viral pathogens, Initiate medical treatment for bacterial and atypical pathogens

Atypical pattern

Abnormal

Lobar pattern

Initiate medical therapy for community acquired bacterial pathogens

Stop

Normal

Chest radiograph

Immunosuppressed patient

422

Chest radiograph

Immunocompetent patient

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occur in persons older than 65 years of age. Individuals with emphysema, congestive heart failure, hemoglobinopathies, and immunosuppression are at increased risk for severe disease.

Pathogenesis and Etiology Influenza is transmitted primarily by respiratory secretions from individuals actively shedding virus. It can also be transmitted by direct contact, and possibly by contact with infected surfaces or objects with self-inoculation of the nasal or oral mucosa or conjunctiva. The incubation period in humans is short and ranges from 1 to 5 days. The virus infects and kills ciliated respiratory epithelial cells causing diffuse inflammation throughout the tracheobronchial tree. Therefore, transient increases in airway reactivity are frequent and wheezing can be present. Influenza manifests as an acute febrile respiratory illness associated with cough, sore throat, headache, myalgias, and malaise. The illness is usually selflimited; major symptoms usually alleviate within 3 to 5 days. Influenza can be complicated by either direct involvement of the lung parenchyma, or more seriously, superimposed bacterial infections caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, or gram-negative pathogens. In the latter instances there is often a history of initial alleviation of influenza symptoms followed by clinical deterioration, recurrent fever, and pneumonia several days later. Patients with suspected secondary bacterial pneumonia require culture of blood and respiratory secretions and appropriate antibiotic coverage for bacterial pathogens.

Diagnosis During community outbreaks of influenza in the winter months, the diagnosis can be confidently made based on typical clinical symptoms. At other times laboratory confirmation by detecting the virus or viral antigens in nasal washes, throat swab, sputum, or BAL fluid is required. Influenza virus can be isolated from respiratory secretions by tissue culture. Immunofluo-rescent and ELISA antigen detection methods for testing respiratory and nasopharyngeal secretions have a sensitivity of more than 80%. PCR-based laboratory tests are also available. Diagnostic yields are better on nasopharyngeal specimens than throat swabs. A fourfold increase in acute and convalescent serum hemagglutination inhibition, enzymatic immunoassay (EIA), complement fixation, or neutralization antibody titers, is diagnostic but requires several weeks for completion and is mainly of epidemiologic importance. Several office and point-of-care tests (Directogen Flu A, Directogen Flu A+B, Flu OIA, Flu OIA A/B, Xpect Flu A&B, Quickvue influenza A, Quickvue influenza A+B, and ZstatFlu) are now available for rapid diagnosis of influenza. These are immunoassays to detect viral nucleoproteins or enzyme assay to detect viral neuraminidase and require 10 to 20 minutes to do on

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nasal or throat swabs or aspirates or sputum. Their specificity for influenza is high (approximately 90%); however, sensitivity is intermediate (approximately 70%), and a negative rapid test does not rule out influenza (10).

Treatment Based on worldwide epidemiologic surveillance data, each year’s vaccine contains the three virus strains (usually two type A and one type B strains) felt most likely to be transmitted in the United States that year. Two influenza vaccines are currently available in the United States—an inactivated split virus vaccine administered intramuscularly and an attenuated live virus vaccine given intranasally. The attenuated live virus vaccine is approved only for healthy individuals. Because of a small risk of transmission of the vaccine virus, health care workers and close contacts of immunosuppressed individuals should avoid contact with the immunosuppressed person for 7 days after receiving the live intranasal vaccine. The inactivated and attenuated live virus vaccines seem to have similar protective efficacy against influenza. The effectiveness of the vaccine depends on the age and general health status of the vaccinee and the antigenic similarity of the influenza strains in the vaccine to those being transmitted in the community. In years when the vaccine is well matched to circulating influenza strains, vaccine efficacy in healthy adults is in the range of 70% to 90% (11). Adults older than 65 years of age and immunocompromised individuals receive lower, but still substantial, benefit. Influenza vaccination is highly beneficial in preventing severe influenza and death in these high-risk groups. Annual influenza vaccination is recommended for all individuals 6 or more months old in highrisk groups and for healthy individuals wishing to decrease their risk for influenza. Health care workers and other staff members of chronic care facilities, and household contacts of high-risk individuals should also be vaccinated (10). The optimal time for influenza vaccination in the United States is late October through November as the influenza season usually occurs from late December through early March. Persons vaccinated after an outbreak of influenza in the community require at least 2 weeks for effective antibody titers to develop. Protective antibody levels typically last for 4 to 6 months after vaccination. Annual vaccination of persons at high risk before the influenza season each year is the most effective measure to decrease illness and death from influenza (Table 22-3). Humoral, and to a lesser degree, mucosal immunity, are required for protection against influenza. Antibodies against the hemagglutinin (H), and, to a lesser degree, the neuraminidase (N) antigens, are the major determinants of host immunity. The surface antigens of influenza A viruses, especially the hemagglutinin antigens, undergo periodic changes. Minor changes caused by point mutations are known as antigenic drift whereas major changes or antigenic shifts are caused by genetic reassortment between strains. Antigenic shifts result in the expression of new

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Table 22-3 High Risk Groups for Complicated Influenza Person older than 65 years of age Nursing home residents Adults and children with chronic cardiopulmonary disease Immunocompromised adults with diabetes mellitus, renal failure, HIV infection, and other immunosuppressive diseases Patients receiving chronic corticosteroids or other immunosuppressive medications Pregnant women who will be in the second and third trimester of pregnancy during influenza season

hemagglutinin and neuraminidase proteins to which most or all of the population have no resistance and thus, are associated with pandemic disease with severe illness and death. Because of the rapid loss of mucosal immunity and these antigenic drifts and shifts, annual vaccination is necessary. The treatment of uncomplicated influenza is supportive with rest, antipyretics, and analgesics. Prophylaxis with antiviral drugs can be useful for unvaccinated individuals, if an outbreak occurs during the 2-week period after vaccination required to develop protective antibodies, and or if the vaccine strains are different from those in the vaccine. Antiviral drugs also are useful in treating vaccinated and unvaccinated persons who develop influenza. Amantadine and rimantadine are oral tricyclic amines (adamantanamine) that target the influenza A M2 protein, a membrane protein essential for viral replication. These drugs prevent viral uncoating after cell entry and are highly active against influenza A. Amantadine and rimantadine are approved in the United States for the prevention and treatment of influenza A infection. Treatment with amantadine or rimantadine within 48 hours after the onset of symptoms decreases the duration of fever and symptoms by several days in adults with uncomplicated disease (11). The efficacy of these drugs in patients with influenza pneumonia or severe influenza is unknown. Amantadine and rimantadine are only active against the influenza A virus. In addition, resistance of influenza A viruses to adamantine can occur spontaneously or emerge rapidly during treatment. A single point mutation in the codons for amino acids at positions 26, 27, 30, 31, or 34 of the M2 protein can confer cross-resistance to both amantadine and rimantadine (Table 22-4). In the United States, the frequency of adamantine resistance increased from 1.9% during the 2003-2004 influenza season to 91% during the 2005-2006 season (12). Based on these data, the Centers for Disease Control recommended that neither amantadine nor rimantadine was to be used for the treatment or chemoprophylaxis of influenza A infections in the United States for the remainder of the 2006-2007 influenza season. Future use of these medications should be only considered if resistance data indicates influenza A is susceptible. The usual adult dosage for amantadine and rimantadine is 100 mg twice a day. Because amantadine and rimantadine are excreted unchanged in the

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Table 22-4 Key Elements of the Revised Centers for Disease Control Case Definition for Severe Acute Respiratory Syndrome Clinical and Epidemiologic ● ●

● ●

Fever >38ºC (100.4ºF) One or more symptoms of respiratory illness (cough, shortness of breath, or radiographic findings of pneumonia or adult respiratory distress syndrome) Recent travel to an area with documented or suspected recent transmission of SARS Close contact (having care for, lived with or having had direct contact with respiratory secretions and/or body fluids) of a person suspected of having SARS and travel within 10 days of onset of symptoms to an area with documented or suspected transmission of SARS

Laboratory ● ● ●

Detection of antibody to SARS-CoV by a reliable test and laboratory Isolation of SARS-CoV in cell culture from a clinical specimen Detection of SARS-CoV RNA by RT-PCR by a reliable test and laboratory

Abbreviations: RT-PCR, reverse transcription polymerase chain reaction; SARS, severe acute respiratory syndrome; SARS-CoV, SARS-associated coronavirus.

urine and are approximately 75% hepatically metabolized, individuals with severe hepatic and renal dysfunction should receive no more than 100 mg daily. Amantadine and rimantadine are also teratogenic in animals and should not be used in pregnant women. Side effects of amantadine include edema, anorexia, nausea, nervousness, insomnia, and lightheadedness. Rimantadine is less likely to cause central nervous system (CNS) side effects than amantadine. Confusion, hallucinations, and seizures also have been reported and are more frequent in the elderly. Influenza virus neuraminidase, which is critical for viral attachment to surface epithelial cells, agglutination of the virus to erythrocytes, and release of mature virions, is the target for the neuraminidase inhibitors, which are active against both influenza A and B (13). Neuraminidase inhibitors block release of virions from infected cells and decrease viral spread in the respiratory tract (14). Zanamivir, the first agent of this class, is poorly bioavailable by mouth and is administered by intranasal inhalation as a dry powder. It has been shown to be effective for the prevention and early treatment of influenza infection when given at 10 mg twice daily for 5 days if started within the first 48 hours of symptoms (15,16). As of the 2005-2006 influenza season, all U.S. influenza viruses screened for antiviral resistance at the Centers for Disease Control had demonstrated susceptibility to neuraminidase inhibitors (12). Zanamivir is administered as a dry powder by inhaler and can cause bronchospasm in patients with asthma and chronic obstructive lung disease. Oseltamivir is an orally bioavailable neuraminidase inhibitor that can be used for prevention of influenza when given at a dose of 75 mg once daily for 6 weeks during periods of local disease activity and for treatment of influenza at 75 mg twice daily for 5 days if started within 36 to 48 hours of symptom onset (17-

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19). Oseltamivir is mainly excreted by means of the kidney, and the dose should be decreased to 75 mg once daily for adults with a creatinine clearance of less than 30 mL/min. Early treatment with zanamivir and oseltamivir reduces the severity and duration of symptoms such as cough and fever by 1 to 2 days and decreases severe influenza-related complications. The main side effects of oseltamivir are minor self-limited nausea, vomiting, and headache during the first 1 to 2 days of administration. The drug is better tolerated when taken with food. Admin-istration of zanamivir and oseltamivir can interfere with the effectiveness of the attenuated-live virus intranasal flu vaccine.

Concerns about Avian Influenza Three major influenza pandemics occurred during the past century—all caused by new type A avian strains of influenza. During 2004 outbreaks of severe avian influenza occurred in eight Asian nations. These strains were responsible for severe disease in poultry and for at least 44 human cases including 32 deaths. Avian influenza strains can be transmitted from birds to human but are usually not readily transmissible from person to person. Cases in humans have been associated with heavy exposure to poultry; however, a likely case of human-to-human transmission was reported from Thailand resulting in the death of a mother who cared for her severely ill daughter (20). The potential for H5N1 and other avian influenza strains to mutate into strains that are readily transmissible from humans to humans is a major global public health concern (21). Current influenza vaccines are not protective against recently encountered avian influenza strains. If human outbreaks occur, at least several months would be required for strain-specific vaccines to be developed and made available. Isolation and quarantine may not be effective in limiting the spread of a new influenza strain, and strategies for stockpiling oseltamivir for patient treatment and prophylaxis of patient contacts and health care workers are being explored. Recent H5N1 influenza strains have been highly resistant to amantadine and rimantadine, and neuraminidase inhibitors such as oseltamivir should be used for prophylaxis and treatment if outbreaks with H5N1 strains occur.

Severe Acute Respiratory Syndrome In November 2002, the first cases of a highly contagious new viral pneumonia named severe acute respiratory syndrome (SARS) were reported in southern China. SARS quickly spread to Singapore, Hong Kong, Vietnam, and Thailand. A North American outbreak occurred in Toronto, Canada. Eight laboratory-confirmed cases occurred in the United States, all in travelers from affected areas. Ultimately 8098 cases with 774 fatalities were

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reported worldwide during the 2002-2003 outbreak, which was successfully contained by international cooperation and strict application of traditional public health measures including rapid case detection, contact investigation, infection control in healthcare facilities, patient isolation, and community quarantine (22). No new cases of SARS have been reported since 2003.

Pathogenesis and Etiology SARS is caused by a previously unknown coronavirus called SARS-associated coronavirus (SARS-CoV) (23). SARS-CoV is genetically distinct from all earlier known coronaviruses. Coronaviruses are a common cause of mild to moderate upper respiratory tract infections in humans. SARS-CoV is highly contagious; the major methods of transmission are direct or indirect contact of oral, nasal, or ocular mucous membranes by infectious droplets from coughing patients and by contact with respiratory secretions or environmental surfaces, aerosolization, and fomites contaminated by the virus. Transmission efficiency of the virus is greatest from severely ill patients in health care settings during the second week of the illness. Most secondary cases occur in individuals with repeated close contact with severely ill SARS patients in hospital and household settings. Aerosol-generating procedures such as endotracheal intubation, airway suctioning, and nebulized aerosol treatments are high-risk procedures for spread of the virus in health care settings. Infectious virus is also present in stool and urine. Occupational exposure during the procurement, care, and slaughter of several wild animal species in live (wet) markets was associated with SARS in patients in southern China during the epidemic. SARS-CoV–like viruses have been isolated from Himalayan palm civets, Chinese ferret badgers, and raccoon dogs, and available evidence suggests that the human SARS-CoV virus originated from SARS-like viruses in animals in Southern China.

Diagnosis The usual incubation period is 4 to 7 days; most secondary cases occur within 10 days of close contact with an infectious case. Most patients present with the relatively insidious onset of fever over 38ºC (100.4ºF), chills, malaise, myalgias, and headache (24). Diarrhea occurs in 10% to 20% of patients. Systemic symptoms of SARS are followed within 2 to 7 days by dry cough and dyspnea, frequently without rhinorrhea or upper respiratory tract symptoms. Ten to twenty percent of patients develop severe diffuse pneumonia and acute respiratory failure requiring mechanical ventilatory support. Physical examination of the chest reveals rales and dullness to percussion in advanced SARS. Lymphopenia, mild thrombocytopenia, and mild elevations of hepatic aminotransferases are frequent. Chest radiograph findings are variable; most have peripheral patchy infiltrates that can progress quickly. Pleural effusion and mediastinal adenopathy are unusual. Case def-

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Table 22-5 Treatment of Severe Respiratory Tract Infections Virus

Therapy

Herpesviruses

HSV VZV CMV

Acyclovir Acyclovir Ganciclovir, foscarnet, IVIG

Paramyxoviruses

RSV Parainfluenza Measles Influenza Adenovirus Hantavirus

Ribavirin*, RSVIG Supportive care, ribavirin* Supportive care, ribavirin* Amantidine, rimantidine, neuraminidase inhibitors (zanamivir, oseltamivir) Ribavirin*, cidofovir* Supportive care, ribavirin*

* Presently not considered standard care or still under investigation Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; IVIG, intravenous immune globulin; RSV, respiratory syncytial virus; RSVIG, respiratory syncytial virus immune globulin; VZV, varicella-zoster virus.

initions for SARS based on clinical, epidemiologic, and laboratory criteria were quickly established at the time of the 2002-2003 outbreak and revised as diagnostic laboratory tests were developed (Table 22-5). Clinicians must be alert to detect the occurrence of new cases of SARS if future outbreaks occur. SARS should be considered in patients requiring hospitalization for pneumonia or adult respiratory distress syndrome of unknown cause and who have one of the following risk factors during the 10 days before becoming ill: (a) travel to affected areas or close contact with sick persons who have recently traveled or resided in affected areas; (b) employment in an occupation associated with risk for SARS-CoV exposure (health care workers with direct patient contact, laboratory workers); or (c) being part of a cluster of cases of atypical pneumonia without an alternative diagnosis. Patients with suspected SARS should be placed on strict droplet (negative pressure rooms, N-95 personal respirator masks for health care workers) and contact isolation precautions. Available laboratory tests for SARS include antibody testing by enzyme immunoassay and RT-PCR methods on respiratory, blood, and stool specimens. Testing is available at state and national laboratories and should be done after consultation with local and regional health authorities.

Treatment Treatment of SARS is supportive. Supplemental oxygen, mechanical ventilation, and hemodynamic support are required in severe cases where management is similar to patients with the adult respiratory distress syndrome. The overall case fatality rate for SARS was approximately 15%; however, death was higher in older patients, up to 50% in patients older than 60 years of age.

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Because of its nonspecific presentation, many patients with SARS were initially treated with broad-spectrum antibiotics for suspected severe bacterial pneumonia. Antibiotics can be stopped after the diagnosis is established, as there is no evidence that they are beneficial. Early anecdotal reports of benefit from treatment with ribavirin (usually in combination with other agents such as corticosteroids) have not been confirmed, and later in vitro studies have shown that ribavirin has little activity against SARS-CoV. Although widely used, there also is no clear evidence that corticosteroids are beneficial in treating patients with SARS, and acute respiratory failure and cases of secondary sepsis and fungal infections have been reported. Interferons alpha and beta and the HIV-protease inhibitors nelfinavir and lopinavir/ritonavir have activity against SARS-CoV in vitro. Reports of uncontrolled studies using treatment with interferon and corticosteroids (25) and combination therapy with ribavirin and lopinavir/ritonavir (26) have suggested some benefit from these approaches. SARS-CoV receptor binding and fusion inhibitors are also being developed. Controlled trials with these agents are needed. Strict airborne aerosol (negative pressure room isolation, use of fittested N95 personal respirator masks by health care workers) and contact (handwashing and glove, gown and goggle use) precautions must be followed to prevent secondary cases in health care settings. Updated epidemiologic and infection control guidelines for suspected cases of SARS are available at the CDC Web site (www.cdc.gov). Although no vaccine is currently available, the prospects for developing one seem to be good. SARS-CoV was fully genetically sequenced within weeks of the initial 2003 outbreak. Follow-up studies of patients with SARSCoV infection have shown that natural infection results in a broad, longlasting neutralizing antibody response to the virus. Recent studies have shown that the virus’s spike protein on its outer surface is the dominant protective antigen and that spike protein vaccines elicit neutralizing antibody responses. Additional studies with adenovirus, modified vaccinia Ankara virus, and parainfluenza virus-vectored and DNA vaccines against SARS-CoV spike proteins are being conducted and early human trials have begun (27).

Paramyxoviruses The paramyxovirus family consists of enveloped, single-stranded RNA viruses that were first recognized to be causes of respiratory tract infections among children. RSV, parainfluenza virus, and measles virus cause significant respiratory tract infections in children and adults.

Respiratory Syncytial Virus RSV is the most common cause of lower respiratory tract infections among infants and children. RSV is the responsible pathogen for 40% to 50% of children hospitalized with bronchiolitis and 25% of children hospitalized

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with pneumonia (28). At highest risk for severe disease are premature infants and children with bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency. Manifestations of RSV infection range from mild upper respiratory tract infection (URI) to bronchiolitis, pneumonia, or rarely, croup. Unfortunately, immunity is incomplete and reinfection can occur later in life presenting as mild URI or tracheobronchitis. Since 1986, RSV has been recognized as a cause of lower respiratory tract infection in the elderly and immunocompromised adults (28-30). It ranks second to influenza as a major viral pathogen in the elderly, and, in fact, can account for a significant portion of adult wintertime deaths previously attributed to influenza (31).

Pathogenesis and Etiology RSV is spread by self-inoculation of the ocular, nasal, or oral mucosa after contact with infected patient secretions or fomites. RSV can survive for several hours on hands or environmental surfaces. Hand washing and contact isolation are important infection control practices to prevent transmission in health care settings. RSV infections can originate in both the community and health care facilities (32,33). Infection can present as a seasonal URI during the winter months in the United States or an outbreak in hospitals, nursing homes, and long-term care facilities. When pneumonia is present it has a death rate ranging from 11% to 78%, depending on the degree of underlying immunocompromise (33). Clinical Manifestations Unlike herpesviruses, asymptomatic RSV infections are rare, even during reinfections. In children RSV causes nasal congestion, sinusitis, otitis media, coryza, and pharyngitis. Lower respiratory tract infection can manifest as tracheobronchitis, bronchiolitis, or pneumonia. In general, RSV manifests similarly in immunocompromised and elderly patients, except that the lower respiratory tract is involved in up to 80% of cases. RSV infection typically presents with fever, nonproductive cough, anorexia, and dyspnea. On physical examination, wheezing and rales are common. Bronchial wall thickening and hyperinflation are distinctive radiographic features of lower respiratory tract RSV infection in hospitalized children (30). Among adults, chest radiographs generally demonstrate bilateral interstitial or patchy infiltrates, with lobar consolidation and pleural effusions present in 25% and 5% of cases, respectively (33), but can also have a bronchiolar reticulonodular distribution. Diagnosis The diagnosis of RSV infection can be made by examination of respiratory tract secretions. Although the nasopharynx is easily accessible for sampling, BAL is twice as sensitive but more invasive. Viral culture is the gold standard but requires several days. The more rapid and recommended test is identification of RSV antigen using a fluorescein-conjugated monoclonal or

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polyclonal antibody or ELISA, both of which have a sensitivity and specificity between 80 and 95% (28). PCR-based assays for diagnosis of RSV infection have been developed but are not yet licensed. A fourfold or greater increase in serum RSV-specific IgG is diagnostic of RSV infection (34). However, convalescent antibody titers are useful only for retrospective diagnosis and epidemiologic studies.

Treatment Ribavirin, a nucleoside analog of guanosine, is the only effective antiviral currently available for the treatment of RSV pneumonia. Because of its high toxicity profile when administered intravenously, ribavirin is delivered as a small-particle aerosol. Although early pediatric investigations demonstrated positive results, several recent studies have found the contrary (35). In adult bone marrow transplant patients with adenovirus pneumonia, treatment with ribavirin was shown to decrease illness and improve survival in one study (36). Combination therapy with ribavirin and intravenous immune globulin (IVIG) increased survival in bone marrow (37) and lung transplant patients with severe RSV pneumonia and, despite data from controlled trials, is now widely used in this setting. Prevention Prophylactic use of ribavirin among high-risk patients has not been demonstrated to decrease the occurrence of severe RSV infections. Palivizumab, a humanized monoclonal antibody against the RSV F glycoprotein, is licensed for use in infants and children with prematurity, chronic lung disease, and congenital heart disease for the prevention of severe RSV disease. Vaccine development has been unsuccessful. An earlier formalininactivated vaccine was not protective and, in fact, was associated with more severe disease among vaccines. Subsequent efforts have focused on the development of live attenuated or subunit vaccines, which although capable of eliciting antibody responses, have not been shown to be protective (38).

Human Metapneumovirus A new paramyxovirus causing upper and lower respiratory tract infection in humans was described by researchers from the Netherlands in 2001 (39). Human metapneumoviruses (hMPV) are found worldwide, are closely related to RSV, and cause a similar spectrum of disease. Transmission is most likely caused by close contact with infected respiratory secretions and fomites. Human metapneumoviruses cause mild, self-limited upper respiratory tract infections in children and adults; however, they also can result in bronchiolitis, asthma exacerbations, and pneumonia in older adults. Most children are infected with human metapneumovirus during infancy. Adult

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disease is usually caused by re-infection, which is frequent. Among hematopoietic cell transplant and lung transplant patients, hMPV is now recognized as a potential cause for serious respiratory tract infections (40-42). The most common symptoms of hMPV infection in adults are cough, nasal congestion, rhinorrhea, dyspnea, hoarseness, and wheezing (43). Fever is infrequent. Human metapneumovirus grows poorly and slowly in tissue culture and is difficult to isolate. Reverse transcriptase PCR-based methods are the most sensitive diagnostic tests but are available only in research laboratories. Serum neutralizing antibody tests are also used in research laboratories but are not well standardized. Treatment is supportive. Ribavirin is active against hMPV in vitro. No vaccine is available.

Parainfluenza Virus There are four serotypes of parainfluenza virus, all of which can produce respiratory diseases in humans. Parainfluenza virus is a common virus that infects most persons during childhood; 90% to 100% of children have antibodies to parainfluenza type 3 by the age of 5 years (33). Unfortunately, immunity is transient and reinfection manifesting as mild upper respiratory tract infections can occur in older children and adults. Depending on the serotype, infection in children can cause croup, bronchitis, pharyngitis, or pneumonia. Because previous episodes of infection result in partial immunity, upper respiratory infections in adults are usually mild, self-limited, and rarely cause pneumonia. Since 1979, parainfluenza virus has been noted to cause severe pneumonia in immunocompromised hosts during the winter months and outbreaks have been reported in extended care facilities in the United States. The viral serotypes differ in epidemic patterns. Infection with serotypes 1 and 2 typically occurs during fall and usually cause croup or laryngotracheobronchitis in late childhood. Upper respiratory tract infection is associated with serotype 4. Serotype 3 is a common cause of bronchiolitis and pneumonia in infants, and croup and tracheobronchitis in older children. It has also been associated with pneumonia in bone marrow and renal transplant patients (30).

Clinical Manifestations Depending on whether infection is primary or secondary, symptoms can range from a very mild illness to life-threatening croup or bronchiolitis. Immunocompetent adults typically develop mild upper respiratory tract symptoms, however, parainfluenza virus infection can result in life-threatening pneumonia in immunosuppressed individuals. Signs and symptoms of parainfluenza pneumonia include fever, cough, coryza, dyspnea, and rales or wheezes. Radiographic findings range from normal to focal to diffuse interstitial infiltrates or diffuse alveolar-interstitial infiltrates consistent with acute lung injury.

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Diagnosis Diagnosis of parainfluenza virus infection depends on clinical characteristics and demonstration of the virus from the respiratory tract. Radiographic findings can vary and can range from a diffuse reticulonodular pattern, to alveolar consolidation, to nodular opacities. The virus can be cultured from the nasopharynx, but this requires 5 to 14 days for identification. Therefore, rapid immunofluorescent and enzyme immunoassay antigen detection tests on nasal and bronchial secretions are preferred. Neutralization, hemagglutination, and complement fixation serologic assays also are available. Highly sensitive (95% to 100%) and specific multiplex PCR assays such as the Hexaplex assay are now available for the detection of influenza A and B, parainfluenza 1 to 3 and RSV viruses in respiratory secretions (44). Interpretation of test results should be made with the realization that parainfluenza virus has a predilection for the upper respiratory tract, and a positive result can be found in the presence of minimal to no respiratory tract symptoms. Treatment Treatment is supportive. Ribavirin has been used to treat lower respiratory tract infections with some benefit in uncontrolled studies, but no effect has been demonstrated in transplant patients. There are currently no available effective vaccines.

Measles Measles typically causes a febrile illness with a typical erythematous, blanching maculopapular rash in children, and mild pneumonia in healthy adults. Severe respiratory involvement is more frequent in children than adults and pneumonia is the leading cause of death caused by measles in children. Although measles is rarely a cause of severe lower respiratory tract infection in immunocompetent adults, it can result in more severe pneumonia in immunocompromised and malnourished hosts (45). Measles is highly contagious and is transmitted from person to person by aerosolized droplet nuclei from patients with cough. The peak incidence of cases in the United States is in the late winter and early spring.

Clinical Manifestations The incubation period is 10 to 14 days. A 2 to 3 day prodrome with fever, cough, headache, conjunctivitis, and coryza usually precedes the onset of the rash. Respiratory complications of measles include primary viral pneumonia, secondary bacterial pneumonia, and atypical measles pneumonia. Primary measles pneumonia typically occurs in immunosuppressed adults, such as patients with hematologic malignancies, primary and secondary immunodeficiency. Primary pneumonia is characterized histologically by diffuse bronchiolar and alveolar inflammation with characteristic multinucleated giant cells containing eosinophilic nuclear and cytoplasmic inclusions. Atypical

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pneumonia tends to occur in the immunocompromised host and healthy individuals that received killed measles vaccine from 1964 to 1967. In these cases, the patient does not present with classic clinical findings. For example, the rash can be atypical (beginning on the hands and feet and then spreading to the trunk) or absent. A severe and often fatal pneumonia called Hecht giant cell pneumonia is more frequent in patients with atypical measles (30).

Diagnosis The diagnosis of measles pneumonia can often be made on clinical grounds in the presence of the characteristic erythematous maculopapular rash that usually begins on the face and then spreads to the trunk and finally to the extremities. Laboratory studies can be helpful if the rash is atypical or absent. The oropharynx should be inspected for the pathognomonic Koplik spots, small raised white spots most prominent on the buccal mucosa opposite the molar teeth present during the early stages of measles. In primary measles pneumonia the chest radiograph usually shows diffuse fine reticular infiltrates and alveolar infiltrates. Like varicella, the course of primary measles pneumonia parallels that of the rash. The presence of patchy alveolar infiltrates and atelectasis should suggest secondary bacterial pneumonia. The virus can be cultured from throat washings and respiratory secretions with visible cytopathic effect in culture after 6 to 10 days’ incubation. Newer rapid immunofluorescent assays also can be used to detect viral antigens in respiratory secretions. Treatment Treatment is primarily supportive. Post-exposure prophylaxis of immunocompromised individuals with IVIG is effective if given within 72 hours of exposure to infectious cases of measles. Vaccination of healthy susceptible persons is accomplished by a two-dose schedule. The measles vaccine is a live attenuated virus vaccine and should not be administered to pregnant women and severely immunocompromised individuals (46,47). HIVinfected children and immunosuppressed adults with measles pneumonia have been successfully treated with intravenous and aerosolized ribavirin in doses similar to those used in severe RSV infection (48).

Herpesviruses The family Herpesviridae consists of large, double-stranded DNA-containing, enveloped viruses which vary widely in their ability to infect different types of cells and share the common ability to induce lifelong latent infection. These viruses rarely cause significant lower respiratory infections in immunocompetent hosts and are more likely to cause disease among immunocompromised patients such as organ and stem cell transplant recipients, and human immunodeficiency virus (HIV) infected persons. Although the use of prophylactic therapy with antiviral drugs has significantly reduced the incidence of serious

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disease caused by herpes viruses in immunocompromised patients, disease caused by reactivation remains a concern in infected immunosuppressed individuals, who can be unable to maintain herpes viruses in their latent state once prophylactic treatment is discontinued. Herpes viruses that most frequently cause disease in humans are HSV, VZV, and CMV.

Herpes Simplex Virus Despite the fact that the herpes simplex virus can cause a wide spectrum of disease in the human host, lower respiratory tract infections are rare. This is most likely caused by the virus’ predilection for infecting squamous epithelium. Unfortunately, factors such as traumatic endotracheal intubation, burns, radiation therapy, cytotoxic chemotherapy, acute respiratory distress syndrome (ARDS), and smoking, all of which promote squamous metaplasia of the tracheobronchial tree, predispose the host to lower respiratory tract infection with HSV (49). Immunocompromised patients are at particular risk for HSV pneumonia. This includes patients who are receiving cancer chemotherapy hematopoietic stem cell and organ transplant patients, those who are neutropenic, HIV infected patients, burn victims, patients with congenital cell-mediated immunodeficiency, and those who are severely debilitated or malnourished caused by prolonged hospitalization (50). Although the lung is frequently involved in disseminated HSV infection, disseminated disease is not commonly associated with mucocutaneous HSV infections. Less than 10% of HSV-seropositive transplant recipients who develop mucocutaneous herpes infection will develop visceral dissemination (51).

Pathogenesis and Etiology HSV pneumonia develops by two principal mechanisms. First, focal or multifocal pneumonia can follow antecedent upper airway infection with HSV. This pattern is most likely caused by direct extension of infection from the upper to the lower respiratory tract, aspiration of infectious secretions, or reactivation of dormant HSV in vagal ganglia (49). These patients often have tracheitis or esophagitis and usually have oral or mucocutaneous lesions before pulmonary disease. Second, diffuse interstitial infiltrates can develop after viremia secondary to dissemination of HSV from genital or oral lesions or transfusion of HSV-infected blood (49). Early dissemination also can be reflected by evidence of other organ dysfunction such as elevated liver enzymes. Clinical Manifestations The spectrum of respiratory disease caused by HSV infection ranges from oropharyngitis to membranous tracheobronchitis to localized or diffuse pneumonia. HSV lesions in the lower respiratory tract are often most severe in the trachea and large bronchi where they can result in a thick inflammatory membrane that can ultimately create significant resistance to venti-

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lation. HSV pneumonia is an uncommon cause of community-acquired pneumonias and usually develops in patients after a prolonged and complicated hospital stay. Dyspnea and cough are the most common clinical reports. Fever, tachypnea, intractable wheezing, chest pain, or hemoptysis also occurs. Findings of cutaneous, genital, or oral mucocutaneous lesions often herald pulmonary or disseminated disease. Focal lesions on chest radiograph begin as small nodules best seen in the periphery away from normal vascular markings. As the disease progresses, the nodules can coalesce to form extensive infiltrates. It should be noted that HSV pneumonia can initially present as a focal or segmental pneumonia caused by spread from upper airway lesions that can ultimately extend to other areas of the lung, producing diffuse infiltrates similar to the pattern seen with viremic HSV infection (51).

Diagnosis The diagnosis of HSV pneumonia should be based on clinical suspicion, radiographic findings, isolation of HSV from the lungs, and histologic findings of a necrotizing or hemorrhagic pneumonia in appropriate specimens. Because HSV can be isolated from oropharyngeal secretions in 2% to 25% of normal hosts, positive sputum cultures for HSV are often difficult to interpret (50). The upper respiratory tract can be bypassed with the use of tracheal aspirates, which significantly alleviates the specificity, although upper airway secretions can still contaminate these samples. Bronchoscopy is especially useful for direct sampling of mucosal ulcers, and obtaining bronchial brushings, washings, and biopsies for histologic and cytologic examination. The presence of Cowdry type A intranuclear inclusion bodies in lower respiratory secretions significantly increases the specificity for the diagnosis of HSV pneumonia. Mucocutaneous lesions also should be investigated for the presence of HSV. Scrapings from the base of ulcerated lesions can be examined with Wright or Giemsa stains for multinucleated giant cells and intranuclear inclusions. Specimens can also be examined by immunofluorescent staining with polyclonal or monoclonal specific antibodies or electron microscopy, as well as enzyme-lined immunosorbent assays (ELISA). Appropriate viral cultures of the mucosal lesions, blood, and respiratory secretions should always be obtained in cases of suspected herpetic pneumonias. Serologic assays are of little diagnostic utility. Treatment Standard antiviral drugs currently used in the treatment of HSV include acyclovir, valacyclovir (the oral prodrug of acyclovir), and famciclovir (the oral prodrug of penciclovir) (52). However, caused by the potential illness and death associated with severe HSV pneumonia, intravenous acyclovir remains the treatment of choice for HSV pneumonia at a dose of 5 mg/kg every 8 hours intravenously. Over half of all cases of HSV pneumonia are complicated by other infections (49). Empirical broad spectrum antibiotic

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therapy including an antistaphylococcal drug such as nafcillin, vancomycin, or linezolid, depending on the local prevalence of methicillin resistant S. aureus, should be instituted in patients with progressive HSV pneumonia that does not respond appropriately to antiviral therapy. If deterioration continues despite the addition of antibiotics, a definitive diagnostic procedure such as bronchoscopy or open lung biopsy should be pursued to search for other opportunistic organisms such as Aspergillus, Candida, and Pneumocystis jiroveci. The role of adjunctive corticosteroids is controversial and should not be considered as standard care, especially in an already immunocompromised host. Ventilatory support is often required caused by severe hypoxemia. Fluid management is of special concern because fulminant pneumonia is frequently associated with pulmonary edema and alveolar hemorrhage. Efforts toward prevention of HSV pneumonia should be directed toward chemoprophylaxis of high-risk seropositive patients during induction of immunosuppression for transplantation. Passive or active immunization has not been proven to be helpful.

Varicella-Zoster Virus VZV is a highly contagious herpes virus infection that is transmitted from person to person by direct contact or aerosolization from skin lesions or respiratory tract secretions. The incubation period ranges from 10 to 21 days. Primary infection with VZV causes chickenpox, a febrile illness with malaise and a characteristic dewdrop on rose petal generalized vesicular rash that lasts 4 to 5 days. VZV also causes herpes zoster, a dermatologic manifestation of reactivated latent virus from the nerve ganglia. Respiratory tract involvement is an uncommon complication of herpes zoster in otherwise healthy individuals. Adults, smokers, pregnant and postpartum women, immunocompromised patients such as those with hematologic malignancies or organ transplants, and HIV infected children can have more severe disease and are at increased risk for complications such as pneumonia, secondary bacterial infections of skin lesions, encephalitis, hepatitis, and Reye syndrome. Varicella pneumonia usually develops several days after the onset of the rash. Approximately 10% of adults with varicella have lower respiratory tract symptoms and approximately 1 in 400 develops overt pneumonia. Five percent of women of childbearing age in the United States have no antibodies against varicella and are at risk for varicella pneumonia. Pneumonia is a more frequent complication of varicella infection in pregnant women than other adults and is more common in the third trimester. Death rates of up to 45% have been reported in pregnant women with varicella pneumonia.

Clinical Manifestations and Diagnosis Pulmonary manifestations of varicella pneumonias correlate with the severity of the rash. Mild cases of varicella pneumonia usually alleviate as the rash begins to subside. Long-term respiratory sequelae are infrequent although

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small, scattered, punctate lung calcifications can persist on chest radiograph. The death rate in severe cases of varicella pneumonias with overt respiratory failure is approximately 50%. Varicella pneumonia characteristically presents with patchy diffuse interstitial infiltrates, but can leave small, calcified granulomas chronically. Lesions can be more prominent in the lower lung fields or perihilar regions. The hilar lymph nodes can be enlarged. Pleural effusions occur infrequently and are small when present. Varicella pneumonia can frequently be diagnosed clinically in the setting of the typical rash with lesions in varying stages of development. However, the rash can be atypical or absent in immunosuppressed patients, and further laboratory testing is warranted. The virus can be isolated from the fluid of the skin vesicles, blood, respiratory tract secretions, and cerebrospinal fluid (CSF). Tzanck smears on cutaneous lesions coupled with rapid immunofluorescent antigen tests can speed the diagnosis. Reliable serologic assays include immunofluorescent antibody to membrane antigen (FAMA) test, adherence hemagglutinin assays, and enzyme immunoassays. PCR-based assays for VZV are now available for use on CSF but, because of their high cost, are not widely used for other purposes.

Treatment Management includes respiratory isolation until skin lesions heal (varicella is highly contagious), supportive care, antivirals, and active and passive immunization. For persons at high risk for complications of varicella such as immunosuppressed individuals and pregnant women, the use of varicella-zoster immune globulin (VZIG) can decrease infection or the severity of illness substantially if administered within 96 hours of exposure. Acyclovir given at 10 to 12 mg/kg every 8 hours intravenously for 7 to 10 days has been shown to be effective in immunocompromised patients (53, 54). No teratogenic effects have been reported in pregnant women (55). The clearance of acyclovir is primarily renal, and the dose should be adjusted for renal insufficiency. Adjunctive corticosteroids have been administered in some cases (56), however, their benefits are controversial and have not been studied in controlled trials. In March 1995 a live, attenuated varicella vaccine was licensed in the United States for use in healthy individuals more than 12 months old. The vaccine is highly protective against severe varicella disease. Varicella vaccine is recommended for routine vaccination of all healthy children at 12 to 18 months of age (57). Vaccination of susceptible individuals (no reliable history of varicella disease or previous vaccination, or no detectable serum antibodies) older than 13 years of age including health care workers and family contacts of immunocompromised patients, teachers, day care workers, staff and residents in institutional settings, adolescents and adults living in households with children, international travelers, and nonpregnant women of childbearing age is also recommended. Adults should receive two 0.5-mL subcutaneous doses of the vaccine administered 4 to 8 weeks apart. In May 2006, a live,

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attenuated single dose zoster vaccine was licensed in the United States for prevention of herpes zoster (shingles) in individuals 60 years of age and older. In a randomly assigned, double-blind, placebo-controlled trial, the zoster vaccine reduced the burden of illness caused by herpes zoster by 61.1%, reduced the incidence of postherpetic neuralgia by 66.5%, and reduced the incidence of herpes zoster by 51.3% (12). These live attenuated vaccines should not be administered to pregnant women, women who plan to become pregnant during the next 4 weeks, persons with congenital cellular immune deficiency syndromes, individuals with leukemia or lymphoma, individuals with untreated active tuberculosis infection, or HIV-infected persons. Intramuscular VZIG at a dose of 125 units per 10 kg (up to a maximum of 625 units) is indicated for passive immunization of immunosuppressed children exposed to varicella or zoster, neonates whose mothers became infected with VZV shortly before delivery, and neonates with postnatal exposure to zoster (57). VZIG is also indicated in immunocompromised adults (patients with primary or acquired immunodeficiency, neoplastic diseases, or receiving immunosuppressive agents), pregnant women, and susceptible hospital personnel with substantial exposure to cases of zoster. Since introduction of the varicella vaccine, death from varicella related illness in the United States has decreased by two thirds, particularly in young children. The vaccine’s effectiveness in preventing varicella decreases over time to approximately 84% protection 8 years after vaccination (57). Breakthrough varicella in previously immunized patients is usually mild but can be more difficult to diagnose as few skin lesions can be present, and they can be papular in appearance. Repeat vaccination can be necessary for long-term protection.

Cytomegalovirus CMV infection is frequent among the general population and is almost always asymptomatic. Seropositivity varies between 50% and 80% in healthy adults in the United States. Acute CMV infection causes a mononucleosislike syndrome in the immunocompetent host, which is associated with pneumonia in 6% of the cases (58). However, because of its ability to reactivate from a latent state, it has become a serious cause of illness and death with the advent of organ and bone marrow transplantation and HIV infection. Although CMV disease in these patient groups can involve nearly any organ system, pneumonia results in the highest death rate. Recently, prophylactic and preemptive treatment strategies have been extensively studied in patients undergoing hematopoietic cell and organ transplants, where their use has reduced the incidence of severe CMV disease significantly. For example, the incidence of CMV disease during the first 3 months after hematopoietic cell transplant decreased from 20% to 30% to less than 5% when prophylactic and preemptive ganciclovir was administered (59).

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CMV infection in the immunocompromised host occurs by means of one of two mechanisms. In CMV seropositive transplant patients, reactivation of latent endogenous virus during profound immunosuppression accounts for approximately 70% of CMV disease. Acquisition of the virus from CMV seropositive bone marrow, blood products, or donor organs led to disease in approximately 36% of CMV seronegative organ recipients (60). Less common is de novo CMV infection among individuals who are seronegative and receive seronegative biologic products. Risk factors for developing CMV disease include CMV seropositive recipients, seropositive donors, older patients, total body irradiation, human leukocyte antigen (HLA)-mismatch, and graft manipulation such as T-cell depletion (60-64). Positive CMV serologic status of the bone marrow donor and use of granulocyte transfusions from seropositive donors also increase the rate of CMV disease almost 2.5-fold (60). Despite the known risks associated with positive CMV serostatus, its effect on transplant outcome is controversial (65). For example, among hematopoietic cell transplant patients, although CMV-seropositive patients have a higher risk of death, the mechanism for this increased death rate is likely caused by direct (e.g., CMV breakthrough, drug-resistant CMV) and indirect (e.g., secondary infections with bacterial or fungal pathogens, sepsis, graft versus host disease) effects of CMV, as well as drug toxicity (e.g., ganciclovir, foscarnet). Donor seropositivity, however, has not been found to have a significant effect on transplant-related death (66), and a recent study examining data from the past two decades found that matching seropositive donors with seropositive patients decreased the hazard for overall morality after hematopoietic cell transplant by up to 35% (67).

Clinical Manifestations CMV pneumonia typically occurs 6 to 12 weeks after transplant in 10% to 40% of bone marrow recipients (61). However, late occurrences between 3 to 9 months are now more frequent because of the use of posttransplant antiviral prophylaxis. Among hematopoietic cell transplant patients, the advent of a less intensive nonmyeloablative conditioning regimen has also significantly delayed the onset of CMV disease, but not reduced its overall incidence (68). Clinical symptoms of CMV pneumonia are subacute and nonspecific. In the normal adult, a dry cough, tachypnea, and lowgrade temperatures are the usual reports. Immunocompromised patients tend to have a more subacute presentation with similar symptoms. Severe hypoxemia and the development of respiratory failure requiring mechanical ventilation are poor prognostic indicators. Chest radiographic patterns are nonspecific, but typically include interstitial infiltrates, patchy alveolar consolidation, or a reticulonodular pattern (62,69). A miliary pattern also has been described with acute viremia in patients with primary CMV infection (70).

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Diagnosis The diagnosis of CMV pneumonia is challenging and should be based on evaluation of clinical features, quantitative cultures of BAL specimens (71), transbronchial or open lung biopsy, and serologic studies such as CMV DNA PCR or viral culture. Although ideally a definitive diagnosis of CMV pneumonia is made based on histologic demonstration of invasive disease in affected tissues, this is not often clinically feasible. Classic histologic evidence of CMV infection include cytopathological findings in respiratory secretions and tissues such as the presence of owl’s eyes cells, which are large cells with basophilic intranuclear inclusions with a surrounding clear zone. Unfortunately, there is still much controversy surrounding the use of BAL specimens for diagnosis of CMV pneumonia, as well as their lack of sensitivity and efficiency (72,73). In the era of preemptive antiviral treatment strategies, which can further decrease the sensitivity of older culture-based assays, the most universally applicable clinical assays are CMV DNA detection methods and the pp65 antigenemia assay (59). CMV is often found in the presence of other pulmonary pathogens such as Pneumocystis jiroveci, thus making it difficult to determine if CMV is a true pathogen. Detection of CMV by DNA PCR on BAL specimens has a high negative predictive value but a low positive predictive value. Studies in bone marrow and lung transplant patients also have suggested that the use of quantitative BAL cultures is useful in predicting the development of CMV pneumonia (71,74,75).

Treatment Because CMV infection and pneumonia are usually self-limited in the immunocompetent host, there are presently no data about treatment of CMV pneumonia in this setting. Treatment of CMV pneumonia in immunocompromised patients has focused on prevention, acute therapy, and passive immunization with immunoglobulins (76). The high incidence and severe illness of CMV pneumonia among posttransplant patients, especially the CMV seropositive individuals, has led to widespread use of prophylactic and preemptive therapy with ganciclovir before and after transplantation (61,75,77). A recent meta-analysis of CMV prevention trials indicated that prophylaxis with acyclovir, ganciclovir, or valacyclovir significantly reduced the risk for CMV disease and all-cause death. Oral ganciclovir or valganciclovir and intravenous (IV) ganciclovir were all effective in preventing CMV disease (78). Preemptive therapy based on CMV detection in BAL specimens, CMV antigenemia, or CMV PCR seropositivity after transplant also has been shown to significantly reduce the incidence of posttransplant CMV pneumonia (62). The recommended treatment of acute CMV pneumonia is intravenous ganciclovir 5 mg/kg every 12 hours for 21 days followed by maintenance oral valganciclovir 900 mg or intravenous ganciclovir 5 mg/kg daily. High-dose intravenous immunoglobulin also has been used successfully in conjunction with ganciclovir for the treatment of CMV pneumonia.

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Combination therapy is based on the premise that lung injury is not caused by direct damage by the virus, but is probably the result of T-cell response to a virally induced antigen on the cells of the lung. Immunoglobulins act by blocking host T-cell recognition of CMV antigens on infected cells. Unfortunately, its use has never been evaluated in a randomly assigned trial. Foscarnet, a competitive inhibitor of CMV replication, is an alternative drug in cases of ganciclovir-resistant CMV infections, which is more frequently encountered in HIV-infected patients who receive chronic suppressive ganciclovir therapy.

Adenoviruses Adenoviruses are nonenveloped, icosahedral DNA viruses that cause upper respiratory tract infections such as pharyngitis, bronchiolitis, and pneumonia. Other than the respiratory tract, adenoviruses can infect the conjunctiva, gastrointestinal, and genitourinary tracts. Most cases of respiratory infection are mild. In nonepidemic settings, one half of adenovirus infections can be asymptomatic. However, severe pneumonia has been reported in outbreaks in adults in communal living settings such as chronic psychiatric hospitals and military recruit training centers. Adenovirus pneumonia has also been reported in immunocompromised patients such as transplant, oncology, and HIV-infected patients. Adenovirus infection is now considered an important cause of illness in bone marrow and solid organ transplant patients (79). In solid organ transplant patients, adenovirus infection frequently results in disease in the transplanted organ but disseminated infection can cause serious pulmonary or CNS disease. There are 41 human serotypes of adenoviruses. Most severe disease is caused by types 3 and 7. Type 4 is associated with outbreaks in military recruits. Infection of the lower respiratory tract with adenoviruses results in necrotizing bronchitis and bronchiolitis.

Clinical Manifestations and Diagnosis Individuals with adenovirus pneumonia present with fever, cough, malaise, hoarseness, sore throat, and less frequently, cervical lymphadenopathy and conjunctivitis. Radiologic manifestations range from patchy lower lobe infiltrates to diffuse interstitial infiltrates and cannot be differentiated from other community-acquired pneumonias. The diagnosis can be established by viral cultures of respiratory secretions, PCR on tissue or blood, complement fixation, hemagglutination inhibition, and neutralization serology. Cytopathic effects from viral growth are visible in cultures on kidney, human laryngeal tumor (HEp-2), or Henrietta Lacks (HeLa) cells after 2 to 20 days of incubation. Rapid immunofluorescence and enzyme immunoassay antigen detection tests also are available and can be done on throat swabs, nasopharyngeal washes, or sputum.

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Treatment Treatment is primarily supportive. There are no currently approved drugs for the treatment of adenoviral pneumonia. Ribavirin has in vitro activity against adenoviruses and has been successfully used anecdotally for the treatment of severe adenovirus pneumonia in adults (80,81). Cidofovir also has been used to treat adenoviral pneumonia; however, nephrotoxicity has been frequent (82). Although vaccines against serotypes 4 and 7 were previously used and highly effective in preventing severe adenoviral disease in military recruits, production of this vaccine ceased in 1995 because of economic reasons.

Hantavirus A member of the family Bunyaviridae, the hantaviruses are spherical lipidenveloped, single stranded RNA viruses that parasitize small rodents and can be transmitted to humans. Different strains of hantavirus have a predominant host rodent species. The most frequently recovered virus in the United States is the Sin Nombre virus, which is transmitted by the deer mouse (Peromyscus maniculatus), the white-footed mouse (Peromyscus leucopus) and several other rodent species. Rodent species harboring the four different hantavirus strains associated with the hantavirus pulmonary syndrome (HPS) in the United States are distributed throughout the lower 48 states. Infected rodents do not develop disease but chronically excrete virus in their urine, feces, and saliva. Aerosolization of their excreta is believed to be the major method of transmission of hantaviruses from rodents to humans. The disease can also be transmitted by direct contact or bites from infected rodents. Person-to-person transmission has not been convincingly demonstrated. HPS is associated with a case fatality rate of 50% (83). Deaths are usually caused by ARDS with diffuse pulmonary capillary leak and multiple organ system failure (84). At autopsy large serous pleural effusions and severe pulmonary edema can be present. Microscopic changes present in the lungs of fatal cases include intraalveolar pulmonary edema with scant to moderate numbers of hyaline membranes, interstitial lymphoid infiltrates, and little evidence of viral cytopathic effect or viral inclusion bodies.

Clinical Manifestations The HPS is characterized by an influenza-like prodrome with rapid progression to ARDS and respiratory failure. The incubation period after infection with hantavirus is approximately 3 weeks. Initial symptoms of HPS include fever, malaise, myalgias of large muscle groups, dyspnea, cough, headache, nausea, and diarrhea. The prodromal phase is followed after several days by hypotension, tachycardia, and tachypnea, which frequently

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and rapidly progress to shock and ARDS. Common laboratory abnormalities include severe leukocytosis with a left shift, atypical lymphocytosis, thrombocytopenia, hemoconcentration, prolonged activated partial thromboplastin time and prothrombin time, hypoproteinemia, elevated serum lactate dehydrogenase levels, and proteinuria. Chest radiographs show rapidly progressive bilateral pulmonary infiltrates in 65% of cases.

Diagnosis The diagnosis of HPS is made by serologic testing for hantavirus-specific IgM antibodies, which are usually detectable at the time of clinical presentation, or by a fourfold increase in acute and convalescent IgG antibodies. Hantavirus antigens also can be detected in tissue by immunohistochemistry and RT-PCR.

Treatment Current therapy for HPS is primarily supportive. Intensive care unit admission, mechanical ventilation, and inotropic and vasopressor support are frequently required. Fluid administration should be carefully monitored. In one controlled trial, intravenous ribavirin reduced the death rate in Chinese patients with hemorrhagic fever and renal failure syndrome when administered early after presentation (85). A subsequent open-label, non–randomly assigned study in 30 patients (86) and a double-blinded, placebo controlled trial of intravenous ribavirin in 36 U.S. patients with HPS (87), which closed early because of slow patient accrual, did not demonstrate any benefit of IV ribavirin on death rate or the development of shock or respiratory failure.

Prevention Because hantavirus is transmitted through contact with rodents, environmental factors play a large role in sporadic cases of hantavirus pulmonary syndrome throughout the United States and Canada (88). Worsening socioeconomic problems such as poor housing conditions also lead to increased contact with rodents. By minimizing human exposure to rodents and their excreta, HPS can be prevented. The most effective measure to minimizing exposure is rodent control, such as proper food storage, eliminating rodent nesting sites, adequate ventilation of infested areas before human entry, use of 10% bleach solution to disinfect infested areas, and use of gloves when handling dead rodents.

Summary Most common respiratory viruses cause mild self-limited illnesses in adults. The elderly and immunocompromised individuals are at increased risk for severe pneumonia. Clinical and radiographic features of viral pneumonias are

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often nonspecific. Newer and faster methods for viral culture, viral antigen detection and PCR-based tests have alleviated capabilities for definitive diagnosis of viral pneumonia in recent years. Preventive measures center on limiting exposure of sick patients to active cases of chicken pox and influenza, annual influenza vaccination, broad use of varicella vaccine in children and susceptible adults, hyperimmune globulin such as VZIG in high-risk patients, and chemoprophylaxis against influenza with adamantine or neuraminidase inhibitors and against CMV with acyclovir or ganciclovir in high-risk groups. Therapy for viral pneumonia is primarily supportive. Adamantine and neuraminidase inhibitors are beneficial for influenza pneumonia as are acyclovir for herpes and varicella pneumonia, ganciclovir and immune globulin in CMV pneumonia, and possibly ribavirin for severe RSV, adenovirus, and hantavirus pneumonia. The emergence of new respiratory viruses such as human metapneumovirus, SARS-CoV, and new strains of influenza pose additional challenges for clinicians and public health authorities. REFERENCES 1. Bartlett JG, Mundy LM. Community-acquired pneumonia. N Engl J Med. 1995;333:1618-24. 2. Greenberg SB. Viral pneumonia. Infect Dis Clin North Am. 1991;5:603-21. 3. Lim WS, Macfarlane JT, Boswell TC, Harrison TG, Rose D, Leinonen M, et al. Study of community acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines. Thorax. 2001;56:296-301. 4. Leland DS, Emanuel D. Laboratory diagnosis of viral infections of the lung. Semin Respir Infect. 1995;10:189-98. 5. Osiowy C. Direct detection of respiratory syncytial virus, parainfluenza virus, and adenovirus in clinical respiratory specimens by a multiplex reverse transcription-PCR assay. J Clin Microbiol. 1998;36:3149-54. 6. Kehl SC, Henrickson KJ, Hua W, Fan J. Evaluation of the Hexaplex assay for detection of respiratory viruses in children. J Clin Microbiol. 2001;39:1696-701. 7. Liolios L, Jenney A, Spelman D, Kotsimbos T, Catton M,Wesselingh S. Comparison of a multiplex reverse transcription-PCR-enzyme hybridization assay with conventional viral culture and immunofluorescence techniques for the detection of seven viral respiratory pathogens. J Clin Microbiol. 2001;39:2779-83. 8. Maertzdorf J, Wang CK, Brown JB, Quinto JD, Chu M, de Graaf M, et al. Real-time reverse transcriptase PCR assay for detection of human metapneumoviruses from all known genetic lineages. J Clin Microbiol. 2004;42:981-6. 9. Cox NJ, Subbarao K. Influenza. Lancet. 1999;354:1277-82. 10. Harper SA,Fukuda K,Uyeki TM,et al for the Centers for Disease Control and Prevention. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP) [erratum appears in MMWR Recomm Rep. 2004 Aug 20;53(32):743]. MMWR Recomm Rep. 2004;53:1-40. 11. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention. MMWR Recomm Rep. 1998;47:1-26. 12. Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-84. 13. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. 2000;355: 827-35. 14. Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med. 2005;353:1363-73. 15. Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. N Engl J Med. 1997;337:874-80. 16. Hayden FG,Treanor JJ, Betts RF, Lobo M, Esinhart JD, Hussey EK. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA. 1996;275:295-9.

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17. Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med. 1999;341:1336-43. 18. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH, et al. Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. Lancet. 2000;355:1845-50. 19. Treanor JJ, Hayden FG,Vrooman PS, Barbarash R, Bettis R, Riff D, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA. 2000; 283:1016-24. 20. Ungchusak K,Auewarakul P, Dowell SF, Kitphati R,Auwanit W, Puthavathana P, et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med. 2005;352:333-40. 21. Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005;353:1374-85. 22. Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med. 2004;10:S88-97. 23. World Health Organization Multicentre Collaborative Network for Severe Acute Respiratory Syndrome Diagnosis. A multicentre collaboration to investigate the cause of severe acute respiratory syndrome. Lancet. 2003;361:1730-3. 24. Lee N, Hui D, Wu A, Chan P, Cameron P, Joynt GM, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med. 2003;348:1986-94. 25. Loutfy MR, Blatt LM, Siminovitch KA, Ward S, Wolff B, Lho H, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA. 2003;290:3222-8. 26. HKU/UCH SARS Study Group. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252-6. 27. Groneberg DA, Poutanen SM, Low DE, Lode H, Welte T, Zabel P. Treatment and vaccines for severe acute respiratory syndrome. Lancet Infect Dis. 2005;5:147-55. 28. Heilman CA. From the National Institute of Allergy and Infectious Diseases and the World Health Organization. Respiratory syncytial and parainfluenza viruses. J Infect Dis. 1990;161:402-6. 29. Mlinaric-Galinovic G, Falsey AR,Walsh EE. Respiratory syncytial virus infection in the elderly. Eur J Clin Microbiol Infect Dis. 1996;15:777-81. 30. Yang E, Rubin BK. “Childhood” viruses as a cause of pneumonia in adults. Semin Respir Infect. 1995;10:232-43. 31. Thompson WW, Shay DK,Weintraub E, Brammer L, Cox N,Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289:179-86. 32. Dowell SF,Anderson LJ, Gary HE Jr., Erdman DD, Plouffe JF, File TM Jr., et al. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis. 1996;174:456-62. 33. Wendt CH, Hertz MI. Respiratory syncytial virus and parainfluenza virus infections in the immunocompromised host. Semin Respir Infect. 1995;10:224-31. 34. Falsey AR, McCann RM, Hall WJ, Criddle MM. Evaluation of four methods for the diagnosis of respiratory syncytial virus infection in older adults. J Am Geriatr Soc. 1996;44:71-3. 35. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics. 1996;97:137-40. 36. McColl MD, Corser RB, Bremner J, Chopra R. Respiratory syncytial virus infection in adult BMT recipients: effective therapy with short duration nebulised ribavirin. Bone Marrow Transplant. 1998;21:423-5. 37. Whimbey E, Champlin RE, Englund JA, Mirza NQ, Piedra PA, Goodrich JM, et al. Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplant recipients. Bone Marrow Transplant. 1995;16:393-9. 38. Groothuis JR, King SJ, Hogerman DA, Paradiso PR, Simoes EA. Safety and immunogenicity of a purified F protein respiratory syncytial virus (PFP-2) vaccine in seropositive children with bronchopulmonary dysplasia. J Infect Dis. 1998;177:467-9. 39. Van den Hoogen BG, de Jong JC, Groen J, Kuiken T, de Groot R, Fouchier RA, et al. A newly discovered human pneumovirus isolated from young children with respiratory tract disease. Nat Med. 2001;7:719-24. 40. Martino R, Porras RP, Rabella N,Williams JV, Rámila E, Margall N, et al. Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant. 2005;11:781-96.

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41. Williams JV, Martino R, Rabella N, Otegui M, Parody R, Heck JM, et al. A prospective study comparing human metapneumovirus with other respiratory viruses in adults with hematologic malignancies and respiratory tract infections. J Infect Dis. 2005;192:1061-5. 42. Kumar D, Erdman D, Keshavjee S, Peret T, Tellier R, Hadjiliadis D, et al. Clinical impact of community-acquired respiratory viruses on bronchiolitis obliterans after lung transplant. Am J Transplant. 2005;5:2031-6. 43. Falsey AR, Erdman D,Anderson LJ,Walsh EE. Human metapneumovirus infections in young and elderly adults. J Infect Dis. 2003;187:785-90. 44. Hindiyeh M, Hillyard DR, Carroll KC. Evaluation of the Prodesse Hexaplex multiplex PCR assay for direct detection of seven respiratory viruses in clinical specimens. Am J Clin Pathol. 2001;116:218-24. 45. Kaplan LJ, Daum RS, Smaron M, McCarthy CA. Severe measles in immunocompromised patients. JAMA. 1992;267:1237-41. 46. Angel JB, Walpita P, Lerch RA, Sidhu MS, Masurekar M, DeLellis RA, et al. Vaccine-associated measles pneumonitis in an adult with AIDS. Ann Intern Med. 1998;129:104-6. 47. Measles pneumonitis following measles-mumps-rubella vaccination of a patient with HIV infection, 1993. MMWR Morb Mortal Wkly Rep. 1996;45:603-6. 48. Forni AL, Schluger NW, Roberts RB. Severe measles pneumonitis in adults: evaluation of clinical characteristics and therapy with intravenous ribavirin. Clin Infect Dis. 1994; 19:454-62. 49. Ramsey PG, Fife KH, Hackman RC, Meyers JD, Corey L. Herpes simplex virus pneumonia: clinical, virologic, and pathologic features in 20 patients. Ann Intern Med. 1982;97:813-20. 50. Graham BS, Snell JD Jr. Herpes simplex virus infection of the adult lower respiratory tract. Medicine (Baltimore). 1983;62:384-93. 51. Feldman S, Stokes DC. Varicella zoster and herpes simplex virus pneumonias. Semin Respir Infect. 1987;2:84-94. 52. De Clercq E. Recent highlights in the development of new antiviral drugs. Curr Opin Microbiol. 2005;8:552-60. 53. Haake DA, Zakowski PC, Haake DL, Bryson YJ. Early treatment with acyclovir for varicella pneumonia in otherwise healthy adults: retrospective controlled study and review. Rev Infect Dis. 1990;12:788-98. 54. Mohsen AH, McKendrick M. Varicella pneumonia in adults. Eur Respir J. 2003;21:886-91. 55. Lim WS, Macfarlane JT, Colthorpe CL. Pneumonia and pregnancy. Thorax. 2001;56:398-405. 56. Mer M, Richards GA. Corticosteroids in life-threatening varicella pneumonia. Chest. 1998;114:426-31. 57. Prevention of varicella. Update recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1999;48:1-5. 58. Klemola E,Von Essen R, Henle G, Henle W. Infectious-mononucleosis-like disease with negative heterophil agglutination test. Clinical features in relation to Epstein-Barr virus and cytomegalovirus antibodies. J Infect Dis. 1970;121:608-14. 59. Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9:543-58. 60. Meyers JD, Flournoy N,Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis. 1986;153:478-88. 61. Soubani AO, Miller KB, Hassoun PM. Pulmonary complications of bone marrow transplantation. Chest. 1996;109:1066-77. 62. Ljungman P. Cytomegalovirus pneumonia: presentation, diagnosis, and treatment. Semin Respir Infect. 1995;10:209-15. 63. McGlave PB, Shu XO,Wen W,Anasetti C, Nademanee A, Champlin R, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years’ experience of the national marrow donor program. Blood. 2000;95:2219-25. 64. van Esser JW, Niesters HG, van der Holt B, Meijer E, Osterhaus AD, Gratama JW, et al. Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation. Blood. 2002;99:4364-9. 65. Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood. 2004;103:2003-8. 66. Kollman C, Howe CW,Anasetti C,Antin JH, Davies SM, Filipovich AH, et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood. 2001;98:2043-51.

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67. Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C. Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood. 2003;102:4255-60. 68. Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood. 2002;99:1978-85. 69. Mera JR,Whimbey E, Elting L, Preti A, Luna MA, Bruner JM, et al. Cytomegalovirus pneumonia in adult nontransplantation patients with cancer: review of 20 cases occurring from 1964 through 1990. Clin Infect Dis. 1996;22:1046-50. 70. Smith CB. Cytomegalovirus pneumonia: State of the art. 1989;95:182S-7S. 71. Storch GA, Ettinger NA, Ockner D,Wick MR, Gaudreault-Keener M, Rossiter J, et al. Quantitative cultures of the cell fraction and supernatant of bronchoalveolar lavage fluid for the diagnosis of cytomegalovirus pneumonitis in lung transplant recipients. J Infect Dis. 1993;168:1502-6. 72. Ruutu P, Ruutu T,Volin L,Tukiainen P, Ukkonen P, Hovi T. Cytomegalovirus is frequently isolated in bronchoalveolar lavage fluid of bone marrow transplant recipients without pneumonia. Ann Intern Med. 1990;112:913-6. 73. Boeckh M, Boivin G. Quantitation of cytomegalovirus: methodologic aspects and clinical applications. Clin Microbiol Rev. 1998;11:533-54. 74. Slavin MA, Gleaves CA, Schoch HG, Bowden RA. Quantification of cytomegalovirus in bronchoalveolar lavage fluid after allogeneic marrow transplantation by centrifugation culture. J Clin Microbiol. 1992;30:2776-9. 75. Schmidt GM, Horak DA, Niland JC, Duncan SR, Forman SJ, Zaia JA. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants; The City of Hope-Stanford-Syntex CMV Study Group. N Engl J Med. 1991;324:1005-11. 76. Meyers JD, Reed EC, Shepp DH,Thornquist M, Dandliker PS,Vicary CA, et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation. N Engl J Med. 1988;318:70-5. 77. Crumpacker C, Marlowe S, Zhang JL,Abrams S,Watkins P. Treatment of cytomegalovirus pneumonia. Rev Infect Dis. 1988;10 Suppl 3:S538-46. 78. Hodson E, Barclay P, Craig J, et al. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2005; CD003774. 79. La Rosa AM, Champlin RE, Mirza N, Gajewski J, Giralt S, Rolston KV, et al. Adenovirus infections in adult recipients of blood and marrow transplants. Clin Infect Dis. 2001;32:871-6. 80. Gavin PJ, Katz BZ. Intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children (Review). Pediatrics. 2002;110:119. 81. Cheng VC,Tang BS,Wu AK, Chu CM,Yuen KY. Medical treatment of viral pneumonia including SARS in immunocompetent adult. J Infect. 2004;49:262-73. 82. Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2003;31:481-6. 83. Khan AS, Khabbaz RF,Armstrong LR, Holman RC, Bauer SP, Graber J, et al. Hantavirus pulmonary syndrome: the first 100 US cases. J Infect Dis. 1996;173:1297-303. 84. Duchin JS, Koster FT, Peters CJ, Simpson GL,Tempest B, Zaki SR, et al. Hantavirus pulmonary syndrome: a clinical description of 17 patients with a newly recognized disease. The Hantavirus Study Group. N Engl J Med. 1994;330:949-55. 85. Huggins JW, Hsiang CM, Cosgriff TM, Guang MY, Smith JI, Wu ZO, et al. Prospective, doubleblind, concurrent, placebo-controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. J Infect Dis. 1991;164:1119-27. 86. Chapman LE, Mertz GJ, Peters CJ, Jolson HM, Khan AS, Ksiazek TG, et al. Intravenous ribavirin for hantavirus pulmonary syndrome: safety and tolerance during 1 year of open-label experience. Ribavirin Study Group. Antivir Ther. 1999;4:211-9. 87. Collaborative Antiviral Study Group. Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America. Clin Infect Dis. 2004;39:1307-13. 88. Hantavirus pulmonary syndrome—Colorado and New Mexico, 1998. MMWR Morb Mortal Wkly Rep. 1998;47:449-52.

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Chapter 23

Community-Acquired Pneumonia THOMAS J. MARRIE, MD

Key Learning Points 1. Pneumonia is increasing as a cause of hospitalization among the elderly. 2. Cigarette smoking and asthma are independent risk factors for invasive pneumococcal disease. 3. In most cases antimicrobial treatment is empirical. A key concept in selecting therapy is to inquire about antimicrobial therapy in the past 3 months. 4. In-hospital observation of low risk patients is not necessary following a switch to oral antibiotics and by following this strategy hospital stay can be reduced by at least 1 day.

P

neumonia is a disease of the alveoli and respiratory bronchioles caused by an infectious agent. Pathologically it is characterized by increased weight and replacement of the normal lung sponginess by induration (consolidation). This induration can involve most or all of a lobe, or it can be patchy and localized around bronchi-bronchopneumonia. Microscopic examination can show dense alveolar infiltration with polymorphonuclear leucocytes as is found in patients with pneumonia because of bacterial agents or interstitial inflammation as is usually seen in viral pneumonia. Pneumonia is defined clinically as a new opacity on chest radiograph in the presence of at least two of the following symptoms and signs: fever, cough, sputum, pleuritic chest pain, oral temperature greater than 38ºC (100.4ºF), crackles, and consolidation (dullness to percussion, bronchial breathing, egophony, whispered pectoriloquy). 450

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New Developments in the Management of Community-Acquired Pneumonia Staphylococcus aureus carrying the Panton-Valentine leukocidin genes has emerged as a cause of necrotizing pneumonia among young otherwise healthy adults. ● New or emerging etiologies of pneumonia include, SARS-CoV, human metapneumovirus, human coronavirus NL-63, and influenza virus H5N1. ● Activated protein C can be of value as adjunctive therapy for patients with severe community-acquired pneumonia. ●

Epidemiology Pneumonia is a common and often a serious illness. It is the sixth leading cause of death in the United States. Approximately 600,000 persons are hospitalized with pneumonia each year, and there are 64 million days of restricted activity caused by this illness (1,2). The rate of pneumonia is highest at the extremes of age. In a populationbased study in a Finnish town, Koivula and colleagues (3) found that 14 in 1000 per year at or older than 60 years of age developed pneumonia. Seventyfive percent of these cases of pneumonia were community-acquired. In this study, independent risk factors for community-acquired pneumonia (CAP) were the following: alcoholism, relative risk (RR) 9; asthma, RR 4.2; immunosuppression, RR 1.9; age older than 70 years of age versus age 60 to 69 years, RR 1.5. The rate of pneumonia is low during young adulthood but begins to increase at around age 55, and there is a sharp increase at age 65. Jackson and colleagues (4) found that the overall rate for CAP among those 65 to 69 years of age was 18.2 cases per 1000 person years compared with 52.3 cases per 1000 person years for those who were at or older than 85 years of age. Just over 59% of episodes among seniors were treated on an outpatient basis, and they estimated that there were approximately 915,900 cases of CAP among seniors annually in the United States. Data from the National Hospital Discharge Survey in the United States indicate that from 1990 to 2002 there were 21.4 million hospitalizations among those 65 years of age and older, and infectious diseases accounted for 48% of these hospitalizations. Forty-six percent of the infectious diseases hospitalizations were caused by lower respiratory tract infections, and 48% of the infectious diseases deaths were caused by these infections (5). Fry and colleagues (5a) also used the National Hospital Discharge Survey to examine pneumonia among those 65 years of age and older over the 15 year period 1988 to 2002. They noted a 20% increase in pneumonia as a first- or any-listed diagnosis. They also saw that the in-hospital death rate was 1.5 times higher for pneumonia as a first-listed diagnosis compared with the other most common causes of hospitalization. For specific causes of pneumonia, the risk factors can differ from those for pneumonia as a whole. Thus, dementia, seizures, congestive heart failure, cerebrovascular disease, and chronic obstructive lung disease were risk

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factors for pneumococcal pneumonia (5b). In addition, both cigarette smoking and asthma have been found to be independent risk factors for invasive pneumococcal disease (6,7). Among HIV-infected patients, the rate of pneumococcal pneumonia is 41.8 times higher than those in the same age group who are not HIV infected (8). However, with the advent of highly active antiretroviral therapy, the incidence of pneumococcal bacteremia among HIVinfected persons has decreased from 24.1 episodes per 1000 patient years to 8.2 per 1000 patient years (9). Risk factors for Legionnaires’ disease include male gender, tobacco smoking, diabetes, hematologic malignancy, cancer, end stage renal disease, and HIV infection (10). Risk factors for severe respiratory syncytial virus infection in elderly persons include the presence of underlying chronic pulmonary disease (odds ratio [OR] 3.97), functional disability OR 1.67, and low serum neutralizing antibody titer OR 5.89 (11). The usual risk factors for aspiration pneumonia are altered level of consciousness and various neurological diseases that interfere with the swallowing mechanism. Recently, there has been an association between the use of gastric acid suppressive drugs and aspiration pneumonia. The incidence rates of pneumonia in non–acid-suppressive drug users and those who used these agents was 0.6 and 2.45 per 100 person years respectively (12). The risk seemed to be highest among those using proton-pump inhibitors. There have been major changes in both the host and microorganisms that are reflected in changes in the epidemiology of pneumonia (Table 23-1). Penicillin-resistant Streptococcus pneumoniae (PRSP) is now a fact of life in most North American communities. Many of the PRSP isolates are resistant to

Table 23-1 Changes in the Epidemiology of Community-Acquired Pneumonia Caused by Host and Microorganism Changes Host Factors

1. Increasing age of the population 2. Marked increase in number of nursing home residents 3. Increase in number of immunocompromised persons living in the community. i) Organ-transplant recipients ii) HIV infected persons iii) Those receiving immunosuppressive treatment for a variety of diseases 4. Alcoholism Microorganism Factors

1. Newly discovered microorganisms as causes of pneumonia, e.g., Hantavirus, Chlamydophila pneumoniae, SARS-CoV, human metapneumovirus 2. Antimicrobial resistance in Streptococcus pneumoniae i) Penicillin resistance ii) Macrolide resistance iii) Multidrug resistance 3. Methicillin-resistant Staphylococcus aureus as a cause of community-acquired pneumonia including strains carrying the Panton-Valentine genes Abbreviations: SARS-CoV, severe acute respiratory syndrome–associated coronavirus.

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three or more antibiotic classes (multidrug resistance). In one study, 14% of bacteremic S. pneumoniae isolates were resistant to penicillin, 12% to ceftazidime, and 24% were resistant to trimethoprim-sulfamethoxazole (8). Doern and colleagues (13) examined 1817 S. pneumoniae isolates collected from patients with community-acquired respiratory tract infections in 44 U.S. medical centers during the winter of 2002-2003. Overall rates of resistance were as follows: penicillin 34.2%, ceftriaxone 6.9%, erythromycin 29.5%, clindamycin 9.4%, tetracycline 16.2%, and trimethoprim-sulfamethoxazole 31.9%. There was no resistance to the following: vancomycin, linezolid, and telithromycin. Multidrug resistance was present in 22.2% of the isolates, and 2.3% of the isolates had ciprofloxacin minimum inhibitory concentrations (MICs) of greater than or equal to 4 mcg/mL. These investigators also made the observation that since 1994-1995, rates of resistance to β-lactams, macrolides, tetracyclines, and trimethoprim sulfamethoxazole have plateaued or have begun to decrease. In contrast, fluoroquinolone resistance is increasing. In Madrid in 1992, 15.2% of S. pneumoniae isolates were resistant to erythromycin (14). Fortunately, it is possible to predict who is likely to have pneumonia caused by PRSP. Previous use of beta-lactam antibiotics, alcoholism, noninvasive disease, age younger than 5 years or older than 65 years, and immunosuppression are risk factors for PRSP pneumonia (15,16). The relevance of PRSP is discussed in the Treatment section. There is a seasonal variation in the rate of pneumonia. Both attack rates and death rates are highest in the winter months (17). This is likely caused by many factors including more time spent indoors (crowding) and hence more opportunity for person to person spread and an interaction between influenza viruses and S. pneumoniae. In a squirrel monkey model, infection with influenza A virus before S. pneumoniae inoculation led to a 75% death rate versus no death for infection with influenza virus alone (18). We are only now recognizing the extent to which genetic factors affect the host inflammatory response and hence the outcome of the pneumonia (19). A 250 base pair insertion deletion polymorphism in the angiotensinconverting enzyme (ACE) gene predisposes elderly people to pneumonia. A polymorphism in the toll-like receptor 5 gene conferred a twofold risk for developing Legionella pneumonia in nonsmokers only. Patients homozygous for the FcγRIIa-R131 allele were more common among patients with bacteremic pneumococcal pneumonia than among control individuals and all the early deaths from pneumonia occurred in this group. The LTA + 250 AA genotype is a risk factor for septic shock in patients with CAP.

Etiology In studies reporting the cause of CAP and in evaluating an individual patient it is wise to categorize the cause of the pneumonia as definite, probable, or possible (20) (Table 23-2).

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Table 23-2 Etiology of Pneumonia Categorized as Definite, Probable, Possible Definite

Pathogen recovered from blood, pleural fluid, or lung tissue. Isolation of Legionella species or Mycobacterium tuberculosis from sputum Positive urinary antigen test for Legionella Fourfold or greater increase in antibody titers between acute and convalescent serum samples Amplification of nucleic acid of a micro-organism from lung tissue or pleural fluid Amplification of nucleic acid of Legionella species from a nasopharyngeal swab specimen Probable

Isolation from a purulent sputum specimen of the following organisms in which a morphologically compatible organism was seen on Gram stain in moderate or large numbers Staphylococcus aureus Streptococcus pneumoniae Hemophilus influenzae Moraxella catarrhalis Pseudomonas aeruginosa Amplification of nucleic acid of Mycoplasma pneumoniae, Chlamydia pneumoniae, or respiratory virus from a nasopharyngeal swab Possible

A. Gram stain of sputum showing a predominance of the following: Gram-positive diplococci—S. pneumoniae Gram-positive cocci in clusters—S. aureus Gram-negative coccobacilli—H. influenzae B. Isolation of a pathogen from a purulent sputum specimen in the absence of a compatible gram stain C. High single or static antibody titers against the following: Titer Organism Legionella pneumophila ≥ 1:1024 Mycoplasma pneumoniae ≥ 1:64 Modified with permission from Marston BJ, Plouffe JF, File TM Jr., et al. Incidence of community-acquired pneumonia requiring hospitalization: Results of a population based active surveillance study in Ohio. Arch Intern Med. 1997;157:1709-18; and Fang G-D, Fine M, Orleff J, et al. New and emerging etiologies for community-acquired pneumonia with implication for therapy. Medicine. 1990;69:307-16.

There are more than 100 different microbiological agents that can cause pneumonia. Fortunately just a few organisms predominate. These include S. pneumoniae, Haemophilus influenzae, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Staphylococcus aureus and to a lesser extent Legionella pneumophila. The rank order of various pathogens does differ in certain clinical situations. For example, in pneumonia treated on an ambulatory basis, M. pneumoniae is the most common cause (21-25). Table 23-3 shows the frequency of the various microbial agents in 439 patients with ambulatory pneumonia. Microorganisms recently identified as causes of CAP include hantaviruses; severe acute respiratory syndrome–associated coronavirus (SARS Co-V), human metapneumovirus, and human coronavirus NL 63. An emerging threat is influenza virus H5N1, which has widely

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Table 23-3 Causes of Pneumonia in 439 Patients Treated on an Ambulatory Basis Agent

Mycoplasma pneumoniae Influenza A virus Streptococcus pneumoniae Haemophilus influenzae Coxiella burnetii Adenovirus Legionella species Unknown etiology Chlamydophila pneumoniae*

Number

Percentage

104 31 23 10 8 6 5 211 16

24 7 5 2.3 1.8 1.4 1.1 48.0 10.7

Data from references 21-25. * Data are from one study only.

infected poultry in Southeast Asia since 2003 and has jumped the species barrier from birds to human. To September 2005 there had been 112 cases reported in humans with 75 deaths. In October 2005, cases in poultry and in humans began to appear in Europe. There is concern that this will be the agent of the next pandemic of influenza. Another new pathogen is methicillin resistant S. aureus carrying the Panton-Valentine leukocidin (PVL) genes (26). It has caused a severe necrotizing pneumonia in healthy adults. In 1932, Panton and Valentine described leukocidin as a virulence factor. Production of this leucocidin is now known to be associated with tissue necrosis. In one study, hemoptysis was found in 38% of 16 patients with severe pneumonia associated with S. aureus strains carrying PVL genes compared with 1 of 33 PVL negative patients (27). It is likely that S. pneumoniae causes more than the reported figure of 5% of cases of ambulatory pneumonia because many patients in these studies did not have sputum or blood cultures done. The cause of pneumonia among patients requiring admission to hospital for treatment of this illness has been studied in many countries (28-38). Because all studies did not test for all causes, it is difficult to know the exact frequency with which each agent causes pneumonia. In a study that used serologic methods to diagnose pneumococcal pneumonia, this agent accounted for 50% of all cases of pneumonia (33). Table 23-4 shows the rank order of the most common causes of CAP requiring admission to hospital. Viruses are not included in this table, but respiratory syncytial virus, and influenza A and B viruses are important in the pathogenesis of CAP. Using polymerase chain reaction (PCR), Templeton and colleagues (34) found that 56% of 105 patients with CAP had a respiratory viral infection. Most common were rhinoviruses at 18%, coronaviruses at 14%, and influenza A at 9%. This study also found that 28% of the patients had mixed infection. Mixed infections were associated with more severe pneumonia. Other viral infections that can cause pneumonia are respiratory syncytial virus, human metapneumovirus, and SARS Co-V. Rhinoviruses are not often thought of as a cause of CAP. However, a recent report of a rhinovirus outbreak in a long-term care facility will probably change that (35). In this

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Table 23-4 Most Common Causes of Community-Acquired Pneumonia Requiring Admission to Hospital Organism

Percentage

Streptococcus pneumoniae Chlamydophila pneumoniae “Aspiration” Haemophilus influenzae Staphylococcus aureus Legionella species Aerobic gram-negative bacilli Pneumocystis jiroveci Mycoplasma pneumoniae Moraxella catarrhalis Mycobacterium tuberculosis

30-50 15 10 7 2-5 2-7 4 3 5-10 1 1

Data from references 25, 28-32, 36-38.

outbreak, 56 residents and 26 staff developed respiratory illness. Thirty-four residents had chest radiography and 15 (27%) showed unilobar or multilobar pneumonia (35). Twelve (21%) residents died (35). Aspiration pneumonia is underdiagnosed. Features that suggest aspiration in a patient with CAP are altered level of consciousness, seizures, impaired gag reflex, alcohol intoxication, and advanced Parkinson or Alzheimer diseases. Clinically, one has to make a distinction between aspiration pneumonitis (inflammatory reaction to gastric acid, no infection) and aspiration pneumonia. Persons with poor dental hygiene aspirate large numbers of anaerobic bacteria and can develop mixed aerobic-anaerobic pulmonarypleural infections, including lung abscess. Pneumocystis jiroveci is still an important cause of pneumonia among HIV-infected persons. Mundy and colleagues (30) studied 385 patients who were admitted to Johns Hopkins Hospital with pneumonia over a 1-year period. One hundred and eighty were HIV infected, and 48 of these (26.7%) had Pneumocystis carinii pneumonia. Clues to the cause of pneumonia can be inferred from historical data and from the clinical setting (Table 23-5).

Clinical Manifestations Fever, cough (can be productive of purulent or rust-colored sputum or can be nonproductive), pleuritic chest pain, chills or rigors, and shortness of breath are classic manifestations of pneumonia. Foul smelling sputum is a clue to anaerobic pulmonary infection. Not infrequently, headache, nausea, vomiting, diarrhea, myalgia, and arthralgia are also reported. The frequency with which these symptoms are seen in patients with pneumonia is given in Table 23-6. The physical signs associated with pneumonia are tachypnea, dullness to percussion, increased tactile and vocal fremitus, egophony,

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Table 23-5 Clues to the Etiology of Pneumonia from the Medical History or Clinical Setting Feature

Possible Etiologic Agents

Occupational History

Health care workers

Veterinarian, farmer, abattoir worker

Mycobacterium tuberculosis, acute HIV seroconversion with pneumonia (if recent needlestick injury from an HIV-positive patient) Coxiella burnetii

Host Factors

Diabetic ketoacidosis Alcoholism Chronic obstructive lung disease Solid organ transplant recipient (pneumonia occurring >3 months after transplant)

Sickle cell disease HIV infection and CD4 cell count of <200/µL

Streptococcus pneumoniae, Staphylococcus aureus S. pneumoniae, Klebsiella pneumoniae, S. aureus S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis S. pneumoniae, H. influenzae, Legionella species, Pneumocystis jiroveci, cytomegalovirus, Strongyloides stercoralis S. pneumoniae S. pneumoniae, P. jiroveci, H. influenzae, Cryptococcus neoformans, M. tuberculosis, Rhodococcus equi

Environmental Factors

Exposure to contaminated air-conditioning, cooling towers, hot tub, recent travel stay in a hotel, exposure to grocery store mist machine, or visit to, or recent stay in a hospital with contaminated (by L. pneumophila) drinking water Pneumonia develops after windstorm in an area of endemicity Outbreak of pneumonia occurs in shelter for homeless men or in a jail Outbreak of pneumonia occurs in military training camp Outbreak of pneumonia in a nursing home

Exposure to infected parturient cats, cattle, sheep, or goats Exposure to contaminated bat caves, excavation in areas of endemicity Exposure to turkeys, chickens, ducks, or psittacine birds Exposure to rabbits

Legionella pneumophila

Coccidioides immitis S. pneumoniae, M. tuberculosis S. pneumoniae, Chlamydia pneumoniae, adenovirus C. pneumonia, S. pneumoniae, respiratory syncytial virus, influenza A virus, Legionella species C. burnetii Histoplasma capsulatum Chlamydia psittaci Francisella tularensis Continued

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Table 23-5 Continued Travel

Travel to Thailand or other countries in Southeast Asia Immigration from countries with high endemic prevalence of tuberculosis

Burkholderia pseudomallei (melioidosis) M. tuberculosis

whispered pectoriloquy, crackles, and pleural friction rub. Unfortunately, most of the time symptoms and signs are neither sufficiently sensitive nor specific enough to make a diagnosis of pneumonia clinically without radiographic confirmation (39). A chest radiograph is necessary to substantiate a clinical diagnosis of pneumonia. The clinical presentation of pneumonia changes with age. Metlay and colleagues (40) found that with increasing age, patients with pneumonia had fewer symptoms. Thus, those 75 years of age and older with pneumonia had 3.3 fewer total symptoms than patients 18 through 44 years of age with pneumonia. There is a considerable clinical spectrum to the severity of illness in patients with CAP. In any age group, patients can be mildly to severely ill. It is useful for the clinician to have a method to categorize severity of illness in patients with pneumonia. This is one simple system: Look for two or more of

Table 23-6 Frequency of Various Symptoms and Signs in 588 Patients Hospitalized with Community-Acquired Pneumonia Symptom

Cough Productive cough Fever Anorexia Chills Pleuritic chest pain Headache Nausea Myalgia Vomiting Sore throat Arthralgia Abdominal pain Diarrhea

Number

Percentage

482 355 402 359 297 232 171 171 161 132 110 92 71 67

82 60 68 61 51 39 29 29 27 22 19 16 12 11

458 459 199 175 171

78 78 34 30 29

Sign

Temperature >37ºC (98.6ºF) Crackles Rhonchi Confusion Consolidation

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the following: respiratory rate more than 30 breaths per minute, diastolic blood pressure less than 60 mm Hg, or blood urea nitrogen greater than or equal to 7 mmol/L (41). Patients with two or more of the preceding findings had a death rate 16 times higher than those who did not have such findings (42). Another variation of the preceding scoring system is the CURB-65 rule wherein age older than 65 years is added to the features just given (43). In this system, one point is given for the presence of any of these findings. For a score of 0 or 1 the death rate is 1.5%, although for 2 it is 9%, and for 3 or more it is 22%. The authors suggested that patients with a CURB-G5 score of 0-1 be treated as outpatients, those with a score of 2 be admitted to the ward, and those with a score of ≥ 3 often require ICU care. A more complex severity of illness scoring system was described by Fine and coworkers (44). Using this method, points are assigned for 20 different items (Table 23-7). These points are then totaled, and a patient is placed into one of five risk strata for death. Patients in risk classes I to III (<90 points) have a death rate less than 1%, although risk class IV (91-130 points) has a 9.3% death rate, and risk class V (>131 points) has a 27% death rate. This scoring system has been used to help with the admission decision. Patients in classes I and II can be treated on an ambulatory basis; those in classes IV and V should be admitted. Patients in class III can require a period of observation in the emergency room before a decision is made about admission or discharge. Those who are improving can be sent home. With further study it has become apparent that the Fine scoring system is a guide only to the point-of-care decision, as are all the other systems designed to predict death. A physician’s judgement is crucial in the admission decision. Many factors including psychosocial ones also influence the admission decision. Functional status in the week before admission predicts in-hospital death (45). For those who were walking without assistance there was a 3.5% in hospital death rate, although for those who required assistance to walk the death rate was 5.6%, and for those who were wheelchair and bed bound the rates were 20% and 25% respectively. Both hypo- and hypercapnia at the time of admission are associated with excess death rates. In a study of 2171 patients, those with a partial pressure of carbon dioxide (PCO2) of less than 32 mm Hg had a 1.8 times higher death rate than those who had a normal value, although those with a PCO2 of greater than 45 had a 2.6 times higher death rate (46). All patients with pneumonia who are discharged from the emergency room should be given printed material clearly stating what indicates worsening of the pneumonia with instructions to return if any of these occur. It is not uncommon that patients who are sent home from the emergency room with CAP will have a positive blood culture reported later. All of these patients should be recalled for assessment. If they are doing well there is no need for admission except for patients with S. aureus bacteremia, in which case rightsided endocarditis must be ruled out. In patients with bacteremia and pleuritic chest pain, a careful assessment for empyema must be carried out.

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Table 23-7 Community-Acquired Pneumonia Severity-of-Illness Scoring System: How to Assign Points* (44) Patient Characteristics

Number of Points

Demographic Factors

Age Men Women Nursing home resident

Age in years Age in years minus 10 10

Coexisting Illnesses

Neoplastic disease1 Liver disease2 Congestive heart failure3 Cerebrovascular disease4 Renal disease5

30 20 10 10 10

Physical Examination Findings

Altered mental status6 Respiratory rate >30/min Systolic blood pressure <90 mmHg Temperature <35ºC (95ºF) or >40ºC (104ºF) Pulse rate >125/min

20 20 20 15 10

Laboratory and Radiographic Findings

Arterial pH <7.35 Blood urea nitrogen >30 mg/dL (11 mmol/L) Sodium <130 mmol/L Glucose >250 mg/dL (14 mmol/L) Hematocrit <30% Partial pressure of arterial oxygen <60 mm Hg Pleural effusion

30 20 20 10 10 10 10

Republished with permission from Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify lowrisk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-50. * Based on Pneumonia Patient Outcomes Research Team (PORT) cohort study data. 1 Any cancer (except basal or squamous cell carcinoma of the skin) active at presentation or within 1 year of presentation for CAP. 2 Clinical or histologic cirrhosis or chronic active hepatitis. 3 Diagnosis documented by history or by findings on physical examination, chest film, echocardiogram, multiple gated acquisition scan, or left ventriculogram. 4 Clinical diagnosis of stroke or transient ischemic attack, or stroke documented by magnetic resonance imaging or computed tomography. 5 History of chronic renal disease or abnormal blood urea nitrogen and creatinine concentrations documented in this medical record. 6 Disorientation as to person, place, or time that is not known to be chronic; stupor or coma. Abbreviations: CAP, community-acquired pneumonia.

Severe Community-Acquired Pneumonia Requiring Admission to the Intensive Care Unit Approximately 10% of patients with CAP who are admitted to the hospital require admission to the intensive care unit (ICU). S. pneumoniae is the most common cause of pneumonia in this setting, although L. pneumophila and

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S. aureus are more common than in patients who do not require admission to the ICU. In one study (47), severe pneumonia requiring ICU admission was independently associated with gram-negative enteric bacilli and Pseudomonas aeruginosa. In a study of 124 patients with CAP who required mechanical ventilation on the first day of admission to the ICU, three independent variables were significantly associated with death: a simplified acute physiological score greater than 45, shock, and acute renal failure (48). In the same study, the pneumonia patients requiring ventilation were age and gender matched with patients without pneumonia who required mechanical ventilation. Both groups had the same acute physiological score. Interestingly, the death rate was the same in both groups at 32% for pneumonia patients and 35% for the non-pneumonia patients. Patients with chronic alcoholism who are admitted to the ICU with pneumonia have a very poor prognosis with a 68% death within 2 months of discharge from the ICU (49). In patients with pneumonia complicated by septic shock, logistic regression analysis demonstrated Acute Physiology and Chronic Health Evaluation (APACHE) II score and serum interleukin 6 (IL-6) concentration to be significant independent predictors of death (50). Patients with Pseudomonas or Acinetobacter infection had significantly higher IL-6 levels and significantly lower tumor necrosis factor alpha levels when compared with the rest of the cohort of patients. The 28-day death rate was 47%.

Diagnosis A chest radiograph (posterior-anterior and lateral views) is needed to confirm the clinical impression that the patient has pneumonia. If the chest radiograph is negative for pneumonia, and it is still suspected clinically, wait 24 hours and repeat the chest radiograph or do a computed tomography (CT) scan of the chest. Studies have shown that CT can increase the diagnostic yield considerably over that of the chest radiograph. The extent of the remainder of the diagnostic workup depends on the severity of the pneumonia and the site of treatment—as an outpatient, on a hospital ward, or in a hospital ICU. Table 23-8 gives a suggested diagnostic workup for patients with pneumonia. For patients who are mildly ill and who are seen in an office setting and who are known to the attending physician, a chest radiograph is probably the only workup that is required. Some authorities question the need for blood cultures in all patients with pneumonia who require admission to the hospital because the yield is low (6%-10%), and the results infrequently change management decisions (51). However, if the blood culture is positive the cause of the pneumonia is certain, and therapy can be modified if necessary. Furthermore, bacteremic pneumococcal pneumonia in those who are 45 years of age or younger should prompt a test for HIV infection, because the rate of such infection in this group of patients is 41.8 times higher than in HIV-negative patients (8). In the current era of changing antimicrobial susceptibility of respiratory

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Table 23-8 Diagnostic Workup for Community-Acquired Pneumonia According to the Site of Treatment Site of Treatment Tests

Outpatient‡ CBC* Creatinine† Oxygen saturation* Glucose† Electrolytes† Hospital Ward CBC* BUN Creatinine* Electrolytes* Liver function tests Glucose* Blood cultures (two sets)* Oxygen saturation (arterial blood gases* if patient has COPD or if oxygen saturation is <92%) Sputum Gram stain and culture* Electrocardiogram Urine for Legionella antigen and pneumococcal antigen Induced sputum for Pneumocystis jiroveci (based on history of possible or proven HIV disease in combination with a compatible chest radiograph) Acute and 2- and 6-week convalescent serum samples for antibody testing in patients in whom atypical pneumonia is suspected. Thoracentesis if clinically significant (>1 cm of fluid on a lateral decubitus chest radiograph) pleural effusion is present Hospital Intensive Care Unit Same as for hospital ward. If no sputum available, consider bronchoalveolar lavage and protected brush specimen to obtain material for culture. * Essential tests † All patients 55 years of age and older and/or those with comorbid illness should have these tests prior to discharge from emergency room. ‡ For patients seen in an office setting who have a mild illness and who are known to the attending physician, a chest radiograph is probably the only diagnostic workup that is required. Abbreviations: BUN, blood urea nitrogen; CBC, complete blood count; COPD, chronic obstructive pulmonary disease.

pathogens, susceptibility of invasive strains of these organisms can be used to guide empiric therapy by providing valuable epidemiological information. The sputum Gram stain and culture is one of the most controversial tests in all of medical practice. Because sputum has to pass through a heavily colonized oral cavity, distinguishing colonization from infection can be problematic; thus, a sputum culture result can only be interpreted in conjunction with a Gram stain. For example, a heavy growth of S. pneumoniae from the sputum in conjunction with many polymorphonuclear leucocytes and only gram-positive diplococci on Gram stain is very suggestive that the pneumonia is caused by S. pneumoniae. In contrast, a heavy growth of Escherichia coli from a sputum specimen showing no gram-negative rodlike bacteria on Gram stain would be more suggestive of colonization.

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Sputum Gram stain and culture is recommended for patients who have not received antibiotic therapy before collection of the specimen because the Gram stain can give a rapid (15 minutes to 1 hour) answer about the cause of the pneumonia. This plus results of the sputum culture allows antibiotic therapy to be directed toward a specific cause. The Legionella urinary antigen test is a rapid (4 hours), sensitive (70%), and specific (99%) test that detects antigen of L. pneumophila serogroup 1 in urine (52). Antigen excretion persists on average for 42 days but can last up to 1 year (53). This test probably should be done on all patients with severe or rapidly progressive pneumonia. The rate of Legionnaires’ disease in a particular geographic area will influence policy decisions about the extent to which this test is used on patients admitted with CAP. There is also a urinary antigen test for the diagnosis of pneumococcal pneumonia. It detects polysaccharide C (which is present in all serotypes of pneumococci). In one study, pneumococcal antigen was detected in 70.4% of 27 patients with pneumococcal pneumonia. Of the 268 patients who had no pathogen detected using conventional diagnostic techniques, 25.7% had a positive pneumococcal urinary antigen test. In 48% of patients, the test is still positive after recovery from the episode of pneumonia. The longest duration of positivity was 89 days. This test should be done in all patients with severe pneumonia. Many causes of pneumonia are best, or only, diagnosed by detecting a fourfold or more increase in antibody titer between acute and convalescent serum samples. These samples are usually obtained 2 weeks apart, but for some infections, such as Legionella, they should be obtained 6 weeks apart. There is also a concern in many instances about the sensitivity of the method used to detect an antibody increase. For example, the complement fixation test that is readily available is approximately 4 times less sensitive than an enzyme immunoassay test for the diagnosis of respiratory-syncytial virus infection in adults. In most instances, however, a serological diagnosis of the cause of pneumonia does not help in the management of an individual patient. These tests, however, are valuable as epidemiological and public health tools. It is now possible to detect DNA of M. pneumoniae, C. pneumoniae, and L. pneumophila from material obtained by nasopharyngeal swabs using PCR method (54). Because these microorganisms do not colonize the oropharyngeal mucosa in patients who do not have pneumonia, the presence of their DNA on the nasopharynx of a patient is evidence that this organism is the cause of the pneumonia. The PCR test has been further refined and now also includes primers for nucleic acids of influenza A and B viruses; respiratory syncytial virus; human metapneumovirus; rhinoviruses; and coronaviruses (34). The role of these tests in the everyday management of patients with CAP has yet to be defined. The commercially available test for rapid detection of respiratory syncytial virus antigen is useful in children, but because of the low titer of virus in adults, it is very insensitive and should not be used.

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The diagnostic workup should be more extensive in seriously ill patients than in those who are mild to moderately ill, especially in those who require admission to the ICU and assisted ventilation. Bronchoscopy, using a protected bronchial brush to obtain a sample of lower respiratory tract secretions or using bronchoalveolar lavage, should be considered in this group of patients. Specimens of respiratory secretions obtained in this manner should be subjected to quantitative culture. The diagnostic yield from these invasive tests is approximately 70% (55). In patients with lobar consolidation, fine needle aspiration can be done (contraindicated in those who are receiving mechanical ventilation) to obtain material for culture (56). Rarely, open lung biopsy has to be done to make a diagnosis (57). Many of the patients who require admission to the hospital for treatment of pneumonia are elderly and have comorbid illness. Additional testing will be dictated by specific comorbidities, but all patients should have a complete blood count, blood urea nitrogen, creatinine, electrolytes, blood glucose, and liver function tests.

Treatment In most instances, treatment of CAP has to be empirical because the cause of the pneumonia is unknown. Guidelines have been developed to help with this decision-making (58). These guidelines are based mostly on expert opinion and not on evidence from randomly assigned clinical trials. Indeed, a recent study has shown that dividing patients who are to be treated on an ambulatory basis into those who are younger than 60 years of age and those who are older as suggested by the American Thoracic Society Guidelines in the past has no basis in fact (59). In this study, older patients treated with macrolides (i.e., treatment inconsistent with the guidelines) showed trends toward better outcomes compared with those treated according to the guidelines. More recent guidelines for the empiric antibiotic therapy for CAP do not divide patients to be treated on an ambulatory basis according to age (60). A key concept in selecting empiric antibiotic therapy is to inquire about antibiotic therapy in the past 3 months. If a macrolide has been used in this time period, then 35% of S. pneumoniae isolates are resistant to a macrolide compared with 7% if the patient didn’t have macrolide therapy in this time period. For penicillin or a cephalosporin, resistance increases from 5% to 9% in this setting. Thus, use a different class of antibiotic than the one that the patient had received in the past 3 months. A major consideration in the decision about which antibiotic to use is the presence of penicillin resistant PRSP in a community, because these organisms can also be resistant to macrolides and trimethoprim-sulfamethoxazole (8,13). The so-called respiratory quinolones (because they have enhanced activity against S. pneumoniae compared with ciprofloxacin) are being advocated to treat CAP because they are also active against PRSP. These agents include levofloxacin, moxifloxacin, and gemifloxacin. File and colleagues

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(61) studied 590 patients with CAP (both inpatients and outpatients were included in this trial); 226 were treated with levofloxacin, and 230 received intravenous ceftriaxone followed by oral cefuroxime or cefuroxime alone or in conjunction with a macrolide or doxycycline if in the opinion of the investigator an atypical pathogen was likely. Clinical success at 5 to 7 days posttherapy was superior for the levofloxacin group—96% versus 90% (95% confidence intervals −10.7, −1.3). Telithromycin is the first of a new class of antibiotics, the ketolides that can be used to treat ambulatory pneumonia (62). It is a semisynthetic derivative of erythromycin. It is characterized by 3 basic chemical modifications to the 14-membered macrolactone ring. The α L-cladinose at position three is replaced by a keto group (the distinguishing chemical feature between the macrolides and ketolides). This prevents telithromycin from inducing macrolide, lincosamide, and streptogramin (MLS)B resistance and results in improved activity against certain macrolide resistant bacteria. The large imidazolyl and pyridyl group-attached carbamate ring is added to c 11-12 of the macrolactone ring and this increases telithromycin’s binding affinity to the bacterial ribosome by 10-fold compared to macrolides. It is noteworthy that constitutively resistant S. pneumoniae is highly susceptible to telithromycin, but S. pyogenes and S. aureus expressing constitutive MLSB resistance are also resistant to telithromycin. Telithromycin is not affected by macrolide efflux mechanisms in bacterial cells. The dose is 800 mg OD for 5 to 10 days. Diarrhea, nausea, and vomiting are the major side effects followed by headache and dizziness. It has also been associated with elevations in hepatic aminotransferases and prolongation of the QT interval. It is a strong inhibitor of cytochrome P450 3A4 isoenzyme. Therefore, it is important to monitor for potential drug interactions with medications that prolong the QT interval or are metabolized by the cytochrome P450 enzyme (CYP) system. There is no need for adjustment in dosage for renal or hepatic failure. Although telithromycin has been used for the treatment of mild-to-moderate CAP, including multidrug-resistant strains of S. pneumoniae, and its effectiveness has been demonstrated in randomized trials of CAP, severe hepatotoxicity, visual disturbances, serious exacerbation of myasthenia gravis, and loss of consciousness have been reported. A US federal advisory panel, in December 2006, concluded that telithromycin should be a secondary alternative to other antimicrobial drugs. The FDA strengthened label warnings regarding the above side effects in February 2007 (http://www.fda.gov/cder/drug/infopage/telithromycin/default.htm). The risk-benefit ratio should be carefully weighed by each prescriber and telithromycin should not be prescribed in patients with known liver disease. In 2007, an Infectious Diseases Society of America/American Thoracic Society guideline on management of community-acquired pneumonia was published (Tables 23-9 and 23-10). This recommends a macrolide or doxycycline for previously healthy individuals who have not received antibiotic

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Table 23-9 Recommended Empirical Antibiotics for Community-Acquired Pneumonia Outpatient Treatment

1. Previously healthy and no use of antimicrobials within the previous 3 months: ● A macrolide (erythromycin 500 q 6 h; clarithromycin 500 mg q 12 h or XL 1000 mg QD; or azithromycin 500 mg once then 250 mg QD) ● Doxycyline (100 mg bid) 2. Presence of comorbidities (which includes: chronic heart, lung, liver or renal disease; diabetes; alcoholism; malignancy; asplenia; immunosuppressing conditions or drugs) or use of antimicrobials within the previous 3 months (in which case, an alternative from a different class should be selected) ● Respiratory fluoroquinolone (moxifloxacin 400 mg QD, gemifloxacin 320 mg QD, levofloxacin (750 mg QD) ● Beta-lactam (ceftriaxone, cefotaxime, ampicillin/sulbactam, or ertapenem) PLUS a macrolide 3. In regions with a high rate (>25%) of high-level (MIC ≥ 16 µg/ml) macrolideresistant S. pneumoniae, consider use of alternative agents listed above in 2 for patients without comorbidities Inpatient Non-ICU Treatment ● ●

Respiratory fluoroquinolone Beta lactam PLUS a macrolide

Inpatient ICU Treatment ●

A beta-lactam (cefotaxime, ceftriaxone, ampicillin-sulbactam) PLUS either azithromycin OR a respiratory fluoroquinolone (for penicillin-allergic patients, a respiratory fluroquinolone and aztreonam are recommended)

Special Concerns

1. If Pseudomonas is a consideration: ● An antipneumococcal, anti-pseudomonal beta-lactam (piperacillin/tazobactam, cefepime, imipenem, meropenem) plus either ciprofloxacin or levofloxacin (750 mg dosage) ● The above beta-lactam plus an aminoglycoside and azithromycin ● The above beta-lactam plus an aminoglycoside and an anti-pneumococcal fluoroquinolone (For penicillin-allergic patients, substitute aztreonam for above beta-lactam) 2. If CA-MRSA is a consideration, add linezolid or vancomycin Modified from Mandell LA. Wunderink RG, Anzueto et al. Reference #60 Abbreviations: bid, twice daily; QD, once daily

therapy within the past 3 months. The rational here is that the rate of macrolide-resistant Streptococcus pneumoniae is relatively low in this setting of patients, and these agents will cover the large majority of S. pneumoniae as well as the “atypical” pneumonias, Mycoplasma and Chlamydophila, which are common in this group of patients. In outpatients with comorbidities or who have used antibiotics within the previous 3 months, the respiratory fluoroquinolones (moxifloxacin 400 mg QD, gemifloxacin 320 mg QD, levofloxacin 750 mg QD) or a blactam plus a macrolide are recommended. The choice of which regimen to use is influenced if there was prior

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Table 23-10 Treatment of the Most Common Pathogens That Cause CommunityAcquired Pneumonia Agent

Streptococcus pneumoniae A. Penicillin susceptible MIC < 0.1 mg/L

B. Intermediate penicillin resistance MIC 0.1-1 mg/L

C. High-level penicillin resistance MIC ≥ 2 mg/L

Moraxella catarrhalis

Staphylococcus aureus (Always check for endocarditis in patients with S. aureus pneumonia) A. Methicillin-susceptible S. aureus

B. Methicillin-resistant S. aureus Haemophilus influenzae

Mycoplasma pneumoniae

Treatment(s)

1. Penicillin V 500 mg q 6 h PO or Penicillin G 500,000 units q 4 h IV 2. Doxycycline 100 mg BID PO × 10 days 3. Clarithromycin 500 mg BID PO × 10 days 4. Azithromycin 500 mg PO once then 250 mg PO QD × 4 days 5. Telithromycin 800 mg QD PO × 7 days 1. Penicillin G 3 MU q 4 h IV 2. Ceftriaxone 1 g q 12 h IV 3. Levofloxacin 750 mg QD or moxifloxacin 400 mg QD; or gemifloxacin 320 mg QD 4. Amoxicillin-clavulanic acid 1 g TID PO × 10 days 5. Telithromycin 800 mg QD PO × 7 days* 1. Vancomycin 1 g q 12 h plus ceftriaxone 2 g q 12 h IV if meningitis has complicated the pneumonia or Levofloxacin 750 mg IV QD; moxifloxacin 400 mg QD IV 1. Cefuroxime** 500 mg BID PO or 750 mg q 8 h IV or Amoxicillin-clavulanic acid 500 mg q 8 h PO

1. Nafcillin or cloxacillin 2 g q 4 h IV or Vancomycin 1 g q 12 h IV 1. Vancomycin 1 g q 12 h IV 1. Cefuroxime** 500 mg BID PO or Azithromycin 500 mg PO once then 250 mg QD × 4 days or Amoxicillin-clavulanic acid 500 mg q 8 h PO or Doxycycline 100 mg BID PO 1. Clarithromycin 500 mg PO BID × 14 days or Continued

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Table 23-10 Continued Agent

Legionella species

Treatment(s)

1.

T

Chlamydophila pneumoniae

1.

Anaerobes

1.

Pseudomonas aeruginosa

1.

Azithromycin 500 mg once then 250 mg PO QD × 4 days or Doxycycline 100 mg BID PO × 14 days Levofloxacin 500-750 mg QD IV or Moxifloxacin 400 mg QD IV until clinical improvement evident then PO therapy to complete a 21-day course of therapy or Azithromycin 1 g IV for one dose then 500 mg QD IV until clinical improvement then 500 mg QD PO to complete a 14-day course of treatment Rifampin 600 mg QD PO can be added to the preceding regimens in patients who are not responding to treatment Doxycycline 100 mg BID PO × 21 days or Clarithromycin 500 mg QD PO × 14 days or Azithromycin 500 mg once then 250 mg PO QD × 4 days Clindamycin or penicillin plus metronidazole Aminoglycoside† plus piperacillin or ticarcillin or mezlocillin or ceftazidime or imipenem or meropenem or ciprofloxacin

* Because of concern for toxicity (see text) telithromycin should be a secondary alternative to other antimicrobials. ** Where cefuroxime is given as a choice other second-generation cephalosporins or a third-generation cephalosporin can be used. † Aminoglycoside includes gentamicin, tobramycin, or amikacin. Abbreviations: BID, twice daily; h, hour; IV, intravenous; MIC, minimum inhibitory concentration; MU, million units; QD, once daily; PO, orally; q, every; TID, three times daily.

antimicrobial therapy, in which case the alternative choice should be used (ie, if the patient had received a fluoroquinolone within the past 3 months, the b-lactam + macrolide regimen is preferred). (Regarding levofloxacin, the standard dose recommended in this new guideline is 750 mg QD [to be adjusted for renal insufficiency] based on better pharmacodynamic target parameters than the 500-mg QD dose.) For general inpatient treatment, combination therapy with a b-lactam such as cefotaxime, ceftriaxone, ertapenem, or ampicillin-sulbactam, plus azithromycin or monotherapy with a respiratory

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fluoroquinolone, is recommended. For patients with severe CAP requiring ICU admission, recommendations are given based on risks for Pseudomonas and/or CA-MRSA (Table 2). If CA-MRSA is a consideration, linezolid or vancomycin should be added to the regimen. Although methicillin-resistant strains of S. aureus are still the minority, the excess mortality of inappropriate antibiotic therapy would suggest that empirical coverage should be considered when CA-MRSA is a concern. The best indicator of S. aureus is the presence of gram-positive cocci in clusters in a tracheal aspirate or adequate sputum sample. Clinical risk factors for S. aureus CAP include end-stage renal disease, intravenous drug abuse, prior influenza, and prior antibiotics (especially fluoroquinolones). The issue of the most appropriate treatment of patients with pneumonia caused by PRSP is unclear. We do know that pneumonia caused by this microorganism can be treated successfully with high-dose intravenous penicillin (63). We also know that treatment with penicillin is not successful if there is concomitant pneumococcal meningitis. In this setting, vancomycin and ceftriaxone are recommended. If beta-lactam antibiotics are used, the concentration of the antibiotic must exceed the MIC of S. pneumoniae 40% of the time for cure of pneumococcal pneumonia (64,65). Such studies indicate that oral cefaclor and oral cefuroxime are unlikely to treat PRSP successfully (65). In addition, Yu and coworkers showed that intravenous cefuroxime should not be used to treat bacteremic pneumococcal pneumonia (66). Amoxicillin was the most effective oral beta-lactam antibiotic for the treatment of PRSP in a study by Goldstein (67). Macrolide resistant S. pneumoniae is also an issue in many communities. Because most cases of ambulatory pneumoniae are of unknown cause and because there is less than 1% death rate among patients with pneumonia well enough to be treated on an ambulatory basis, a worse outcome for macrolide treated patients versus other antibiotics cannot be detected unless large randomly assigned clinical trials are done (68). It will be necessary to use antibiotics active against PRSP and atypical agents such as M. pneumoniae to settle the question about the best antibiotic therapy for ambulatory patients. Other outcome measures that could be used to evaluate the efficacy of treatment of pneumonia on an ambulatory basis are subsequent hospitalization and time to clinical resolution of the pneumonia compared with more effective agents. Currently, approximately 2% of penicillin susceptible S. pneumoniae isolates are resistant to macrolides; 12% of isolates intermediately resistant to penicillin are resistant to macrolides although 25% of isolates that are highly resistant to macrolides are resistant to penicillin (67). Macrolide susceptibility of S. pneumoniae is defined as an MIC up to 0.5 mg/L. The mean MICs for strains resistant because of an efflux mechanism is 10 mg/L: This accounts for 55% of the macrolide resistance in S. pneumoniae. Modification of the target (ribosomal) site accounts for 45% of the resistance and results in MICs of 64 mg/L (68). Ongoing studies are necessary to provide guidance about the best treatment of CAP caused by macrolide resistant S. pneumoniae.

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One of the reasons for debate about empiric treatment of CAP is inadequacy of clinical trials in this area to date. Most of these trials have enrolled small numbers of patients and do not reflect the spectrum of severity of CAP because usually only mild to moderately ill patients are enrolled as reflected by the very low death rates and by the extremely high cure rates. An intriguing feature of several recent studies is that the combination of a beta-lactam antibiotic and a macrolide has resulted in a better outcome when treating bacteremic pneumococcal pneumonia than using either antibiotic alone (69,70). Unfortunately these studies have not been randomly assigned clinical trials so it is not clear if the combination is indeed better. Osterheet and colleagues (71) attempted to answer the question of whether combination therapy or monotherapy with a fluoroquinolone as recommended by the North American guidelines is better than other therapy for the empiric treatment of CAP. They carried out a Medline search of studies published from January 1997 to April 2003. Only 8 of the 135 articles fit their criteria for further analysis. In six of the eight studies, a significant reduction in the all-cause death rate was found for patients treated with a combination of a beta-lactam plus a macrolide or with monotherapy with a fluoroquinolone. Three of these studies involved only patients with bacteremic pneumococcal pneumonia, and in one study an effect was noted in one study year, 1993, but not in 1995 or 1997 (72). Seven of the studies were retrospective, and two involved administrative databases. Clearly, a properly designed and conducted randomly assigned clinical trial is necessary to answer this, the most fundamental question in the treatment of CAP. In a study of 399 patients with CAP treated on an ambulatory basis, 67% had resolution of their symptoms by 14 days, and the median time to return to work was 6 days (73).

Treatment of Pneumonia in the Nursing Home Degelau and colleagues (74) found that if two or more of the following factors were present, the failure rate of therapy for pneumonia in the nursing home was high: respiratory rate greater than 30 breaths per minute, temperature greater than 38ºC (100.5ºF), pulse rate greater than 90 beats per minute, and feeding dependence and mechanically altered diet. Nicolle and coworkers (75) noted that 70% of patients with nursing-home acquired pneumonia treated with ampicillin were cured compared with 93% of those treated with ceftriaxone. It would seem that treatment of nursing home acquired pneumonia with one of the “respiratory fluoroquinolones” would be appropriate although data from randomly assigned clinical trials are still lacking for this group of patients. Of note, nursing home pneumonia is now considered under the classification of Healthcare-Associated Pneumonia.

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Switch from Intravenous to Oral Antibiotic Therapy Ramirez and coworkers (76,77) have shown that patients with CAP who are treated intravenously with antibiotics can be changed to oral antibiotics when the leukocyte count is returning toward normal, there are two normal temperature recordings 16 hours apart, and there is subjective alleviation in the cough and shortness of breath. Indeed, if patients can eat and drink and are normotensive, oral antibiotic therapy is sufficient for most patients (78).

Other Aspects of the Treatment of Community-Acquired Pneumonia It has been shown that in-hospital observation of low-risk patients is not necessary after a switch to oral antibiotics (79). Elimination of this practice can usually reduce hospital stay by 1 day. Prompt administration (≤4 hours from the time of presentation) of antibiotic therapy seems to result in a lower death rate (80,81). The duration of antibiotic therapy for CAP has not been adequately defined, but for most infections, 10 to 14 days of treatment is usually sufficient. Legionnaires’ disease, however, should be treated for 21 days (52) except in those who are mildly ill. In this latter group of patients if there has been a good response to therapy by 72 hours and no complications a minimum of 5 days is probably sufficient (81a). Patients who respond to therapy do not require repeat chest radiographs while in the hospital; however, those who are 40 years of age or older and all tobacco smokers should have a follow-up chest radiograph to ensure that the pneumonia has resolved. It is a wise practice to have a follow-up chest radiograph in all patients with pneumonia to be sure that the pneumonia has resolved. In 2% of patients with CAP, the pneumonia is the presenting manifestation of cancer of the lung (82); 50% of these cancers are evident at the time of presentation, but the remaining 50% will only be detected on a follow-up chest radiograph. The time for radiographic resolution of pneumonia depends on the age of the patient and the presence of chronic obstructive pulmonary disease (83). Certainly, if the opacity has not resolved in 10 weeks, bronchoscopy should be carried out. Patients with pneumonia and a pleural effusion should have a lateral decubitus chest radiograph, and if the effusion is greater than 1 cm wide it should be aspirated. Subsequent management is dependent on the characteristics of the fluid (84). Other aspects of the treatment of pneumonia, including management of comorbid illnesses, will not be discussed here, although recent data suggest that control of hyperglycemia reduces the death rate in patients with CAP (85). For patients with severe pneumonia who are admitted to the ICU and

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who have an APACHE II score of 25 or greater, consideration should be given to treating with activated protein C. In the PROWESS study in severe CAP patients treated with activated protein C, a relative risk reduction in the death rate of 28% was seen at 28 days, and there was a relative risk reduction of 14% at 90 days from the start of the infusion (86). Both the ketolides and the macrolides have immunomodulatory effects, although it is difficult to know what benefit, if any, is conferred when these agents are used to treat pneumonia (87). There is a growing body of evidence that adherence to guidelines for treatment of CAP is associated with a lower death rate among patients with CAP (45,88).

Quality of Care Measures The Centers for Medicare and Medicaid Services (CMS), as part of the National Pneumonia Medicare Quality Improvement Project, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and the National Quality Forum have established performance indicators to assess the quality of care for patients admitted to the hospital (89,90). These measures include: 1. Assessment of arterial oxygenation by arterial blood gas or pulse oximetry. 2. Screening and administration of pneumococcal vaccination if indicated for patients aged 65 and older. 3. Performance of blood cultures within 24 hours before or 24 hours after hospital arrival for patients who are admitted to or transferred to the ICU within 24 hours of hospital arrival. 4. Blood cultures performed in the ER should be obtained before initial antibiotic received in the hospital. 5. Adult smoking cessation advice/counseling. 6. Receipt of the first dose of antibiotic within 6 hours of arrival at the hospital. 7. Receipt of an antibiotic selection consistent with current guidelines during the first 24 hours of hospitalization. 8. Screening and administration of influenza vaccine if indicated for patients aged 50 and older, discharged during October—February.

Failure of Treatment of Community-Acquired Pneumonia An important concept in the management of pneumonia is the time to stability of various vital signs. Halem and coworkers (91) studied 686 patients

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with CAP and found that the median time to achieve a heart rate of 100 beats per minute or less and a systolic blood pressure of 90 mm Hg or less was 2 days. Three days were required to achieve a respiratory rate of 24 breaths per minute or less, an oxygen saturation of 90% or more, and a temperature of 37.2ºC (98.9ºF) or less. Using a lenient definition, 3 days were required after admission and for a conservative definition, 7 days. Most importantly, once stability was achieved deterioration occurred in 1% or less of patients. Among patients with CAP who are admitted to hospital for treatment, the failure rate is 11 to 15% (92,93). In one study (91), a cause for treatment failure was established for 65% of the 49 patients studied. Infections (primary, persistent, and nosocomial) were the most common cause of treatment failures. They also found that definite but not probable persistent infections were mostly caused by microbial resistance. Nosocomial infections were frequent in patients with progressive pneumonia and were the only cause of treatment failure independently associated with death. In a large study of 215 patients who failed treatment of CAP, the authors noted early failure (within 72 hours) occurred in 62.3% and late failure in 37.7%. Factors associated with treatment failure in a stepwise logistic regression analysis were liver disease, pneumonia risk class, leucopenia, multilobar pneumonia, pleural effusion, and radiological signs of cavitation. Independent factors associated with a lower risk of treatment failure were influenza vaccination, initial treatment with a fluoroquinolone, and chronic obstructive pulmonary disease. The death rate was higher in patients with treatment failure, 25% versus 2%.

Outcomes CAP requiring admission to the hospital is a serious illness with an overall death rate of 8% to 10% (45). The death rate for those with CAP who require admission to the ICU is 31% to 47% (94). In a large study of 3043 patients, 40% of the 246 patients who died did so within 5 days (early deaths). Some factors such as increasing pneumonia severity risk score, increasing age, site of hospitalization, functional status, and the need for consultation with a pulmonologist or infectious disease physician were significantly associated with both early and late death. A low lymphocyte count and a high potassium level were associated with early but not late death. Partial or complete use of a pathway for the management of pneumonia was associated with decreased early death. The immediate causes of death in patients with CAP are respiratory failure (38%), cardiac conditions (13%), and infectious conditions (11%). The most frequent underlying causes of death were neurological conditions (29%), malignancies (24%), and cardiac conditions (14%). Just over half (53%) of the deaths were pneumonia related, and these were 7.7 times more likely to occur within the 30 days of presentation compared with pneumonia unrelated deaths (95).

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The use of ACE inhibitors before admission for CAP has been associated with lower death rates (96) as has been the use of statins (97). However these observations have not yet been subjected to a randomly assigned clinical trial. Empyema has been reported as complicating pneumonia in 10% of cases (98). In more recent studies, it complicates less than 1% of pneumonia cases (Marrie TJ unpublished observations). Intrapleural administration of streptokinase as part of the management of empyema does not improve the death rate, length of stay, or the rate of surgery (99). Chest tube drainage and in many instances thoracotomy are necessary for the management of empyema.

Prevention Yearly influenza vaccination of target populations (those ≥65 years old; nursing home residents; and those with cardiac or pulmonary disease) is associated with a reduction in the rate of hospitalization for pneumonia and influenza by 48% to 57% (100). There is an unexpected benefit from influenza vaccination in that the rate of hospitalization for congestive heart failure is reduced by 37% during influenza A epidemics (100). Pneumococcal vaccine has been shown to be cost effective in those older than 65 years of age (101) and protective against bacteremic pneumococcal pneumonia (102). A somewhat unexpected benefit of the use of a proteinpolysaccharide conjugated pneumococcal vaccine during childhood has been the reduction of invasive pneumococcal disease in 20 to 39 year olds and among those 65 years of age or older (103). Indeed, the incidence of invasive pneumococcal disease among adults 50 years of age and older declined from 40.8 cases/100,000 before the introduction of the vaccine to 29.4 4 years later (104). The rates of death after an episode of invasive pneumococcal disease among adults aged 50 years or older decreased from 6.9 in 100,000 to 5.7. The authors estimated 6250 fewer cases and 550 fewer deaths per year among those 50 years of age and older in the United States compared with the years before introduction of the conjugate vaccine (104). Prevention of aspiration in those at risk (poststroke, advanced Parkinson and advanced Alzheimer disease) is difficult (105). Head positioning, stimulation techniques, and exercises to enhance the swallowing reflex and pureed foods can all help to reduce the risk of aspiration (106). In addition intensive oral care (cleaning teeth after every meal with an applicator of povidone iodine, and frequent dental care to control plaque) reduced the rate of pneumonia from 19% in the control group to 11% in the treatment group (107).

Summary The treatment of CAP is a challenge. A key element in the successful treatment of this condition is an accurate assessment of the severity of the illness.

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A pneumonia-specific severity of illness scoring system is now available to help with the admission decision. The diagnostic workup and antimicrobial therapy should be tailored to the severity of illness of the patient.

REFERENCES 1. Dixon RE. Economic costs of respiratory tract infections in the United States. Am J Med. 1985;78:45-51. 2. National Centre for Health Statistics. National hospital discharge survey: Annual summary 1990: Vital Health Statistics. 1992;13:1-225. 3. Koivula I, Sten M, Mäkelä PH. Risk factors for pneumonia in the elderly. Am J Med. 1994;96: 313-20. 4. Jackson ML, Neuzil KM,Thompson WW, Shay DK,Yu O, Hanson CA, et al. The burden of community-acquired pneumonia in seniors: results of a population-based study. Clin Infect Dis. 2004;39:1642-50. 5. Curns AT, Holman RC, Sejvar JJ, Owings MF, Schonberger LB. Infectious disease hospitalizations among older adults in the United States from 1990 through 2002. Arch Intern Med. 2005;165:2514-20. 5a. Fry AM, Shay DK, Holman RC, Curns AT,Anderson LJ. Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988-2002. JAMA. 2005;294:2712-9. 5b. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factors for acquiring pneumococcal infections. Arch Intern Med. 1986;146:2179-85. 6. Talbot TR, Hartert TV, Mitchel E, Halasa NB,Arbogast PG, Poehling KA, et al. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med. 2005;352:2082-90. 7. Nuorti JP, Butler JC, Farley MM, Harrison LH, McGeer A, Kolczak MS, et al. Cigarette smoking and invasive pneumococcal disease. Active Bacterial Core Surveillance Team. N Engl J Med. 2000;342:681-9. 8. Plouffe JF, Breiman RF, Facklam RR. Bacteremia with Streptococcus pneumoniae. Implications for therapy and prevention. Franklin County Pneumonia Study Group. JAMA. 1996;275:194-8. 9 Spanish Pneumococcal Infection Study Network (G03/103). Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of highly active antiretroviral therapy. Arch Intern Med. 2005;165:1533-40. 10. Marston BJ, Lipman HB, Breiman RF. Surveillance for Legionnaires’ disease. Risk factors for morbidity and mortality. Arch Intern Med. 1994;154:2417-22. 11. Walsh EE, Peterson DR, Falsey AR. Risk factors for severe respiratory syncytial virus infection in elderly persons. J Infect Dis. 2004;189:233-8. 12. Laheij RJF, Sturkenboom MCJM, Hassings R-J, et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292;1955-60. 13. Doern GV, Richter SS, Miller A, Miller N, Rice C, Heilmann K, et al. Antimicrobial resistance among Streptococcus pneumoniae in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis. 2005;41:139-48. 14. Moreno S, García-Leoni ME, Cercenado E, Diaz MD, Bernaldo de Quirós JC, Bouza E. Infections caused by erythromycin-resistant Streptococcus pneumoniae: incidence, risk factors, and response to therapy in a prospective study. Clin Infect Dis. 1995;20:1195-200. 15. Clavo-Sánchez AJ, Girón-González JA, López-Prieto D, Canueto-Quintero J, Sánchez-Porto A, Vergara-Campos A, et al. Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae: a multicenter study. Clin Infect Dis. 1997;24:1052-9. 16. Nava JM, Bella F, Garau J, Lite J, Morera MA, Martí C, et al. Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population-based study. Clin Infect Dis. 1994;19:884-90. 17. Flournoy DJ, Stalling FH, Catron TL. Seasonal and monthly variation of Streptococcus pneumoniae and other pathogens in bacteremia (1961-1981). Ecol Dis. 1983;2:157-60. 18. Berendt RF, Long GG, Walker JS. Influenza alone and in sequence with pneumonia due to Streptococcus pneumoniae in the squirrel monkey. J Infect Dis. 1975;132:689-93. 19. Wunderink RG,Waterer GW. Community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. Infect Dis Clin North Am. 2004;18:743-59, vii.

Tan ch23.qxd 10/12/07 10:22 AM Page 476

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Expert Guide to Infectious Diseases

20. Marston BJ, Plouffe JF, File TM Jr., Hackman BA, Salstrom SJ, Lipman HB, et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group. Arch Intern Med. 1997;157:1709-18. 21. Berntsson E, Lagergård T, Strannegård O,Trollfors B. Etiology of community-acquired pneumonia in out-patients. Eur J Clin Microbiol. 1986;5:446-7. 22. Marrie TJ, Peeling RW, Fine MJ, Singer DE, Coley CM, Kapoor WN. Ambulatory patients with community-acquired pneumonia: the frequency of atypical agents and clinical course. Am J Med. 1996;101:508-15. 23. Erard PH, Moser F, Wenger A, et al. Prospective study on community-acquired pneumonia diagnosed and followed up by private practitioner. Abstracts of the 1991 Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology. 1991;108:56A. 24. Langille DB, Yates L, Marrie TJ. Serological investigation of pneumonia as it presents to the physicians office. Can Infect Dis. 1993;4:328-32. 25. Porath A, Schlaeffer F, Lieberman D. The epidemiology of community-acquired pneumonia among hospitalized adults. J Infect. 1997;34:41-8. 26. Francis JS, Doherty MC, Lopatin U, Johnston CP, Sinha G, Ross T, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005;40:100-7. 27. Gillet Y, Issartel B, Vanhems P, Fournet JC, Lina G, Bes M, et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet. 2002;359:753-9. 28. Burman LA, Trollfors B, Andersson B, Henrichsen J, Juto P, Kallings I, et al. Diagnosis of pneumonia by cultures, bacterial and viral antigen detection tests, and serology with special reference to antibodies against pneumococcal antigens. J Infect Dis. 1991; 163:1087-93. 29. Bohte R, van Furth R, van den Broek PJ. Aetiology of community-acquired pneumonia: a prospective study among adults requiring admission to hospital. Thorax. 1995;50:543-7. 30. Mundy LM,Auwaerter PG, Oldach D,Warner ML, Burton A,Vance E, et al. Community-acquired pneumonia: impact of immune status. Am J Respir Crit Care Med. 1995; 152:1309-15. 31. Marston BJ, Plouffe JF, File TM Jr., et al. Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance study in Ohio. Arch Intern Med. 1997;157:1709-817. 32. Marrie TJ, Durant H,Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis. 1989;11:586-99. 33. Kauppinen MT, Herva E, Kujala P, Leinonen M, Saikku P, Syrjälä H. The etiology of communityacquired pneumonia among hospitalized patients during a Chlamydia pneumoniae epidemic in Finland. J Infect Dis. 1995;172:1330-5. 34. Templeton KE, Scheltinga SA, van den Eeden WC, Graffelman AW, van den Broek PJ, Claas EC. Improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction. Clin Infect Dis. 2005;41:345-51. 35. Louie JK,Yagi S, Nelson FA, Kiang D, Glaser CA, Rosenberg J, et al. Rhinovirus outbreak in a long term care facility for elderly persons associated with unusually high mortality. Clin Infect Dis. 2005;41:262-5. 36. Levy M, Dromer F, Brion N, et al. Community-acquired pneumonia. Importance of initial noninvasive bacteriologic and radiographic investigations. Chest. 1988;92:43-8. 37. Fang GD, Fine M, Orloff J, Arisumi D,Yu VL, Kapoor W, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy. A prospective multicenter study of 359 cases. Medicine (Baltimore). 1990;69:307-16. 38. Garb JL, Brown RB, Garb JR,Tuthill RW. Differences in etiology of pneumonias in nursing home and community patients. JAMA. 1978;240:2169-72. 39. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA. 1997;278:1440-5. 40. Metlay JP, Schulz R, Li YH, Singer DE, Marrie TJ, Coley CM, et al. Influence of age on symptoms at presentation in patients with community-acquired pneumonia. Arch Intern Med. 1997;157: 1453-9. 41. The aetiology, management and outcome of severe community-acquired pneumonia on the intensive care unit. The British Thoracic Society Research Committee and The Public Health Laboratory Service. Respir Med. 1992;86:7-13. 42. Karalus NC, Cursons RT, Leng RA, Mahood CB, Rothwell RP, Hancock B, et al. Community acquired pneumonia: aetiology and prognostic index evaluation. Thorax. 1991;46:413-8.

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Community-Acquired Pneumonia

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43. Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N,Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377-82. 44. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997; 336:243-50. 45. Marrie TJ, Wu L. Factors influencing in-hospital mortality in community-acquired pneumonia: a prospective study of patients not initially admitted to the ICU. Chest. 2005; 127:1260-70. 46. Sin DD, Man SF, Marrie TJ. Arterial carbon dioxide tension on admission as a marker of in-hospital mortality in community-acquired pneumonia. Am J Med. 2005;118:145-50. 47. Ruiz M, Ewig S,Torres A,Arancibia F, Marco F, Mensa J, et al. Severe community-acquired pneumonia. Risk factors and follow-up epidemiology. Am J Respir Crit Care Med. 1999;160:923-9. 48. International Mechanical Ventilation Study Group. Prognosis factors and outcome of community-acquired pneumonia needing mechanical ventilation. J Crit Care. 2005;20:230-8. 49. Cuny J, Chagnon JL, Lambiotte F. [Prognosis of severe community-acquired pneumonia in alcoholic patients hospitalized in intensive care]. Presse Med. 2003;32:1162-4. 50. Marik PE. The clinical features of severe community-acquired pneumonia presenting as septic shock. Norasept II Study Investigators. J Crit Care. 2000;15:85-90. 51. Chalasani NP,Valdecanas MA, Gopal AK, McGowan JE Jr., Jurado RL. Clinical utility of blood cultures in adult patients with community-acquired pneumonia without defined underlying risks. Chest. 1995;108:932-6. 52. Stout JE,Yu VL. Legionellosis. N Engl J Med. 1997;337:682-7. 53. Koler RB,Winn WC Jr.,Wheat LJ. Onset and duration of antigen excretion in Legionnaires disease. J Clin Microbial. 1984;20:605-7. 54. Ramirez JA, Ahkee S, Tolentino A, Miller RD, Summersgill JT. Diagnosis of Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae lower respiratory infection using the polymerase chain reaction on a single throat swab specimen. Diagn Microbiol Infect Dis. 1996;24:7-14. 55. Jiménez P, Saldías F, Meneses M, Silva ME,Wilson MG, Otth L. Diagnostic fiberoptic bronchoscopy in patients with community-acquired pneumonia. Comparison between bronchoalveolar lavage and telescoping plugged catheter cultures. Chest. 1993;103:1023-7. 56. Palmer DL, Davidson M, Lusk R. Needle aspiration of the lung in complex pneumonias. Chest. 1980;78:16-21. 57. Dunn IJ, Marrie TJ, MacKeen AD, Bhan V, Janigan DT. The value of open lung biopsy in immunocompetent patients with community-acquired pneumonia requiring hospitalization. Chest. 1994;106:23-7. 58. Neiderman MS, Mandell LA, Anzeuto A, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy and prevention. Am J Respir Critical Care Med. 2001;163:1730-54. 59. Gleason PP, Kapoor WN, Stone RA, Lave JR, Obrosky DS, Schulz R, et al. Medical outcomes and antimicrobial costs with the use of the American Thoracic Society guidelines for outpatients with community-acquired pneumonia. JAMA. 1997;278:32-9. 60. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell D, Dean NC. et al. Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the management of community-acquired pneumonia in adults. Clin Infect. Dis. 2007;44:527–72. 61. File TM Jr., Segretti J, Dunbar L, et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrobial Agents Chemother. 1997;41:1965-72. 62. Nguyen M, Chung EP. Telithromycin: The first ketolide antibiotic. Clin Therap. 2005; 27:1144-63. 63. Pallares R, Liñares J, Vadillo M, Cabellos C, Manresa F, Viladrich PF, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med. 1995;333:474-80. 64. Craig WA. Antimicrobial resistance issues of the future. Diagn Microbiol Infect Dis. 1996;25:213-7. 65. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis. 1998;26:1-10; quiz 11-2. 66. International Pneumococcal Study Group. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis. 2003;37:230-7.

Tan ch23.qxd 10/12/07 10:22 AM Page 478

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67. Goldstein FW. Choice of an oral beta-lactam antibiotic for infections due to penicillin-resistant Streptococcus pneumoniae. Scand J Infect Dis. 1997;29:255-7. 68. Low DE. Resistance issues and treatment implications: pneumococcus, Staphylococcus aureus, and gram-negative rods. Infect Dis Clin North Am. 1998;12:613-30, viii. 69. Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med. 2001;161:1837-42. 70. Martínez JA, Horcajada JP, Almela M, Marco F, Soriano A, García E, et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower inhospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2003;36:389-95. 71. Oosterheert JJ, Bonten MJ, Hak E, Schneider MM, Hoepelman IM. How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalized because of community-acquired pneumonia? A systematic review. J Antimicrob Chemother. 2003;52: 555-63. 72. Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among medicare pneumonia inpatients in 10 western states: 1993, 1995, and 1997. Chest. 2001;119:1420-6. 73. Marrie TJ, Beecroft MD, Herman-Gnjidic Z. Resolution of symptoms in patients with community-acquired pneumonia treated on an ambulatory basis. J Infect. 2004;49:302-9. 74. Degelau J, Guay D, Straub K, Luxenberg MG. Effectiveness of oral antibiotic treatment in nursing home-acquired pneumonia. J Am Geriatr Soc. 1995;43:245-51. 75. Nicolle LE, Kirshen A, Boustcha B, Montgomery P. Treatment of moderate-to-severe pneumonia in elderly, long-term care facility residents. Infect Dis Clin Practice. 1996;5:130-7. 76. Ramirez JA Sr.inath L, Ahkee S, Huang A, Raff MJ. Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia. Arch Intern Med. 1995;155:1273-6. 77. Ramirez JA,Ahkee S. Early switch from intravenous antibiotics to oral clarithromycin in patients with community-acquired pneumonia. Infect Med. 1997;14:319-23. 78. Chan R, Hemeryck L, O’Regan M, Clancy L, Feely J. Oral versus intravenous antibiotics for community acquired lower respiratory tract infection in a general hospital: open, randomised controlled trial. BMJ. 1995;310:1360-2. 79. Rhew DC, Hackner D, Henderson L, Ellrodt AG,Weingarten SR. The clinical benefit of in-hospital observation in ‘low-risk’ pneumonia patients after conversion from parenteral to oral antimicrobial therapy. Chest. 1998;113:142-6. 80. Meehan TP, Fine MJ, Krumholz HM, Scinto JD, Galusha DH, Mockalis JT, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA. 1997;278:2080-4. 81. Houck PM, Bratzler DW, Nsa W, Ma A, Bartlett JG. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med. 2004;164:637-44. 81a. File TM Jr., Niederman MS. Antimicrobial therapy of community-acquired pneumonia. Infect Dis Clin North Am. 2004;18:993-1016, xi. 82. Marrie TJ. Pneumonia and carcinoma of the lung. J Infect. 1994;29:45-52. [PMID: 7963634] 83. Jay SJ, Johnson WG Jr., Pierce AK. The radiographic resolution of Streptococcus pneumoniae pneumonia. N Engl J Med. 1975;293:791-794. 84. Bryant RE, Salmon CJ. Pleural empyema. Clin Infect Dis. 1996;22:747-62; quiz 763-4. 85. McAlister FA, Majumdar SR, Blitz S, Rowe BH, Romney J, Marrie TJ. The relation between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired pneumonia. Diabetes Care. 2005;28:810-5. 86. PROWESS Clinical Evaluation Committee. Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study. Crit Care Med. 2005;33:952-61. 87. Parnham MJ. Immunomodulatory effects of antimicrobials in the therapy of respiratory tract infections. Curr Opin Infect Dis. 2005;18:125-31. 88. NEUMOFAIL Group. Guidelines for the treatment of community-acquired pneumonia: predictors of adherence and outcome. Am J Respir Crit Care Med. 2005;172:757-62. 89. http://www.qualityforum.org/pdf/1sEndorsedStandardsALL07-01-07.pdf 90. Jha AK, Li Z, Orav EJ, Epstein AM. Care in U.S. hospitals—the Hospital Quality Alliance program. N Engl J Med. 2005;353:265-74. 91. Halm EA, Fine MJ, Marrie TJ, Coley CM, Kapoor WN, Obrosky DS, et al. Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. JAMA. 1998;279:1452-7.

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92. Arancibia F, Ewig S, Martinez JA, Ruiz M, Bauer T, Marcos MA, et al. Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications. Am J Respir Crit Care Med. 2000;162:154-60. 93. Neumofail Group. Risk factors of treatment failure in community acquired pneumonia: implications for disease outcome. Thorax. 2004;59:960-5. 94. Ewig S,Torres A. Severe community-acquired pneumonia. Curr Opin Crit Care. 2002;8:453-60. 95. Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor WN, et al. Causes of death for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team cohort study. Arch Intern Med. 2002;162:1059-64. 96. Mortensen EM, Restrepo MI,Anzueto A, Pugh J. The impact of prior outpatient ACE inhibitor use on 30-day mortality for patients hospitalized with community-acquired pneumonia. BMC Pulm Med. 2005;5:12. 97. Mortensen EM, Restrepo MI,Anzueto A, Pugh J. The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia. Respir Res. 2005;6:82. 98. Light RW, Girard WM, Jenkinson SG, George RB. Parapneumonic effusions. Am J Med. 1980;69:507-12. 99. First Multicenter Intrapleural Sepsis Trial (MIST1) Group. U.K. Controlled trial of intrapleural streptokinase for pleural infection. N Engl J Med. 2005;352:865-74. 100. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med. 1994;331:778-84. 101. Sisk JE, Moskowitz AJ,Whang W, Lin JD, Fedson DS, McBean AM, et al. Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people. JAMA. 1997;278:1333-9. 102. Fine MJ, Smith MA, Carson CA, Meffe F, Sankey SS,Weissfeld LA, et al. Efficacy of pneumococcal vaccination in adults. A meta-analysis of randomized controlled trials. Arch Intern Med. 1994;154:2666-77. 103. Active Bacterial Core Surveillance of the Emerging Infections Program Network. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348:1737-46. 104. Active Bacterial Core Surveillance Team. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA. 2005;294:2043-51. 105. Holas MA, DePippo KL, Reding MJ. Aspiration and relative risk of medical complications following stroke. Arch Neurol. 1994;51:1051-3. 106. Neumann S, Bartolome G, Buchholz D, Prosiegel M. Swallowing therapy of neurologic patients: correlation of outcome with pretreatment variables and therapeutic methods. Dysphagia. 1995;10:1-5. 107. Yoneyama T, Yoshida M, Matsui T, Sasaki H. Oral care and pneumonia. Oral Care Working Group [Letter]. Lancet. 1999;354:515.

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Chapter 24

Nosocomial Pneumonia THOMAS M. FILE, JR, MD, MS MICHAEL NIEDERMAN, MD

Key Learning Points ●

●

●

●

Healthcare-associated pneumonia (HCAP) is included in the spectrum of nosocomial pneumonia Early, appropriate antimicrobial therapy (based on the presence or absence of risk factors for multi-drug resistant pathogens) should be prescribed to optimize outcomes In order to avoid overuse of broad-spectrum antimicrobials, deescalation of antimicrobials should be considered on the basis of results of lower respiratory tract cultures and the clinical response of the patient A shorter duration of therapy (7-8) days is recommended for most patients who have a good clinical response

N

osocomial pneumonia (NP) is the second most common nosocomial infection but is considered the most serious hospital-acquired infection because of its high rates of illness and death, serving as the number 1 cause of death from hospital-acquired infection (1, 2). NP is associated with significant excess risk of death (attributable death) in the range of 33% to 50% (2). This attributable death is greater for medical than for surgical patients, infection with multidrug-resistant pathogens, and patients who are initially treated with ineffective therapy. Recent updated guidelines for the management of adults with NP have been published (2). Consistent with new developments in the field of NP, patients can now be classified into 1 of 3 categories:

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New Developments in the Management of Nosocomial Pneumonia ●

New Guidelines for management of nosocomial pneumonia were published in 2005 and are reviewed in this chapter

1. Hospital-acquired pneumonia (HAP) is pneumonia that occurs 48 hours or more after admission, which was not incubating at the time of admission. 2. Ventilator-associated pneumonia (VAP) refers to pneumonia that develops more than 48 to 72 hours after endotracheal intubation. 3. Healthcare-associated pneumonia (HCAP) includes any patient who was either hospitalized in an acute care hospital for 2 or more days within 90 days of the infection; resided in a long-term care facility; received intravenous antimicrobial therapy, chemotherapy, or wound care within the 30 days before the current infection; or attends a hospital or hemodialysis clinic. Included in this category are patients with these risk factors who either develop pneumonia in the hospital or come to the hospital with pneumonia. This latter group has been traditionally considered to have CAP, but recent data show that they have a bacteriology and natural history of disease more similar to nosocomial than community-acquired infection. (3) General principles for the management of NP emphasize the need to use early, appropriate antimicrobial therapy, while avoiding excessive antibiotics by de-escalation of initial antibiotic therapy, based on microbiologic cultures and the clinical response of the patient, and shortening the duration of therapy to the minimum effective period. Initial, empirical therapy is based on the relative risk a patient has for being infected with a resistant pathogen. In addition, the choice of therapy should be guided by knowledge of local patterns of microbiology and resistance that are present in the hospital where the patient is being managed. Thus, an awareness of the susceptibility patterns of the nosocomial pathogens within a given health care setting is important for achieving appropriate empiric antimicrobial therapy.

Epidemiology Available data suggest that NP occurs at a rate of 5 to 10 cases per 1000 hospital admissions, with the incidence increasing by as much as 6- to 20fold in patients who are ventilated mechanically (2). The incidence of NP is much lower in community and small hospitals and among patients admitted to obstetric or psychiatric wards than it is in large tertiary centers and

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among patients admitted to medical or surgical wards (partly because of the underlying conditions that are more commonly associated with patients in these settings). NP accounts for up to 25% of all intensive care unit (ICU) infections and VAP occurs in 9% to 27% of all intubated patients (2). In mechanically ventilated patients, the risk of VAP is estimated to be 1% per day of ventilation; however, the rate of new cases decreases with prolonged length of stay. The onset of NP is an important epidemiological variable and risk factor for specific organisms and outcomes. Early onset NP is defined as occurring within the first 4 days of hospitalization, usually carries a better prognosis, and is more likely to be caused by antibiotic-susceptible bacteria.

Pathogenesis and Risk Factors The primary route of infection of the lower respiratory tract that is associated with HAP involves the microaspiration of organisms that have colonized the oropharyngeal tract. Most healthy individuals are colonized by organisms with limited virulence; however, in patients in the health care setting, the frequency of oropharyngeal colonization with Staphylococcus aureus and enteric gramnegative bacilli increases with the severity of the underlying disease and the duration of hospitalization. Therefore, risk factors for the development of NP usually are associated with increased microbial colonization of upper airway secretions or an increased risk of aspiration. These factors generally can be categorized as being patient related, infection-control related, or intervention related. Patient-related risk factors for NP include age, severity of underlying illness, malnutrition, coma or other causes of impaired consciousness (e.g., sedating medications), prolonged hospitalization, and certain comorbid conditions (e.g., diabetes, heart disease, chronic obstructive pulmonary disease). Risk factors related to infection control include poor hand-washing practices, inappropriate use of gloves, and contaminated respiratory therapy devices and equipment. Therapeutic interventions that adversely affect host defenses can result in the direct inoculation of pathogens into the lower respiratory tract. The most significant intervention-related risk factor for NP is endotracheal intubation and mechanical ventilation; the risk of developing pneumonia increases with the duration of mechanical ventilation. However, this risk only applies for intubated patients, and the risk is much lower for patients treated with noninvasive ventilation, suggesting a role for the endotracheal tube itself and its ability to allow for direct inoculation of bacteria into the lower respiratory tract. Additional intervention-related risk factors include feeding by nasogastric tube, increased gastric volume or distention, and supine positioning of the patient. The role of the stomach may vary, with factors that include elevated gastric pH, presence of ileus or upper gastrointestinal disease, use of antacid medications or enteric feeding, gastric

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reflux associated with the supine position, and the presence of a gastric or nasogastric tube. Migration of microorganisms from the stomach to the lungs may occur through various mechanisms (4). A nasogastric tube may act as a conduit for microorganisms to ascend into the nasopharynx The nasogastric tube also may affect lower esophageal sphincter competence and thus allow the reflux of organisms from the stomach to the nasopharynx. This is most likely to occur when the patient is in the supine position. Once the nasopharynx becomes colonized, organisms may descend into the respiratory tract and cause lower respiratory tract disease. Many of these risk factors are directly modifiable, and recently hospitals have begun to implement a ventilator bundle strategy that ensures that some risk factors are being regularly evaluated. Commonly included in such a bundle is daily interruption of sedation, daily evaluation of ability to wean, and assurance of positioning at a minimum of 30 degrees upright in bed. Predictors of death for pneumonia include the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the number of dysfunctional organs, nosocomial bacteremia, the presence of an underlying fatal disease, and admission from another ICU (4).

Etiology Many studies have evaluated pathogens associated with NP; however, variations in patient populations, the methods used to obtain and analyze specimens, and even the definitions used for NP have led to variable results. Additionally, the upper respiratory tract of hospitalized patients often is colonized by potentially pathogenic microorganisms; thus, it is difficult to know which of the many organisms present in a respiratory specimen culture are colonizing organisms and which are true pathogens. Because aspiration of upper airway secretions is the most common route of entry for microorganisms into the lower airways, the cause of NP often depends on the organisms colonizing the oropharynx. Most reliable bacteriologic data on nosocomial pneumonia have been collected from intubated patients with VAP, and recent guidelines have assumed that the same pathogens are present, in those with risk factors, when HAP and HCAP are present. HAP, VAP, and HCAP may be caused by a wide variety of pathogens and can be polymicrobial. Common pathogens include aerobic gram-negative bacilli (e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter spp, Pseudomonas aeruginosa, Acinetobacter species) and grampositive cocci (e.g., Streptococcus species, Staphylococcus aureus, including methicillin-resistant S. aureus [MRSA]). Nosocomial pneumonia caused by viruses or fungi is significantly less common except in the immunocompromised patient. For patients with early HAP (<5 days after admission) and without risk factors for resistant pathogens (see Risk Factors for Multidrug Resistant Pathogens

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section in the following text), Streptococcus pneumoniae, Haemophilus influenzae, S. aureus, and Enterobacteriaceae species are common pathogens (2). Microorganisms associated with HAP in patients with risk factors for multidrug resistant (MDR) organisms are more varied but include all of the aforementioned organisms plus MDR gram-positive and gram-negative bacteria. Less common etiologic agents include influenza, Legionella species, fungal pathogens, and perhaps anaerobes.

Risk Factors for Multidrug Resistant Pathogens The cause of HAP, VAP, and HCAP depends on whether the patient has risk factors for MDR pathogens (2). The frequency of specific MDR pathogens varies among hospitals and specific hospital units, patient populations including those with recent exposure to antibiotics, and also changes over time. The frequency of MDR bacteria as etiologic agents of nosocomial pneumonia is increasing, especially among patients in ICUs. Host risk factors for infection with MDR pathogens include the following (2): ● ● ●

●

●

Receipt of antibiotics must be within the preceding 90 days. Current hospitalization must be at least 5 days. Admission must be from a health care-related facility, such as a long-term care facility or dialysis unit. High frequency of antibiotic resistance must be in the community or in the specific hospital unit. Presence of risk factors for HCAP must include the following: hospitalization for 2 days or more in the preceding 90 days; residence in an extended care facility; home infusion therapy; chronic dialysis; home wound care; and a family member with an MDR pathogen.

The following specific organisms also are associated with the epidemiologic setting of NP: ●

●

●

●

Although anaerobes are in association with abdominal surgery or after aspiration, recent data suggest that for those with aspiration risk factors and HCAP, enteric gram-negatives are the predominant pathogens (5). S. aureus is in association with coma, head trauma, recent influenza infection, diabetes mellitus. Legionella species are in association with corticosteroid use in hospitals that have the presence of Legionella species in the hospital water supply. Aspergillus species are associated with construction in patients who are immune suppressed (including with systemic corticosteroids).

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Diagnosis and Microbiological Studies The standard clinical criteria often used to establish a diagnosis (or possible diagnosis) of NP include some combination of fever, leukocytosis, and purulent respiratory secretions in association with a new or progressive infiltrate on chest radiography. Unfortunately, these criteria do not provide a reliably accurate diagnosis of NP; rather, the definition they give is sensitive but not specific for NP, particularly in mechanically ventilated patients (in whom other conditions may cause fever and pulmonary infiltrates). When all 4 criteria (i.e., fever, leukocytosis, purulent respiratory secretions, and a new pulmonary infiltrate) are present, specificity improves but sensitivity drops to less than 50% (6). In some studies, less than half of patients who have fever and pulmonary infiltrates have the diagnosis of bacterial pneumonia confirmed microbiologically. Other conditions that can mimic NP clinically include pulmonary infarction, adult respiratory distress syndrome, pulmonary edema with another infection site, pulmonary hemorrhage, vasculitis, malignancy, drug toxicity, radiation pneumonitis, and preexisting lung disease (e.g., fibrosing alveolitis). A way to improve the clinical diagnosis of pneumonia is to combine all the features into a single score as has been done with the Clinical Pulmonary Infection Score (CPIS) (7). This tool has been accurate for separating ventilated patients with pneumonia from those without, by measuring (on a scale from 0-2) fever, leukocytosis, purulence of respiratory secretions, radiographic abnormalities, and oxygenation. In addition, either a Gram stain or culture of a deep respiratory tract sample can be added to the scoring system, with dramatic improvements in its sensitivity and specificity (8). Using this approach, pneumonia is more likely in those with a CPIS of at least 6, compared to those with a lower score. Unfortunately, the techniques now used to obtain respiratory secretions for culture are not consistently helpful in diagnosing NP because it is difficult to obtain specimens that are not contaminated with upper respiratory tract organisms. Therefore, the value of examining expectorated sputum in patients with NP is limited and any interpretation of the microbiological results is challenging and must be done with caution. Expectorated sputum from a nonintubated patient is often contaminated with upper respiratory flora acquired by patients after hospitalization. In the intubated patient, lower airway secretions usually are obtained easily with routine endotracheal aspiration. Sputum (or endotracheal secretions) should be examined microscopically by Gram staining and screening for the appropriateness of the specimen (using cytologic criteria based on the presence of polymorphonuclear leukocytes and the absence of squamous cells). Cultures of endotracheal aspirates often are used for microbiological studies because health care workers can do the aspiration procedure at the bedside with minimal training. Such cultures usually identify not only the pathogenic organisms found by invasive tests (suggesting a high level of sensitivity) but also the

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nonpathogenic organisms (reducing the positive predictive value of the procedure). Most studies have shown that when VAP is present, the etiologic pathogens usually are contained in the endotracheal aspirate, suggesting a high sensitivity of endotracheal aspiration even though additional colonizing organisms also may be present (6). Thus, the absence of a specific organism from an endotracheal-aspirate culture, assuming that the specimen is obtained while the patient is not receiving effective antibiotic therapy, is highly predictive against that organism as a pathogen. This information may allow the clinician to exclude certain pathogens and may be helpful when modifying antimicrobial therapy once culture results are known. Various quantitative culture methods that can use invasive bronchoscopic or nonbronchoscopic methods have been used to differentiate colonization from active infection and, thus, to define the presence of pneumonia and more specifically identify the etiologic organisms. However, the sensitivity and specificity of invasive diagnostic techniques for determining the true microbiological identity of bacteria associated with NP are variable. The sensitivity of quantitative bronchoalveolar lavage (BAL) fluid cultures ranges from 40% to 90%, with a mean of approximately 70% (6). The variability in sensitivity reflects the characteristics of the study population as well as the effect of previous antibiotic therapy, which reduces the rate of isolation. Most studies cite 104 colony-forming units (CFUs)/mL as a positive result. The finding of an intracellular organism by BAL is highly specific and has a high positive predictive value (90%-100%). The sensitivity of the protected specimen brush (PSB) technique ranges from 33% to 100%, with a median of 67% and specificity of approximately 95% (6). Concerns about diagnostic accuracy and the lack of clinical outcome data have made it difficult to interpret the results of studies using BAL and the PSB technique. This is further complicated when the patient has received antimicrobial agents within the preceding few days. A change in antimicrobial therapy within 72 hours before obtaining a quantitative culture by invasive means reduces the accuracy of the culture results. Therefore, it is recommended that such tests be done either before the use of antibiotics or after 72 hours of an existing antimicrobial regimen. Isolating organisms in a significant quantity (>104 CFU/mL for BAL; >103 CFU/mL for PSB) after 72 hours of antimicrobial therapy suggests that the treatment regimen is ineffectual. Studies differ on the utility of invasive versus noninvasive diagnostic management strategies for HAP, particularly VAP. A study from France evaluated whether an invasive diagnostic approach using PSB or BAL was superior to clinical criteria in 413 ICU patients with a clinical suspicion of VAP (9). Patients managed with the invasive strategy had a significantly lower 14 day death (16% versus 26%); this advantage persisted at day 28 and was also associated with significantly more antibiotic-free days and a lower mean number of antibiotics administered. However, other studies have not shown that these invasive techniques affect patient outcome. As an example, 1 study of 132 patients with VAP who had bronchoscopy demonstrated no improvement in mortality when

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bronchoscopy successfully defined the pathogen, which occurred in approximately 50% of the patients (10). The adequacy of initial, empiric antibiotics seemed to be a more important factor in determining death. Recently, the American College of Chest Physicians assembled a panel of scientific experts to develop recommendations for assessing diagnostic tests for VAP based on a rigorous review of the literature (6). The panel concluded there is insufficient high-level evidence to indicate that quantitative testing procedures produce better clinical outcomes than empiric therapy. However, 1 benefit of quantitative culture is reduced use of antibiotics. Antibiotics can be safely stopped in patients with negative quantitative cultures, with no adverse effect on mortality (2). This strategy should reduce the selective potential for antimicrobial resistance, adverse effects, and costs, which are associated with overuse of broad spectrum antimicrobials. In the new ATS/IDSA guidelines, the emphasis was to tie diagnostic approaches to management, and it was acceptable to use either a clinical or bacteriologic strategy, provided that there was an effort to use the culture data to achieve appropriate therapy with the least exposure to antibiotics possible. Thus, it is always necessary to obtain a lower respiratory tract sample before initiating or changing therapy and to use the results, along with serial evaluations of the clinical course, to modify therapy. In the new guidelines, the emphasis on antibiotic control is not at the time of diagnosis, but rather on day 2 to 3, when more data are available, and it is possible to use this information to modify therapy (see the following text). In summary, the diagnosis of HAP, VAP, and HCAP is imprecise when using clinical data alone, but the use of bronchoscopic methods to obtain respiratory specimens for microbiologic diagnosis remains controversial. Thus, the most important intervention is to obtain a lower respiratory tract sample for culture, if available, from all patients suspected with HAP before antimicrobial therapy. However, the collection of a sample for culture should not hold up the initiation of therapy, because delay of antimicrobial therapy is associated with poor outcomes.

Treatment Available information suggests that the outcome of NP is improved when effective antimicrobial agents are given initially (2). The importance of providing early effective antimicrobial therapy for NP patients has been demonstrated in several recent investigations of VAP patients. These studies have shown that the death attributable to VAP was significantly greater among patients who received inappropriate initial antimicrobial therapy (during the first 24 hours) than it was among patients who received appropriate initial therapy. In the new guidelines, the term appropriate was used to refer to a therapy that was active, in vitro, against the etiologic pathogen. The term adequate referred to not only using appropriate therapy, but

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using it in a timely manner, by the right route, having it penetrate to the site of infection, and having it administered in the correct dosage. Antimicrobial management of NP can be divided into empirical and pathogen-directed therapy. Certainly, once a pathogen is isolated from an appropriate lower respiratory tract specimen, therapy can be given on the basis of in vitro-susceptibility test results and other characteristics of the antimicrobial agent and host. However, most patients initially are treated empirically, and the choice of antimicrobial agent(s) should be based on local susceptibility patterns and the most likely pathogens. Clinicians should be aware of the most common bacterial pathogens in NP and their susceptibility patterns associated in the hospitals where they practice. A summary of management strategies is represented in Figure 24-1. Antimicrobial selection for each patient should be based on risk factors for MDR pathogens (Figure 24-2). The choice of antibiotic should be influenced by the patient’s recent antibiotic therapy (if any), the resident flora in the hospital or ICU, the presence of underlying diseases, and available culture data (interpreted with care). For patients with risk factors for MDR pathogens, empiric broad spectrum, multidrug therapy is recommended to provide the

HAP, VAP or HCAP Suspected

Obtain Lower Respiratory Tract (LRT) Sample for Culture (Quantitative or Semi-quantitative) & Microscopy Unless There Is Both A Low Clinical Suspicion for Pneumonia & Negative Microscopy of LRT Samply, Begin Empiric Antimicrobial Therapy Using Algorithm in Figure 2 & Local Microbiologic Data Days 2 & 3: Check Cultures & Assess Clinical Response: (Temperature, WBC, Chest X-ray, Oxygenation, Purulent Sputum, Hemodynamic Changes & Organ Function)

Clinical Improvement at 48-72 Hours

YES

NO Cultures −

Search for Other Pathogens, Complications, Other Diagnoses or Other Sites of Infection

Cultures + Adjust Antibiotic Therapy, Search for Other Pathogens, Complications, Other Diagnoses or Other Sites of Infection

Cultures −

Consider Stopping Antibiotics

Cultures +

De-escalate Antibiotics, if Possible. Treat Selected Patients for 7-8 Days & Reassess

Figure 24-1 Summary of management strategies for nosocomial pneumonia. Republished with permission from: Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

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Empiric Antibiotic Therapy for HAP HAP, VAP or HCAP Suspected (All Disease Severity)

HAP, VAP or HCAP Suspected Late Onset ( >5 days) or Risk Factors for Multi-drug Resistant (MDR) Pathogens (Table 2) No

Limited Spectrum Antibiotic Therapy (Table 1)

Yes Broad Spectrum Antibiotic Therapy For MDR Pathogens (Table 2)

Figure 24-2 Decision for initiating empiric therapy for nosocomial pneumonia. Republished with permission from Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

best chance of effective therapy. Recommendations for antimicrobial regimens for initial empiric therapy are listed in Tables 24-1 and 24-2. Once the results of initial cultures are available, therapy should be narrowed based on the susceptibility pattern of the pathogens identified. If there is no laboratory or epidemiologic evidence of coinfection, treatment regimens should be simplified and directed to that pathogen, with specific agents being dictated by the results of susceptibility testing. It is crucial to avoid broad-spectrum therapy once a pathogen has been identified (2). Patients who are improving clinically, hemodynamically stable, and able to take oral medications can be switched to oral therapy. If the pathogen has been identified, the choice of antibiotic for oral therapy is based on the susceptibility profile for that organism. If a pathogen is not identified, the choice of antibiotic for oral therapy is either the same antibiotic as the intravenous antibiotic, or an agent in the same drug class. Treatment of pneumonia caused by gram-negative enteric bacilli should be based on the susceptibility profile for that organism.

Duration of Therapy The duration of therapy should be based on the clinical response. The standard duration of therapy in the past was 14 to 21 days in part because of a concern for difficult to treat pathogens (e.g., Pseudomonas spp). However,

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Table 24-1 Initial Empiric Therapy for Hospital-Acquired Pneumonia or VentilatorAssociated Pneumonia in Patients with Early Onset or No Known Risk Factors for Multidrug-Resistant Pathogens Potential Pathogen

Recommended Antibiotic*

Streptococcus pneumoniae

Ceftriaxone 1-2 g qd or Levofloxacin 750 mg qd, Moxifloxacin 400 mg q12h, Ciprofloxacin 400 mg q8-12h (levofloxacin or moxifloxacin preferred for S. pneumoniae) or Ampicillin/sulbactam 3 g q6h or Ertapenem 1 g qd

Haemophilus influenzae Methicillin-susceptible Staphylococcus aureus

Antibiotic-susceptible enteric gram-negative bacilli (e.g., Escherichia coli, Klebsiella pneumoniae, Enterobacter species)

* Doses are based on normal renal and hepatic function. Republished with permission from: Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. Abbreviations: d = day; h = hour; q = every.

Table 24-2 Empiric Therapy for Hospital-Acquired Pneumonia,Ventilator-Associated Pneumonia, or Healthcare-Associated Pneumonia in Patients with Late Onset or Known Risk Factors for Multidrug-Resistant Pathogens Potential Pathogens

Antimicrobial Therapy*

Pathogens listed in Table 24-1 and MDR pathogens Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL**+)

Antipseudomonal cephalosporin (Cefepime 1-2 g q8-12h, Ceftazidime 2 g q8h) or Antipseudomonal carbapenem (imipenem 500 mg q6h or 1 g q8h or meropenem 1 g q8h) or Beta-lactam/beta-lactamase inhibitor (piperacillin-tazobactam 4.5 g q6h) plus Antipseudomonal fluoroquinolone (ciprofloxacin 400 mg q8h or levofloxacin 750 mg qd; these are preferred if Legionella possible) or Aminoglycoside (gentamicin or tobramycin 7 mg/kg per d, amikacin 20 mg/kg per d) plus Linezolid 600 mg q12h or vancomycin 15/kg mg q12h*** (if MRSA a concern)

Acinetobacter species MRSA Legionella pneumophila

* Doses are based on normal renal and hepatic function. ** Extended spectrum beta-lactamase producing strain (a carbapenem is preferred). *** Trough levels should be 15-20 µg/mL. Republished with permission from: Niederman MS, Craven DE, Bonten MJ, et al. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. Abbreviations: d = day; ESBL = extended-spectrum beta-lactamase; h = hour; MRSA = methicillin-resistant Staphylococcus aureus; q = every.

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a shorter course could significantly reduce the amount of antimicrobials used in hospitals where the emergence of resistant pathogens is a concern. Recent studies have suggested that short-course treatment is effective. This is illustrated by the following: ●

●

●

A prospective, randomly assigned, multicenter trial of 401 patients with VAP compared outcomes after 8 versus 15 days of treatment (11). All patients had bronchoscopy for quantitative cultures and were empirically treated with either a combination of an antipseudomonal beta-lactam plus an aminoglycoside or a fluoroquinolone. If initial therapy was appropriate, patients were randomly assigned to either 8 or 15 days of therapy. There was no significant difference between patients treated for 8 days compared to 15 in such outcomes as 28-day mortality or recurrent infection; as expected, patients treated for 8 days had more antibiotic-free days. Among patients who developed recurrent infections, MDR pathogens were isolated less frequently in those treated for 8 days (42% versus 62% for those treated 15 days). However, patients with VAP caused by nonfermenting gramnegative bacilli (e.g., Pseudomonas species) had a higher pulmonary infection recurrence rate when treated for 8 versus 15 days (41% versus 25% with 15 days of treatment), but the death rate was not different. An ICU study evaluated clinical outcomes, including duration of treatment, following implementation of a clinical guideline for the treatment of VAP compared to historical controls (patients with VAP treated before implementation of the guideline) (12). The clinical guideline recommended empiric treatment with vancomycin, imipenem, and ciprofloxacin with modification of the antibiotic regimen after 24 to 48 hours based on the patient’s clinical course and culture results. Duration of therapy in the clinical guideline group was 7 days unless the patient had persistent signs and symptoms of active infection or had not alleviated. The duration of antibiotic treatment was significantly less in the clinical study group (8.6 versus 14.8 days in the historical controls). A prospective study evaluated the ability of the CPIS (summarized in Table 24-3) to determine the duration of therapy for ICU patients with new pulmonary infiltrates (13). Patients were included in the study if they had new-onset pulmonary infiltrates and a CPIS less than 6 (low likelihood of having pneumonia). The patients were randomly assigned to either a control group (current standard therapy; e.g., number, choice and duration of antibiotics measured by the care providers) or to the experimental group (intravenous ciprofloxacin 400 mg every 8 hours for 3 days). The CPIS was reevaluated at 3 days and in patients with a CPIS less than 6,

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Table 24-3 Clinical Pulmonary Infection Score (CPIS) Scoring Sheet Assess on entry and on day 3:

_____Temperature: ≥36.5˚C or ≤38.4˚C (afebrile) = 0 point; ≥38.5˚C or ≤38.9˚C = 1 point; ≥39˚C or ≤36.5˚C = 2 points _____Blood leukocytes, mm3: ≥4000 or ≤11,000 = 0 points; <4000 or >11,000 = 1 point; + band forms ≥50% = add 1 point _____Tracheal secretions: absence of tracheal secretions = 0 point; presence of nonpurulent tracheal secretions = 1 point; presence of purulent tracheal secretions = 2 points _____Oxygenation: PaO2/FiO2, mm Hg >240 or ARDS (ARDS defined as PaO2/FiO2 ≤200, pulmonary arterial wedge pressure ≤18 mm Hg and acute bilateral infiltrates) = 0 points; ≤240, no ARDS = 2 points _____Pulmonary radiography: no infiltrate = 0 point; diffuse (patchy) infiltrate = 1 point; localized infiltrate = 2 points Assess only on day 3:

_____Progression of pulmonary infiltrate: no radiographic progression = 0 point; radiographic progression (after CHF and ARDS excluded) = 2 points _____Culture of tracheal aspirate: pathogenic bacteria cultured in rare or light quantity or no growth = 0 point; pathogenic bacteria cultured in moderate or heavy quantity = 1 point; same pathogenic bacteria seen on Gram stain = 1 point _____Total Using this approach, pneumonia is more likely in those with a CPIS of at least 6, compared to those with a lower score. Modified with permission from: Pugin J, Auckenthaler R, Mili N, et al. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am Rev Respir Dis. 1991;143:1121. Abbreviations: ARDS = adult respiratory distress syndrome; CHF = congestive heart failure.

antibiotics were discontinued in the experimental group. If the CPIS was more than 6 at day 3, the ciprofloxacin was continued or antibiotics were changed based on the microbiologic results. Significantly more patients in the control group received antibiotics beyond 3 days compared to those in the experimental group (90% compared to 28% in the experimental group). In addition to reduced antibiotic use, the experimental group was less likely to have colonization/infection with resistant organisms (15% compared to 35% of patients in the control group) and had a trend toward lower death.

Recommendations Based on these data, we recommend that all patients with HAP, VAP, and HCAP be evaluated after 72 hours of initial empiric antimicrobial therapy. At 72 hours, we recommend assessment of both the CPIS and the results of microbiologic tests. If the initial CPIS was less than 6 and remains so at 72 hours, we would discontinue antimicrobial therapy, especially if

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there is no microbiologic documentation of a pathogen in significant quantity. If the initial CPIS was greater than 6, the patient has alleviated after 72 hours, and a pathogen is isolated, antimicrobial therapy should be changed to a pathogen-directed regimen based on the susceptibility pattern. Therapy should be continued to complete a total course of 7 to 8 days; we would treat up to 15 days if P. aeruginosa were the etiologic agent. If no pathogen were identified, we would narrow the regimen, discontinuing therapy for Pseudomonas species and MRSA. If the patient is not improving at 72 hours and a resistant pathogen is identified, therapy can be changed to pathogen-directed treatment based on the susceptibility pattern. In addition, failure to alleviate at 72 hours should prompt a search for infectious complications, other diagnoses, or other sites of infection (Figure 24-1).

Prevention The pathogenesis of NP usually requires 2 major processes: microbial colonization of upper airway secretions and aspiration of these secretions into the lung. Therefore, strategies aimed at reducing the incidence of NP focus on reducing the amount of bacterial colonization or reducing the incidence of aspiration (14). The most effective methods that are supported by controlled studies include adequate hand washing between patient contacts, maintaining semirecumbent patient positioning, avoiding gastric over distention, continuous subglottic suctioning for patients on mechanical ventilation, limiting stress-ulcer prophylaxis, and using chlorhexidine oral rinses. Importantly, the use of aerosolized antibiotic prophylaxis and routine use of antimicrobial agents for selective digestive decontamination have not been found to be beneficial. Isolating patients with resistant organisms (e.g., MRSA) can decrease the likelihood of transferring these pathogens between patients. REFERENCES 1. Craven DE, Palladino R, McQuillen DP. Healthcare-associated pneumonia in adults: management principles to improve outcomes. Infect Dis Clin North Am. 2004;18:939-62. 2. American Thoracic Society. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416. 3. Kollef MH, Shorr A,Tabak YP, et al. Epidemiology and outcomes of healthcare-associated pneumonia: Results from a large US database of culture-positive pneumonia. Chest. 2005. In press. 4. Fagon JY, Chastre J, Vuagnat A, Trouillet JL, Novara A, Gibert C. Nosocomial pneumonia and mortality among patients in intensive care units. JAMA. 1996;275:866-9. 5. El-Solh AA,Pietrantoni C,Bhat A,Aquilina AT,Okada M,Grover V,et al. Microbiology of severe aspiration pneumonia in institutionalized elderly. Am J Respir Crit Care Med. 2003;167:1650-4. 6. Grossman RF, Fein A. Evidence-based assessment of diagnostic tests for ventilator-associated pneumonia: Executive summary of the clinical practice guideline panel. Chest. 2000;117 (suppl 2):177-81S.

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7. Pugin J,Auckenthaler R, Mili N, Janssens JP, Lew PD, Suter PM. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am Rev Respir Dis. 1991;143:1121-9. 8. Fartoukh M, Maitre B, Honoré S, Cerf C, Zahar JR, Brun-Buisson C. Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Am J Respir Crit Care Med. 2003;168:173-9. 9. Fagon JY, Chastre J,Wolff M, Gervais C, Parer-Aubas S, Stéphan F, et al. Invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med. 2000;132:621-30. 10. Ruiz M,Torres A, Ewig S, Marcos MA,Alcón A, Lledó R, et al. Noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome. Am J Respir Crit Care Med. 2000;162:119-25. 11. PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290:2588-98. 12. Ibrahim EH,Ward S, Sherman G, Schaiff R, Fraser VJ, Kollef MH. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001; 29:1109-15. 13. Singh N, Rogers P,Atwood CW,Wagener MM,Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162:505-11. 14. Kollef MH. The prevention of ventilator-associated pneumonia. N Engl J Med. 1999;340:627-34.

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Chapter 25

Tuberculosis SCOTT MAHAN, MD JOHN J. JOHNSON, MD

Key Learning Points 1. One third of the world population is infected with M. tuberculosis. Nine million new cases of TB and 2 million deaths due to TB occur worldwide each year. 2. TB most commonly presents as apical fibrocavitary reactivation pulmonary disease. 3. Patients with advanced HIV/AIDS often present atypically when infected with TB. 4. Standard 6 month short course chemotherapy with two months of isoniazid, rifampin, ethambutol and pyrazinamide followed by 4 months of isoniazid and rifampin is highly effective for the treatment of drug-susceptible TB when fully administered. 5. Directly observed therapy (DOT), where treatment is supervised and facilitated by a health care worker or trained lay supervisor, is the global standard for TB treatment.

T

uberculosis (TB) is a chronic granulomatous disease caused by organisms of the Mycobacterium tuberculosis complex. Most human tuberculous disease is caused by M. tuberculosis, an intracellular pathogen primarily infecting mononuclear phagocytes. Although tuberculosis can affect many organs and cause disseminated disease, the most frequent and important form is pulmonary tuberculosis, which is spread in the community by aerosol droplet transmission. Despite the availability of highly effective treatment, TB remains one of the world’s leading infectious disease killers. In the United States and other industrialized countries, great strides have been made in controlling TB; 495

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New Developments ●

●

●

A whole blood interferon-gamma assay, an in vitro T-cell based assay using specific MTB antigens, has potential benefits for screening and has been recently recommended by the CDC as an acceptable alternative to tuberculin skin testing for contact investigations, screening of immigrants, and for sequential testing of health care workers. Fluoroquinolones such as moxifloxacin are currently being evaluated in clinical trials for their potential role in shortening the required duration of treatment of drug-susceptible TB. New classes of drugs with novel mechanisms of action such as the nitroimidazopyran PA-824 and the diarylquinoline TMC-207 are in preclinical and early clinical testing for TB treatment.

however, the emergence of multidrug resistant (MDR) TB and a high incidence of disease in foreign-born persons, marginalized populations in poor urban areas, and HIV-infected persons are ongoing challenges to TB control. The primary care physician is charged with the vital role of identifying and treating persons with latent TB infection and quickly diagnosing and beginning initial therapy in persons with active TB. Most patients with TB should be referred to an infectious disease specialist or public health clinic with expertise in TB care.

Epidemiology The World Health Organization estimates that up to one third of the world’s population is infected with M. tuberculosis (1). Approximately 9 million new cases of active TB and 2 million deaths caused by TB occur each year. TB is the second leading cause of death worldwide from an identifiable infectious pathogen, exceeded only by HIV/AIDS. Tuberculosis is a major public health problem in developing countries where 95% of all cases and 98% of TB-related deaths occur. Eighty percent of TB cases occur in 22 high burden countries—mainly in sub-Saharan Africa, Asia, and regions of the former Soviet Union. In the United States, TB is primarily a disease of immigrants from high-prevalence countries and the socially and economically disadvantaged. During the early 1980s declining case rates in the United States led to the underfunding and dismantling of public clinics and agencies that provided TB care. This, combined with the HIV pandemic, led to a sharp increase in cases during the late 1980s. With renewed funding, the rebuilding of the public health infrastructure for TB care, the widespread implementation of directly observed therapy (DOT), and improved case management strategies, the TB case rate in the United States has now decreased by approximately 5% annually since 1992.

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TB control remains a public health concern in the United States because of the infectiousness of M. tuberculosis as a respiratory pathogen and persistently high TB case rates among certain groups. In 2004 a total of 14,511 confirmed TB cases (4.9 per 100,000 population) were reported to the U.S. Centers for Disease Control (CDC) (2). In the United States, TB disproportionately affects the poor, the foreign-born, and native-born non-Hispanic blacks. Case rates are 8- to 20-fold greater among Hispanics, African Americans, and Asian Americans than whites. For the first time in 2002, the number of TB cases among foreign-born persons exceeded the number of cases in those born in the United States; most occurred in immigrants from Mexico, the Philippines, Vietnam, India, China, Haiti, and South Korea. Geographic disparities also exist. Some states and large cities have disproportionate numbers of TB cases; California, Florida, Illinois, New York, and Texas are among the states with the highest number of TB cases.

Etiology and Pathogenesis Tuberculosis is caused by the M. tuberculosis complex, which consists of M. tuberculosis (MTB), Mycobacterium bovis, Mycobacterium bovis bacille Calmette-Guérin (BCG), Mycobacterium africanum, Mycobacterium microti, and Mycobacterium canetti. MTB is the main pathogen in humans. MTB is an obligate aerobic, nonmotile bacillus with a lipid rich cell wall that stains acid fast, meaning it maintains a reddish hue after staining with carbol fuchsin followed by washing with acid alcohol. Humans are the only known reservoir for MTB. The primary method of transmission of TB is when an infected person with active pulmonary disease coughs, sneezes, sings, or talks and creates fine aerosolized droplets of tuberculous bacilli, 1 to 5 µm in size, that are inhaled by another person and deposited in the distal respiratory tree (3). Persons who have detectable acid-fast bacillus (AFB) on sputum smear are more likely to transmit TB than persons whose sputum smears are negative. Increased duration of exposure to a smear-positive patient, close contact, and poor ventilation all increase the likelihood of transmission (4). After deposition in the lungs, the tubercle bacilli are ingested by alveolar macrophages that initiate a cascade of immunologic events. The vast majority of persons infected with MTB are asymptomatic or have transient flu-like symptoms. More than 90% of infected persons are able to contain the infection and do not go on to develop active TB. In these persons, the only marker that tuberculous infection has occurred is the conversion of the tuberculin skin test (TST) from negative to positive approximately 4 to 6 weeks after infection. A small percentage of individuals, particularly infants and young children, the elderly, and immunocompromised persons develop progressive primary TB after infection. The risk of progression to active TB is approximately 5% during the first 2 years after tuberculous infection with a subsequent 5%

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additional risk over the person’s lifetime giving an approximate 10% lifetime risk of developing active TB (5).

Clinical Manifestations Most cases of TB are caused by reactivation of latent tuberculosis infection in the following settings: immunosenescence caused by aging; immunosuppression caused by comorbid conditions such as HIV infection, diabetes mellitus, cancer, or end stage renal disease, or immunosuppressive agents such as corticosteroids. The most frequent signs and symptoms of TB are a productive cough for more than 3 weeks, fever, weight loss, night sweats, anorexia, malaise, and chest pain (6). Hemoptysis occurs in only 10% to 20% of smear-positive patients. Chest radiographs in reactivation TB commonly show infiltrates, cavities, and destructive lesions most frequently in the apical and posterior segments of the upper lobes and the superior segments of the lower lobes (7).

Diagnosis The diagnosis of TB is made by demonstrating the presence of the tubercle bacillus, its antigens, or its genomic products in smears, cultures, or tissue samples. The key examination for the diagnosis of pulmonary TB is sputum smear and culture. Sputum smears for AFB are done using hot (Ziehl-Neelsen) or cold (Kinyoun) carbol fuchsin stains, or fluorescent auramine staining methods. Approximately 5000 to 10,000 tubercle bacilli per mL of sputum must be present for consistent detection of a positive sputum smear (8). Sputum smears can be done quickly and facilitate the rapid diagnosis of patients with the most infectious form of TB. Sputum smears are approximately 60% to 70% sensitive for the diagnosis of TB. Fluorescent auramine staining allows more rapid scanning of large numbers of smears under lower magnification and is used by laboratories examining large numbers of specimens. The sensitivity and specificity of carbol fuchsin and fluorescent auramine staining methods are roughly equivalent when done in experienced laboratories. Because of the limited sensitivity of sputum examination, at least three sputum samples should be obtained for acid-fast smear and culture. Collection of early morning sputum specimens, which samples respiratory sections accumulating in the bronchial tree during sleep is best, but spot collections are acceptable. In those unable to produce adequate sputum samples, sputum production can be induced by inhalation of aerosolized 3% (hypertonic) sterile saline solution, or samples can be collected by early morning gastric lavage or by means of bronchoscopy. When bronchoscopy is done, transbronchial biopsy can be done for culture and histologic evaluation. In miliary TB, sputum AFB

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smears and culture are frequently negative. Biopsy of the lung, bone marrow, or liver is frequently required to confirm the diagnosis. Cultures should be done on all sputum and tissue specimens. Cultures have improved sensitivity versus smears (80%-85%) as well as a specificity of approximately 98% (4). Cultures allow species identification and drug susceptibility testing. Historically, culture has been grown on solid media such as the egg-based Lowenstein-Jensen media and the clear oleicalbumin agar based Middlebrook media. Because of the slow growth of MTB (dividing time 12-18 hours), it can take several weeks before growth is evident. Therefore, cultures should be examined weekly until growth is present or for a total of 8 weeks. Organisms from culture can then be speciated to identify them as MTB or atypical mycobacteria by the use of biochemical, morphologic, and genomic methods. Drug susceptibility requires an additional 2 to 4 weeks using traditional methods. The time for detection of growth in culture has been shortened through the use of automated liquid culture systems such as BACTEC and the Mycobacterial Growth Indicator Tube (MGIT). These systems shorten the time for positive cultures by measuring metabolically active mycobacteria, thereby signaling growth more rapidly than the traditional method of waiting for visible growth on solid culture media. By using automated liquid culture systems, the time to detectable growth of mycobacteria has been shortened to roughly 14 days from smear positive sputa and to approximately 21 days in smear negative cases (9). Promising new rapid diagnostic techniques involve the use of nucleic acid amplification to identify MTB. These tests, however, are not a replacement for sputum acid-fast smears and mycobacterial cultures that provide an indication of infectivity and allow for drug susceptibility testing. Several nucleic acid amplification tests that can be done directly from sputum specimens (or from positive cultures) have been approved by the U.S. Food and Drug Administration. These amplified tests detect genetic sequences that are highly conserved among M. tuberculosis species. They have been shown to have a sensitivity of 84% to 92% for smear positive cases, but only 41% to 75% for smear negative cases, with a specificity of 96% to 99% (10). The lower diagnostic yield in sputum-smear–negative patients is likely caused by the lower bacillary load in smear-negative patients and the smaller inoculum of specimen examined compared with culture. Because of their higher costs and limited availability, the current roles of nucleic acid testing methods for TB are for the rapid confirmation of the diagnosis of TB in smear-positive patients and for the evaluation of patients with negative smears where the physician has a high clinical suspicion for TB. Although licensed only for examining sputum and respiratory secretions, nucleic acid amplification methods have been used to evaluate other specimens such as cerebrospinal fluid (CSF) or pleural fluid where their sensitivity has also been reported to be limited. The performance of smears, cultures and nucleic acid based methods is compared in Table 25-1.

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Table 25-1 Microbiologic Tests for the Diagnosis of Tuberculosis Sputum Smear (percentage)

One Culture (percentage)

Three Cultures (percentage)

Sensitivity

60-70

80-85

80-100

Specificity

95

98

98

Nucleic Acid Amplification (PCR) (percentage)

80-100 (95 in smear positive; 60 in smear negative) 98

Abbreviations: PCR, polymerase chain reaction.

Drug susceptibility testing should be done on an initial positive culture, and should be repeated if there is failure to respond clinically and when sputum cultures remain positive after 2 months of treatment. Standard methods of testing that determine drug susceptibility of mycobacteria by observing for inhibition of growth in critical concentrations of drugs, often require 2 to 4 weeks to do after initial culture positivity. The use of radiometric or fluorescent-based detection systems using liquid culture media speeds resistance testing, but still requires several weeks. Rapid molecular methods for identifying resistant isolates to rifampin (RMP) have been developed, based on detection of mutations in a short portion of the mycobacterial RNA polymerase gene. Other rapid susceptibility tests are in development. In addition to sputum microscopy and culture, chest radiography is useful in evaluating patients with suspected TB. Active pulmonary TB classically presents with upper lobe involvement of one or both lungs. The apical and posterior segments of the upper lobes are the most commonly involved areas of the lung. In the right clinical situation, active pulmonary TB is suggested by consolidation, nodular infiltrates, and cavitation. Although highly suggestive of TB, these findings are nonspecific. Other diseases such as histoplasmosis, chronic necrotizing pulmonary aspergillosis, sarcoidosis, and atypical mycobacterial infections can present with very similar findings and must be considered in the differential diagnosis. Approximately 5% of patients with pulmonary TB, such as those with endobronchial TB, can have normal chest radiographs at the time of presentation. Tuberculin skin testing has a limited role in the evaluation of patients with suspected TB. It is important to remember that a positive tuberculin skin test only indicates that a patient has been infected with MTB and does not indicate whether or not a patient has active TB. Tuberculin skin testing is useful, however, when information about previous tuberculous infection is important in narrowing the differential diagnosis and guiding decisions about further testing or empiric treatment in appropriate clinical situations.

Treatment Modern RMP-containing short-course chemotherapy is highly effective for the treatment of TB. When fully administered, cure rates of more than 95% can

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be achieved in patients with drug-susceptible TB. In the United States, four regimens are currently recommended for the treatment of patients with drugsusceptible TB (Table 25-2). Each includes an initial 2-month intensive phase with four drugs followed by a 4 to 7 month continuation phase with two drugs. The intensive phase targets the initial high burden of tubercle bacilli, and the continuation phase targets the remaining slowly dividing organisms. Previously untreated patients without risk factors for drug-resistant TB should initially be treated with INH (INH), RMP, pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by INH and RIF for 4 months. Drugsusceptibility testing against standard first-line anti-TB drugs should be done on an initial isolate from all patients whenever possible. If the patient’s isolate is susceptible to INH, RMP, and PZA, EMB can be discontinued. Patients with cavitary disease on chest radiograph whose sputum cultures are still positive after 2 months of treatment, patients who were not treated with PZA during the initial phase of therapy, and patients being treated with once-weekly INH and rifapentine whose sputum cultures are positive after 2 months of treatment should be treated for 7 months during the continuation phase (11). Baseline evaluation before beginning treatment should include HIV testing, testing for viral hepatitis in at-risk individuals, serum liver function tests, serum creatinine, and platelet count. Vision testing, including red-green color discrimination testing, should be done if EMB is part of the regimen. The main serious toxicity of anti-TB drugs is hepatotoxicity. Hepatotoxicity can be caused by INH, RMP, and PZA. Drug-induced hepatitis is defined as a serum aspartate aminotransferase (AST) more than three times the upper limit of normal with symptoms, or five times the upper limit without symptoms. The risk of clinical hepatitis with INH-containing regimens is approximately 3% (12). Minor, asymptomatic, self-limited increases in hepatic aminotransferases occur in approximately 20% of patients treated for TB with standard short-course chemotherapy. The risk for clinical hepatitis increases with advancing age, preexisting liver disease, in those with heavy alcohol consumption, and in pregnant and postpartum women. Patients should be instructed about symptoms and signs of hepatotoxicity and told to stop taking their drugs and seek immediate medical attention for persistent nausea, jaundice, anorexia, or abdominal pain. INH, RIF, PZA, and any other potentially hepatotoxic drugs that the patient is taking should be stopped. Evaluation for other causes of hepatitis should be done. Two or more antituberculous medications without hepatotoxicity should be substituted until the AST has returned to less than two times the upper limit of normal, and symptoms have resolved. Then the first-line drugs (Table 25-3) can be reintroduced sequentially (usually starting with RIF, then INH, then PZA) with close monitoring of hepatic function (11). During treatment, sputum should be examined monthly by smear and culture until two consecutive samples are negative on culture. It is also important for patients to have monthly clinical evaluations for evidence of treatment failure, drug side effects, and to assess adherence. Patients on

INH RIF PZA EMB

INH RIF PZA EMB

INH RIF PZA EMB INH RIF EMB

1

2

3

4

Drugs

Regimen

‡

Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)¶

Seven days per week for 14 doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 d/wk for 10 doses (2 wk),¶ then twice weekly for 12 doses (6 wk) Three times weekly for 24 doses (8 wk)

Seven days per week for 56 doses (8 wk) or 5 d/wk for 40 doses (8 wk)¶

Interval and doses (minimal duration)

Initial phase

INH/RIF

INH/RIF

4a

4b

INH/RIF

INH/RIF INH/RPT INH/RIF INH/RPT

1b 1c** 2a 2b**

3a

INH/RIF

Drugs

1a

Regimen

Seven days per week for 217 doses (31 wk) or 5 d/wk for 155 doses (31 wk)¶ Twice weekly for 62 doses (31 wk)

Three times weekly for 54 doses (18 wk)

Seven days per week for 126 doses (18 wk) or 5 d/wk for 90 doses (18 wk)¶ Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk) Twice weekly for 36 doses (18 wk) Once weekly for 18 doses (18 wk)

Interval and doses ठ(minimal duration)

Continuation phase

(26 (26 (26 (26

wk) wk) wk) wk)

(I) (I) (II) (I)

B (I)

A B A B

118–102 (39 wk) C (I)

273–195 (39 wk) C (I)

78 (26 wk)

92–76 74–58 62–58 44–40

C (II)

C (II)

B (II)

A (II)# E (I) B (II)# E (I)

A (II)

Rating* (evidence)† HIV − HIV +

182–130 (26 wk) A (I)

Range of total doses (minimal duration)

502

Table 25-2 Drug Regimens for Culture-Positive Pulmonary Tuberculosis Caused by Drug-Susceptible Organisms

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Definition of abbreviations: EMB = Ethambutol; INH = isoniazid; PZA = pyrazinamide; RIF = rifampin; RPT = rifapentine. * Definitions of evidence ratings: A = preferred; B = acceptable alternative; C = offer when A and B cannot be given; E = should never be given. † Definition of evidence ratings: I = randomized clinical trial; II = data from clinical trials that were not randomized or were conducted in other populations; III = expert opinion. ‡ When DOT is used, drugs may be given 5 days/week and the necessary number of doses adjusted accordingly. Although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. § Patients with cavitation on initial chest radiograph and positive cultures at completion of 2 months of therapy should receive a 7-month (31 week; either 217 doses [daily] or 62 doses [twice weekly]) continuation phase. ¶ Five-day-a-week administration is always given by DOT. Rating for 5 day/week regimens is AIII. # Not recommended for HIV-infected patients with CD4+ cell counts <100 cells/µl. ** Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the time of completion of 2 months of therapy and who do not have cavitation on initial chest radiograph (see text). For patients started on this regimen and found to have a positive culture from the 2-month specimen, treatment should be extended an extra 3 months. Reprinted from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;603-62.

Table 25-2 Continued

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5 mg/kg (10-15 mg/kg in children); maximum 300 mg/day) 10 mg/kg (10-20 mg/kg in children); maximum 600 mg/day Weight 40-55 kg— 1000 mg; 56-75 kg— 1500 mg; above 76 kg 2000 mg (15-30 mg/kg in children); maximum 2 g/day Weight 40-55 kg— 800 mg; 56-75 kg— 1200 mg; above 76 kg— 1600 mg PO (15-25 mg/kg in children— up to 1 g/day) 15 mg/kg IM (up to 1000 g/d); in persons older than 50 years of age, 10 mg/kg (up to 750 mg/day) (20-40 mg/kg in children)

Isoniazid

–

–

15 mg/kg (20-30 mg/kg in children); maximum 900 mg/dose 10 mg/kg (10-20 mg/kg in children); maximum 600 mg/dose Weight 40-55 kg— 1500 mg; 56-75 kg— 2500 mg; above 76 kg 3000 mg (50-70—30 mg/kg in children); maximum 3 g/d Weight 40-55 kg—1200 mg; 56-75 kg—2000 mg; above 76 kg—2400 mg PO (25-30 mg/kg in children)

Thrice-Weekly Dosage

IM

PO

PO

PO

PO

Renal toxicity, ototoxicity

Optic neuritis

Hepatotoxicity, peripheral neuropathy, GI disturbance Hepatotoxicity, change in color of body fluids, thrombocytopenia Arthralgias, hepatotoxicity

Route of Administration Adverse Effects

a Adapted from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-62. b Children younger than 15 years of age. c Ethambutol should not be used routinely in children younger than 5 years of age who cannot be reliably monitored for ophthalmological toxicity. d Streptomycin is usually initially given daily. The dosing frequency is decreased to twice or thrice weekly after the first several months of treatment or after sputum cultures have become negative. * Twice weekly therapy is not recommended in patients with advanced HIV (CD4 <100) because of increased incidence of failure with this regimen. Abbreviations: GI, gastrointestinal; IM, intramuscularly; PO, orally.

Streptomycind

Ethambutolc

Pyrazinamide

15 mg/kg (20-30 mg/kg in children); maximum 900 mg/dose 10 mg/kg (10-20 mg/kg in children); maximum 600 mg/dose Weight 40-55 kg— 2000 mg; 56-75 kg— 3000 mg; above 76 kg 4000 mg (50-70 mg/kg in children); maximum 4 g/d Weight 40-55 kg— 2000 mg; 56-75 kg— 2800 mg; above 76 kg— 4000 mg PO (50 mg/kg in children)

Twice-Weekly Dosage*

504

Rifampin

Daily Dosage

Drug

Table 25-3 Doses of First-Line Anti-Tuberculosis Drugs for Adults and Childrena,b

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EMB should be asked about blurred vision or scotomata. Routine laboratory monitoring is not recommended for all patients but should be done for patients at increased risk of hepatotoxicity. These include patients with heavy alcohol consumption, hepatitis B or C infection, or other chronic liver conditions. Lack of adherence to treatment is the greatest risk factor for the development of drug-resistant organisms and treatment failure. DOT increases cure rates and decreases the development of acquired drug resistance, and is highly cost-effective (13). In DOT, a health care worker or treatment supervisor observes the patient swallowing each dose of anti-TB treatment. Public health clinics and agencies usually have better resources than a physician’s office to administer DOT, report new TB cases to health authorities, and do needed follow-up and contact investigations. Physicians diagnosing and treating new cases of TB should refer patients to their local public health clinic or TB-control program for care. DOT can be successfully accomplished in the community, at the patient’s home, workplace, or other convenient location or at the clinic. DOT is most likely to be successful in curing the patient if it is convenient for the patient and takes into account his or her life circumstances.

First-Line Anti-Tuberculous Agents INH, RMP, EMB, and PZA are standard first-line oral agents for treating drug susceptible tuberculosis. Rifabutin and rifapentine are other rifamycins similar in activity and toxicity to RMP that are used in certain circumstances. Streptomycin is infrequently used as a first-line drug. Standard first-line drug dosages are shown in Table 25-3.

INH INH is bactericidal against rapidly dividing tubercle bacilli. It is used in combination chemotherapy for active TB and is the most frequently used drug for the treatment of latent TB infection. INH is usually well tolerated; its most important side effect is hepatotoxicity. Asymptomatic elevation of hepatic aminotransferases occurs in 10% to 20% of patients taking INH alone for the treatment of latent TB infection. Clinically significant hepatitis, although less common than once thought, occurs in up to 3% of persons taking combination chemotherapy for active TB. The risk of hepatotoxicity is increased in patients with preexisting liver disease, a history of heavy alcohol use, and among pregnant and postpartum women. Peripheral sensorimotor neuropathy, often presenting with pins- and needles-like paresthesia in the hands and feet, can develop in persons taking INH and is more frequent in malnourished, pregnant, and HIV-infected individuals. Oral vitamin pyridoxine (B6) 25 mg daily should be given along with anti-TB treatment to decrease the risk of this complication. A lupus-like syndrome occurs in less than 1% of patients although approximately 20% develop antinuclear antibodies.

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Other side effects include central nervous symptoms, including seizures and rashes or hypersensitivity reactions.

Rifampin RMP is the most active first-line anti-TB drug. It is bactericidal against both rapidly dividing bacilli and slowly dividing, persistent bacilli. When administered alone, RMP has little hepatotoxicity; however, when combined with INH, there is a 2.6% risk of clinical hepatitis. RMP is a potent inducer of hepatic enzymes and has clinically important effects on the dosing and effectiveness of many drugs including warfarin, theophylline, protease inhibitors, and hormonal contraceptives. Other less common side effects include gastrointestinal symptoms, pruritus, and flu-like symptoms. Patients should be informed that RMP causes orange discoloration of body secretions (urine, sweat, and tears) and can discolor soft contact lenses. Ethambutol EMB is a mycobacteriostatic drug that is used as part of the first-line multidrug regimen. Its main toxicity is retrobulbar neuritis that is more common at dosages greater than 15 mg/kg. Patients receiving this drug should be instructed about the symptoms of ocular toxicity, which presents as blurred vision, or decreased peripheral or color vision. Patients should receive baseline visual acuity using a Snellen or illiterate E chart and color-discrimination testing using Ishihara color vision testing plates and should also be questioned about visual disturbances at each monthly visit. Young children should usually not be treated with EMB because of unreliability in reporting visual changes. Pyrazinamide PZA is most effective against slowly dividing tubercle bacilli and is usually given during the first 2 months (intensive phase) of anti-TB treatment. Its most frequent side effects are gastrointestinal intolerance, hepatotoxicity (~1%), arthralgias, and asymptomatic hyperuricemia. Minor arthralgias, which occur in up to 40% of those treated with daily PZA, usually respond to symptomatic management with nonsteroidal anti-inflammatory drugs (NSAIDs) and rarely require discontinuation of the drug. Patients with a history of gout should not be treated with PZA. Streptomycin Some now consider this a second-line agent because of the requirement for intravenous or intramuscular injection. Its main adverse effects are ototoxicity and nephrotoxicity. Rifapentine and Rifabutin Rifapentine is a once weekly agent that can be used along with INH in the continuation phase of anti-tuberculous treatment in HIV-uninfected patients

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Table 25-4 Second-Line Antituberculous Drugs Drugs

Cycloserine Ethionamide Amikacin and kanamycin Capreomycin p-Aminosalicylic acid (PAS) Fluoroquinolones (levofloxacin, moxifloxacin, gatifloxacin*)

Total Adult Daily Dose (maximum dose)

Common Side Effects

10-15 mg/kg/day (1000 mg) Psychosis, seizures, headaches, restlessness 15-20 mg/kg/day (1000 mg) Nausea, vomiting, hepatotoxicity, peripheral neuritis 15 mg/kg/day (1000 mg) Ototoxicity, nephrotoxicity 15 mg/kg/day (1000 mg) 200 mg/kg/day (12 g)

400-1000 mg/day

Nephrotoxicity, ototoxicity Hepatotoxicity, gastrointestinal upset, hypothyroidism, coagulopathy Gastrointestinal upset, dizziness, insomnia, rash, photosensitivity

Adapted from American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-62. * Gatifloxacin no longer available in United States.

with noncavitary TB whose sputum cultures are negative after 2 months of anti-TB treatment. Rifabutin can be used as a substitute for RMP in those with unacceptable drug interactions, such as HIV-infected patients on protease inhibitors. Side effects of rifapentine and rifabutin are similar to RMP.

Second-Line Antituberculous Drugs Second-line agents are used in the treatment of patients who are intolerant to first-line drugs, patients with known or suspected drug-resistant TB, when there are contraindications to first-line drugs, and during retreatment of TB until drug susceptibility testing results are available. In general, these drugs are more toxic, less well tolerated, less effective, and must be given for a longer period of time than standard first-line agents. A specialist in the treatment of TB should be consulted whenever use of these agents is considered. Table 25-4 gives a quick overview of these agents and notable toxicities (11).

Special Situations Extrapulmonary Tuberculosis At the time of initial infection, tubercle bacilli widely disseminate throughout the body before the containment of infection after the development of cellmediated immunity. As a result, any organ system can be involved. Although pulmonary disease is the most common form of TB, extrapulmonary TB is the initial presentation in 15% to 20% of HIV-uninfected adults (3). Patients with

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extrapulmonary TB can be difficult to diagnose. They frequently present with fever or localizing signs at the site of disease. In addition, as a general rule, chest radiographs are normal in one quarter to one third of patients with extrapulmonary TB. Tuberculin tests should be done to evaluate the patient for previous tuberculous infection, but are frequently negative. The diagnosis of extrapulmonary TB hinges on detecting the presence of tubercle bacilli or its genomic constituents on smears or cultures of infected secretions or tissues from affected sites. Because the number of tubercle bacilli present in extrapulmonary TB is generally lower than in pulmonary disease, the sensitivity of smears and cultures is lower in extrapulmonary TB, and many specimens should be examined. In the developed world, extrapulmonary TB is most common in the elderly and the immunocompromised. The most common sites of extrapulmonary TB include the pleura, lymph nodes (particularly the cervical nodes), the central nervous system, kidneys, and the bones and joints (14). Because of the excellent tissue penetration of most anti-TB drugs and the smaller numbers of tubercle bacilli present in most forms of extrapulmonary TB, the standard 6-month RMP-containing regimens used for treating pulmonary TB are also highly effective for the treatment of most forms of extrapulmonary disease. Many authorities, however, recommend 9 to 12 months of treatment of tuberculous meningitis and bone and joint TB. Adjunctive corticosteroids have been shown to be helpful in patients with tuberculous meningitis and tuberculous pericarditis (11).

Coinfection with HIV and Tuberculosis Patients with TB should routinely be offered HIV testing because of a high rate of HIV and TB coinfection. TB can be the initial presenting infection in HIV. HIV-coinfection is the greatest risk factor known for the development of TB in persons with latent or recent MTB infection. Patients with HIV, regardless of CD4 count, are at increased risk of developing active TB. The yearly risk of developing active TB is 8% to 10% per year among TST-positive HIV-infected individuals compared to a 10% lifetime risk for non-HIV infected persons. HIV-infected individuals with CD4 lymphocyte counts greater than 200 uL−1, tend to present similarly to non-HIV infected individuals with typical apical fibrocavitary reactivation pulmonary disease. Those with more advanced HIV/AIDS with CD4 counts less than 200 uL−1, are more likely to present atypically with lower lung infiltrates or noncavitary disease, are less likely to be sputum-smear positive, and are more likely to have extrapulmonary disease (15). Clinicians should have a high clinical suspicion for TB in patients with advanced HIV/AIDS presenting with cough and undiagnosed pulmonary disease. If hospitalized, such patients should be initially placed in respiratory isolation until sputum can be examined for AFB. The treatment of HIV-infected patients with TB is similar to non-HIV infected individuals. Six months of treatment with recommended standard

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short-course chemotherapy regimens is highly effective. Although relapse rates are slightly higher in HIV-infected patients, clinical responses to TB treatment are similar to non-HIV infected persons. Relapse rates are significantly greater after treatment with twice weekly RMP or rifabutin-containing regimens during the continuation phase in patients with CD4 counts less than 100 uL−1, when using once weekly rifapentine-containing regimens during the continuation phase and when using non-rifamycin–containing regimens during the continuation phase. Rifapentine-containing regimens should not be used in treating HIV-infected patients for TB. Daily or thrice weekly treatment regimens including RMP or rifabutin should be used in treating patients with low CD4 counts. Response to therapy should be monitored closely both clinically and microbiologically with monthly sputum examinations. Treatment should be prolonged if there is evidence of slow or inadequate response to therapy. Many patients with previously undiagnosed HIV infection and TB are severely immunosuppressed at the time when they are diagnosed with TB. Patients with CD4 counts less than 200 uL−1 and TB are at high risk for death and require prompt treatment of both TB and HIV. Drug interactions of RMP with antiretroviral drugs is a significant concern when treating HIV-infected patients for TB. RMP is a potent inducer of the cytochrome P-450 enzyme (CYP) 3A enzyme and should not be used with protease inhibitors and most non-nucleoside reverse transcriptase inhibitors, with the exception of efavirenz. If a patient requires highly active antiretroviral therapy (HAART) in conjunction with anti-TB treatment, rifabutin is an alternative to RMP that has fewer drug interactions and can be given with certain protease inhibitors (16). Updated treatment recommendations can be found at the CDC Web site (http://www.cdc.gov/ nchstp/tb/TB_HIV_Drugs/TOC.htm). The care of patients with HIV and TB is a rapidly evolving area of clinical practice and best accomplished by physicians and clinics skilled in the management of both diseases. HIVinfected patients with TB should be referred early. Immune reconstitution inflammatory syndrome (IRIS) should be considered if patients on HAART and TB therapy develop clinical worsening, such as new effusions, worsening infiltrates, fever, or lymphadenitises. IRIS reactions are more frequent in patients with low CD4 counts who begin antiretroviral and anti-TB treatment at the same time, and usually present during the first several weeks of treatment. When possible, delaying the initiation of antiretroviral therapy until at least 2 months after beginning anti-TB therapy is preferred (11). IRIS reactions are believed to be caused by the reconstitution of the host’s immune response and the secondary increased inflammatory response. IRIS reaction is a diagnosis of exclusion and should only be made after ruling out treatment failure or other ongoing disease processes. These reactions are usually self-limited. Therapy is supportive, and discontinuation of the anti-TB or HAART treatment is infrequently required. Some authorities recommend brief treatment with prednisone or methylprednisolone for patients with severe IRIS reactions.

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Drug-Resistant Tuberculosis Drug resistance to anti-TB drugs is a growing problem worldwide. In parts of the former Soviet Union and Asia, newly diagnosed cases have a greater than 10% risk of being MDR (resistant to at least INH and RMP). Rates of MDR-TB in newly diagnosed U.S. patients with TB are low—0.6% in U.S.born individuals and 1.2% in foreign-born persons (17). The greatest risk factors for MDR-TB are previous anti-TB treatment or close contact with a patient with known drug-resistant TB. The clinical and radiographic presentation of MDR-TB is similar to drugsusceptible TB. From a public health standpoint, MDR-TB strains are as transmissible to other persons as drug-susceptible strains. MDR-TB is much more difficult to treat and is associated with worse outcomes. In general, the treatment of MDR-TB is longer, more complex, and associated with increased toxicity because of the required use of many second-line agents. Patients with suspected or known MDR-TB should be managed by an infectious disease specialist or care giver with expertise in TB. Some basic tenets of the treatment of resistant TB are as follows: 1. Never add a single drug to a failing regimen. 2. When resistance is confirmed, use at least three drugs known to be active against the isolate. 3. Use DOT throughout the entire course of treatment. 4. Therapy should be taken for at least 24 months and at least 18 months after bacteriologic conversion (10). Rarely, lung resection surgery is indicated for the treatment of localized disease unresponsive to drug therapy, for patients unable to tolerate medical treatment, or for patients with massive hemoptysis (18). Referral to specialized centers with expertise in this area is recommended.

Treatment during Pregnancy and Lactation Treatment of TB in pregnant and lactating women is similar to treatment of nonpregnant women. Nine months of daily INH and RMP (plus EMB until results of initial drug susceptibility tests are known) is the regimen most frequently used and is highly effective (11). INH, RMP and EMB have excellent long-term safety records for the treatment of TB during pregnancy. Because of limited information about teratogenicity, PZA is not used routinely during pregnancy in the United States although it is used by many TB-control programs worldwide. Aminoglycosides such as streptomycin should not be used to treat TB during pregnancy because of the risk of ototoxicity in the fetus. Pregnant women also are at increased risk for INHassociated peripheral neuropathy and should routinely receive pyridoxine 25 mg daily to prevent this complication. Breast-feeding is safe during antiTB chemotherapy (19).

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Liver Disease INH, RMP and PZA can all cause hepatitis, as well as additional liver injury in patients with underlying chronic liver disease. Patients with an AST elevated greater than three times the upper normal limit can be treated with regimens that exclude PZA, such as INH and RMP for 9 months, and initially with EMB until drug susceptibility testing results return. Patients with severe chronic disease should be referred to a TB specialist for treatment. All patients should have frequent clinical and laboratory monitoring during treatment (11).

Renal Insufficiency and Renal Failure Normal doses of INH and RMP can be given in renal failure as these agents are eliminated by biliary excretion. Patients with chronic renal disease are at an increased risk of peripheral neuropathy and should receive pyridoxine 25 to 50 mg per day. Most anti-TB drugs can be given, even to patients on hemodialysis, with appropriate dose adjustments (3).

Tumor Necrosis Factor Antagonists and Tuberculosis Tumor necrosis factor (TNF) alpha plays an important role in the formation of granulomas. Patients treated with TNF antagonists such as infliximab have been reported to have an increased risk of developing reactivation TB. Tuberculin skin testing is recommended before beginning TNF antagonist therapy. A pretreatment chest radiograph should be considered for patients with other risk factors for TB and those originating from countries or settings with a high prevalence of TB. Patients should receive INH for treatment of latent TB infection if their tuberculin skin test is positive. TB and other opportunistic pathogens should be considered in the differential diagnosis and initial management when persons receiving these agents develop respiratory symptoms (20).

Treatment of Latent Tuberculosis Infection Treatment of latent tuberculosis infection (LTBI) is the treatment of persons who are infected by MTB, but who have not developed active tuberculosis. Treatment of LTBI is recommended to decrease the risk that persons infected with MTB will later develop active TB. The number of viable tubercle bacilli in persons with LTBI is low, and treatment with a single drug is adequate to eradicate the persisting bacilli. Latent tubercle bacilli are metabolically quiescent and divide slowly, however, treatment of LTBI must be taken for up to 9 months. Large, well-designed clinical trials conducted throughout the world have demonstrated the efficacy of treatment of LTBI in non-HIV infected

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persons and purified protein derivative (PPD)-positive HIV-infected individuals. Treatment of LTBI with INH is approximately 70% effective (up to 90% in highly adherent individuals) for the prevention of TB. In non-HIV infected persons, the duration of protection has been documented for up to 19 years and can be lifelong; the benefit is shorter among HIV-infected persons. Treatment of LTBI is most effective when focused toward persons and groups at high risk for TB infection and those at high risk for developing active TB after infection. Currently, the CDC recommends targeted screening for TB in at-risk groups (Table 25-5) (21). The groups who can benefit most from treatment of LTBI are persons with recent TB infection (because the risk of developing active TB is greatest during the first 2 years after infection), close contacts of patients with active TB, and persons with clinical conditions, such as HIV-infection, that place them at increased risk to develop active TB. Routine screening of low-risk groups is not recommended. Definitions for a positive PPD skin test in different risk categories are listed in Table 25-6. Recent PPD skin test conversion is defined as an increase in the size of the PPD skin test reaction by at least 10 mm induration within a 2-year period. Targeted screening of high-risk groups facilitates detection of persons with active TB who need combination chemotherapy and persons with LTBI who can benefit from preventive therapy. Identification and treatment of these groups has both individual and public health benefits. A decision to treat a patient for LTBI must balance the patient’s risk for developing active TB versus the risks of drug treatment. The principal safety consideration about treatment of latent TB infection is INH-related hepatotoxicity. Although minor transient liver function test abnormalities occur in 10% Table 25-5 Targeted Screening for Tuberculosis Persons and groups at high risk for exposure to or infection with tuberculosis (TB)

Recent close contacts of persons known to or suspected to have TB Foreign-born persons from high-burden countries Residents and employees of congregate settings (nursing home, prisons, etc.) Health care workers Persons and groups at increased risks for developing TB after infection

HIV-infected persons Persons who have recently converted their PPD skin test from negative to positive Persons with other chronic immunosuppressive conditions such as silicosis, diabetes mellitus, chronic renal failure, underlying malignancy, and those receiving immunosuppressive therapy with corticosteroids, antineoplastic chemotherapy, and TNF alpha antagonists such as infliximab Persons with chest radiographic findings such as apical scarring, fibrotic residual lesions or calcifications suggestive of earlier TB Adapted from the American Thoracic Society/Center for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-47. Abbreviations: PPD, purified protein derivative; TNF, tumor necrosis factor.

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Table 25-6 Treatment considerations in latent TB infection Patient Category Recent contact with a person with active TB and the following categories: Child < 5 years* HIV-infected person* Immunosuppressed person* Persons at risk to develop active TB+ No high-risk factor present but belongs to high-incidence group# No high-risk factor present, low-incidence group

Treat when PPD test

<5 mm <5 mm <5 mm ≥5 mm ≥10 mm ≥15 mm

Drug therapy

Isoniazid 5mg/kg po daily for 9 months Isoniazid 5mg/kg po 2 × wk for 9 months with directly observed therapy Vitamin B6 50 mg/d (to prevent peripheral neuropathy) * Close contacts of patients with active TB should undergo PPD skin testing at the time of initial evaluation. Because of the very high risk of developing active TB, these patients should be started on treatment even if their skin test is negative. Repeat PPD test in 3 months. In a healthy child, treatment may be stopped if the second PPD test is negative. + Risk factors include HIV infection; close contact with newly diagnosed TB person; chest x-ray with fibrotic lesions suggestive of TB; persons with diabetes mellitus, silicosis, leukemia or lymphoma, chronic renal failure, malnutrition, gastrectomy, or jejunoileal bypass; treatment with immunosuppressive therapy; or recent PPD skin test conversion. # High-incidence groups include foreign-born persons from high-prevalence areas, medically underserved Americans, residents and staff of long-term care facilities or other institutions, including correctional facilities and homeless shelters. (reproduced with permission from Furin JJ, Johnson JL. Managing Tuberculosis in the United States: An Update. Resident & Staff Physician 2004;50:12-16,19-21.)

to 20% of persons receiving INH preventive therapy, the risk of symptomatic hepatitis caused by INH is low—approximately 1% to 3% per 1000 persons— and increases with age (22, 23). Heavy ethanol consumption (especially on a daily basis), preexisting liver disease, pregnancy, and the early postpartum period are associated with a greater risk for INH-related hepatotoxicity. Active TB must be excluded before beginning treatment of LTBI. Treatment of active TB with a single drug is inadequate and risks the development of acquired drug resistance. Routine measures to exclude active TB include history and physical examination, a chest radiograph, and additional tests based on specific signs and symptoms (Figure 25-1). Sputum should be examined for AFB and other pathogens in persons with cough or other respiratory symptoms and those with radiographic abnormalities consistent with remote or current TB. The clinician should be cautious in attributing chest radiographic lesions to old, inactive TB, particularly in persons with any respiratory symptoms. Baseline hepatic function testing (serum AST and total serum bilirubin) is recommended for HIV-infected persons, pregnant women, women within 3 months postpartum, persons with chronic liver disease, persons who regularly drink ethanol, and persons receiving other hepatotoxic medications. Active hepatitis or cirrhosis are relative contraindications to INH preventive therapy.

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Figure 25-1

Regimens for Treatment of Latent Tuberculosis Infection Regimens for treatment of LTBI are summarized in Table 25-7. Nine months of daily treatment with INH (5 mg/kg/day; maximum 300 mg/day) is now recommended in the United States for the treatment of LTBI for children and most adults. INH preventive therapy also can be given (twice weekly at a dose of 15 mg/kg/dose; maximum 900 mg/dose) under direct supervision. Six months of treatment with INH is an alternative when longer treatment is not feasible. INH has few significant interactions with other drugs, including antiretrovirals. Four months of daily RMP (10 mg/kg/day; maxi-

6 months (180 doses)

4 months (120 doses)

INHa

Rifampin

a

5 mg/kg (up to maximum 300 mg/day) 5 mg/kg (up to maximum 300 mg/day) 10 mg/kg (up to 600 mg/day)

Daily Dose

15 mg/kg/dose (up to maximum 900 mg/day) 15 mg/kg/dose (up to maximum 900 mg/day) —

Twice Weekly Dose

Hepatitis; rash; thrombocytopenia; orange discoloration of urine and body fluids

Hepatitis; peripheral neuropathy; rash

Side effects

Potent hepatic enzyme inducer; many important drug interactions including warfarin, hormonal contraceptives, and antiretrovirals especially protease inhibitors

Risk of hepatitis increases with age. No drug interactions with antiretroviral agents.

Comment

Pyridoxine 25 to 50 mg daily should be administered to persons taking INH to prevent INH-associated peripheral neuropathy

INH

9 months (270 doses)

Duration (Minimum Number of Doses)

a

Drugs

Table 25-7 Regimens for the treatment of latent TB infection

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mum 600 mg/day) is an alternative regimen for patients intolerant to INH, those exposed to patients with INH-resistant TB, and in circumstances where it is unlikely that a 9-month course of treatment can be completed. In 2000, a 2-month preventive therapy regimen using RMP and PZA was introduced based on acceptable efficacy and safety in HIV-infected adults. Unfortunately, severe hepatotoxicity and several deaths occurred when this regimen was more widely used in non-HIV infected persons. The cause of the increased hepatotoxicity is unknown. This regimen is no longer recommended except in special situations where other regimens cannot be used and with biweekly monitoring of hepatic function tests (24). Several large clinical trials are now underway comparing the efficacy of 3 months of once weekly INH and rifapentine, a long acting rifamycin, for the treatment of LTBI; results are anticipated in 2010. If effective, this 3-month, 12-dose regimen should be more convenient for patients and physicians and improve completion rates for treatment of latent TB infection.

Monitoring Persons Receiving Treatment of Latent Tuberculosis Infection Monthly follow-up is recommended for all persons receiving treatment of LTBI. Clinical monitoring based on patient education and questioning patients about signs and symptoms of INH toxicity is safe and satisfactory for most patients (23). All persons receiving INH preventive therapy should be instructed to stop taking INH and seek prompt medical attention if symptoms of hepatotoxicity, such as nausea, vomiting, dark urine, icterus, abdominal pain (particularly right upper quadrant pain), or anorexia develop. Routine liver function monitoring should be done during followup for HIV-infected persons, pregnant women, persons with chronic liver disease, and regular ethanol drinkers (21). INH should be stopped if serum AST levels are greater than 3 times the upper limit of the laboratory’s normal value in symptomatic individuals or if serum AST levels exceed 5 times the upper limit of normal in asymptomatic persons. INH hepatotoxicity is usually reversible if the drug is stopped promptly when patients develop symptoms and signs of toxicity.

Tuberculosis Prevention and Control In the United States, the emphasis of TB control is on the rapid diagnosis and treatment of persons with active TB, combined with targeted tuberculin skin test screening to identify cases of latent TB. Worldwide, early diagnosis and treatment of active cases is again emphasized, but rather than screen for latent TB, BCG vaccination is used for prevention. BCG vaccination is effective against serious forms of disease in children, but has variable efficacy in adults (3).

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New Developments Intense research for alternatives to the TST for the diagnosis of latent TB infection is ongoing. A whole-blood interferon-gamma assay, an in vitro T-cell based assay using specific MTB antigens, has potential benefits for screening and has been recently recommended by the CDC as an acceptable alternative to tuberculin skin testing for contact investigations, screening of immigrants, and for sequential testing of health care workers. It is not as reliable in immunocompromised persons (25). On the treatment front, fluoroquinolones such as moxifloxacin are currently being evaluated in clinical trials for their potential role in shortening the required duration of treatment of drug-susceptible TB. New classes of drugs with novel mechanisms of action such as the nitroimidazopyran PA-824 and the diarylquinoline TMC207 are in preclinical and early clinical testing for TB treatment.

Summary Tuberculosis remains a major global health problem with an estimated one third of the world’s population infected with MTB. Despite great strides in controlling TB in industrialized nations, the worldwide burden of disease will ensure a steady stream of cases in the United States. MDR-TB and TB in HIV-infected persons have created new challenges. Expanded use of DOT and the development of better diagnostic tests, new drugs, and vaccines that allow a shorter duration of treatment are key needs for global TB control.

REFERENCES 1. World Health Organization. Global tuberculosis control: Surveillance, planning, financing: WHO report 2005. Geneva: World Health Organization. Report No. WHO/HTM/TB 2005.349. 2. Centers for Disease Control and Prevention. Trends in tuberculosis—United States. MMWR. 2005;54:245-9. 3. Frieden TR, Sterling TR, Munsiff SS,Watt CJ, Dye C. Tuberculosis. Lancet. 2003;362:887-99. 4. Dunlap NE, Bass J, Fujiwara P, et al. Diagnostic standards and classification of tuberculosis in adults and children. Am J Resp Crit Care Med. 2000;161:1-40. 5. Comstock GW, Livesay BT,Woolpert SF. The prognosis of a positive tuberculin reaction in childhood and adolescence. Am J Epidemiol. 1974;99:131-8. 6. Khan MA, Kovnat DM, Bachus B, et al. Clinical and roentgenographic spectrum of pulmonary tuberculosis in the adult. Am J Med. 1977;62(1):31-8. 7. Palmer PE. Pulmonary tuberculosis—Usual and unusual radiographic presentations. Sem Roentgenol. 1979;14:204-43. 8. Hobby GL, Holman AP, Iseman MD, Jones J. Enumeration of tubercle bacilli in sputum of patients with pulmonary tuberculosis. Antimicrob Agents Chemother. 1973;4:94-104. 9. Drobniewski FA, Caws M, Gibson A, Young D. Modern laboratory diagnosis of tuberculosis. Lancet Infect Dis. 2003;3:141-7. 10. Nachega JB, Chaisson RE. Tuberculosis drug resistance: a global threat. Clin Infect Dis. 2003;36:S24-30. 11. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-62. Available at http://www.thoracic.org/adobe/statements/rr5211.pdf.

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12. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest. 1991;99:465-71. 13. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med. 1994;330:1179-84. 14. Fanning A. Tuberculosis: 6. Extrapulmonary disease. CMAJ. 1999;160:1597-603. 15. Perlman DC, el-Sadr WM, Nelson ET, Matts JP,Telzak EE, Salomon N, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virusrelated immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect Dis. 1997;25:242-6. 16. Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med. 1999;340:367-73. 17. Centers for Disease Control and Prevention. Trends in tuberculosis—United States, 1998-2003. MMWR Morb Mortal Wkly Rep. 2004;53(10);209-14. 18. Pomerantz B J, Cleveland JC Jr., Olson HK, Pomerantz M. Pulmonary resection for multi-drug resistant tuberculosis. J Thorac Cardiovasc Surg. 2001;121:448-53. 19. American Academy of Pediatrics Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics. 1994;93:137-50. 20. Wallis RS, Broder MS,Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38:1261-5. 21. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med. 2000;161:S221-47. 22. LoBue PA, Moser KS. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am J Respir Crit Care Med. 2003;168:443-7. 23. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA. 1999;281:1014-8. 24. American Thoracic Society/Centers for Disease Control and Prevention. Update: Adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for the treatment of latent tuberculosis infection—United States, 2003. MMWR. 2003;52:735-9. 25. Mazurek GH, Jereb J, LoBue P, et al. Guidelines for using the QuantiFeron-TB test for detecting Mycobacterium tuberculosis infection. MMWR Recomm Rep. 2005;54(RR-15): 49-55.

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Part VII

Deep Fungus Infections

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Chapter 26

Blastomycosis CAROL A. KAUFFMAN, MD

Key Learning Points 1. Blastomycosis is acquired from the environment through the inhalation route. 2. Cutaneous lesions reflect hematogenous dissemination. 3. With the exception of acute pulmonary blastomycosis, which is rarely seen, all patients with blastomycosis require treatment with an antifungal agent. 4. Itraconzole is the agent of choice for treatment of mild to moderate blastomycosis. 5. Amphotericin B is reserved for life-threatening and CNS blastomycosis

Epidemiology Blastomycosis is an endemic mycosis that is caused by Blastomyces dermatitidis, a dimorphic fungus that exists as a mold in the environment and as a yeast in vivo. The organism is present in many diverse geographic areas worldwide. Most cases are noted in the south central and north central United States, but occasional cases are reported from areas, such as Colorado and Florida, that are outside the usual boundaries. The endemic area for blastomycosis overlaps that of histoplasmosis but extends further north into Wisconsin, Minnesota, and the southern portions of the midwestern Canadian provinces. B. dermatitidis is also found in the Middle East and throughout Africa.

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Amphotericin B is now rarely used for treating non-life-theatening forms of blastomycosis Lipid formulations of amphotericin B are preferred over standard amphotericin B because they have less nephrotoxicity and fewer infusion reactions.

The ecology of B. dermatitidis has not been totally clarified. The presumption is that soil or decaying wood are natural reservoirs; however, it is very difficult to isolate the organism directly from these materials. In one large outbreak, students who explored a beaver lodge developed acute blastomycosis (1). Both the lodge and decomposed wood on the pond bank yielded B. dermatitidis. Most persons who develop blastomycosis are healthy middle-aged men whose vocation or avocation places them outside in the environment in the endemic area. Both hunters and their dogs have acquired blastomycosis, presumably after exposure to the same environmental source (2).

Pathogenesis Infection begins when the conidia (or spores) of B. dermatitidis are inhaled into the alveoli. The filamentous form converts to the yeast form in the lungs. Both neutrophils and cell-mediated immunity are important in the response to infection with B. dermatitidis. Blastomycosis tends to be more severe in those with cell-mediated immune dysfunction, but it does not seem to occur more frequently in this population, in contrast to histoplasmosis (3). This likely reflects both the lack of environmental exposure to B. dermatitidis and the importance of neutrophils in host defense against B. dermatitidis. In most patients with blastomycosis, hematogenous dissemination occurs but is rarely associated with any clinical manifestations. It is common for patients to present with cutaneous or other organ involvement after the pulmonary lesion has healed. Although patients often assume that skin lesions develop after direct inoculation, this is only very rarely the case (4). It should be presumed that all extrapulmonary lesions represent hematogenous dissemination.

Clinical Manifestations Acute pulmonary blastomycosis is usually manifested by fever, cough, myalgias, and a localized pulmonary infiltrate. Most patients are thought to have an atypical bacterial pneumonia and receive antibiotics. A fungal infection is only considered when the infection does not clear. Most patients are clinically

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improved by the time the diagnosis is made. Overwhelming pulmonary disease with adult respiratory distress syndrome occurs uncommonly and is a life-threatening event (5). Subacute or chronic pulmonary blastomycosis resembles tuberculosis and chronic cavitary histoplasmosis. Fever, night sweats, weight loss, and fatigue are common; and patients manifest dyspnea, cough, sputum production, and hemoptysis. The radiographic findings, upper lobe cavitary infiltrates, are the same as those noted with either tuberculosis or chronic histoplasmosis. Other radiographic findings include mass-like lesions that resemble carcinoma and many nodular lesions. Pleural effusions and hilar or mediastinal lymphadenopathy each occur in approximately 20% of patients (6). Patients with disseminated blastomycosis often have no pulmonary symptoms or have a history of an undiagnosed lower respiratory tract infection that has resolved. Cutaneous lesions are the most common manifestation of dissemination. The lesions, which are generally multiple, are well-circumscribed papules, nodules, or plaques. They can become verrucous and develop punctate draining areas in the center, or they may ulcerate. The verrucous lesions are rarely painful, but ulcerating lesions may be extremely painful. The lesions are most common on the face and extremities but can appear anywhere. The skin lesions of blastomycosis mimic those caused by nontuberculous mycobacteria, coccidioidomycosis, bromide use, and pyoderma gangrenosum. Other manifestations of disseminated blastomycosis include osteoarticular involvement that may be contiguous to cutaneous lesions or at a distant site and oropharyngeal or laryngeal nodules that mimic cancer. Genitourinary involvement is also common and may present as a prostatic nodule with or without symptoms of prostatism. Central nervous system (CNS) involvement is rare; chronic meningitis or an intracerebral mass lesion are both possible.

Diagnosis The diagnosis of blastomycosis is definitively established when the organism is grown from a tissue or fluid sample (7). B. dermatitidis takes several weeks to grow at room temperature in the mold form. Once growth occurs, firm identification can be made quickly with the use of highly specific and sensitive DNA probes. Before the growth of the organism in culture, a tentative diagnosis of blastomycosis often can be made by examination of tissue or fluids from involved sites. B. dermatitidis is distinctive in its appearance. The organisms are large (8-10 µm), thick-walled yeasts that have a single, broad-based bud, distinguishing them from Cryptococcus, Coccidioides, and Histoplasma. When skin lesions are present, biopsy should be done for both culture and histopathology. Pseudoepitheliomatous hyperplasia is the typical pathological finding, and the yeasts can be visualized by methenamine silver or

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periodic acid Schiff stains. In patients who have pulmonary lesions, sputum, bronchoalveolar lavage fluid, and lung biopsy specimens should be sent for both culture and visual examination. The distinctive yeast forms can be seen on potassium hydroxide or calcofluor preparations of sputum and bronchoalveolar lavage fluid. Papanicolaou stains on cytological examination readily demonstrate the distinctive yeast forms of B. dermatitidis. The standard fungal serological assays, immunodiffusion and complement fixation, are neither sensitive nor specific for blastomycosis and should not be done. Other tests that should be considered to help define the extent of involvement and length of therapy with disseminated blastomycosis include culture of urine obtained before and after prostatic massage and a bone scan to define osteoarticular involvement.

Treatment The Mycoses Study Group, under the auspices of the Infectious Diseases Society of America, has published guidelines for the treatment of blastomycosis (Table 26-1) (8). Their recommendations are based on several multicenter, nonrandomly assigned, open-label treatment trials conducted by the Mycoses Study Group and retrospective and prospective reports from individual institutions.

Table 26-1 Recommended Treatment Regimens for Blastomycosis Type of Infection First-Line Therapy

Second-Line Therapy

Pulmonary

Mild, moderate Severe

Itraconazole, 200-400 mg qd AmBisome, 3-5 mg/kg/d or Abelcet, 5 mg/kg/d until stable, then change to itraconazole 400 mg qd

Fluconazole, 800 mg qd Amphotericin B, 0.7-1 mg/kg/d until stable, then change to itraconazole 400 mg qd

Itraconazole, 200-400 mg qd AmBisome, 3-5 mg/kg/d or Abelcet, 5 mg/kg/d until stable, then change to itraconazole 400 mg qd AmBisome, 3-5 mg/kg/d or Abelcet, 5 mg/kg/d, total dose unknown; consider long-term therapy with fluconazole or itraconazole 400 mg qd

Fluconazole, 800 mg qd Amphotericin B, 0.7-1 mg/kg/d until stable, then change to itraconazole 400 mg qd

Disseminated

Mild, moderate Severe

CNS

Amphotericin B, 0.7-1 mg/kg/d, total dose 2 g; consider longterm therapy with fluconazole 800 mg or itraconazole 400 mg qd

Modified with permission from: Chapman SW, Bradsher RW, Campbell DG, et al. Guidelines for the management of patients with blastomycosis. Clin Infect Dis. 2000;30:679-83. Abbreviations: d = day; q = every.

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The overall recommendations are similar to those for all the endemic mycoses. Patients who have mild to moderate infection should be treated with an azole agent, and patients who have severe illness should be treated with amphotericin B as initial therapy. All patients with blastomycosis, even a single cutaneous lesion, should be treated with an antifungal agent. Itraconazole is the drug of choice for the treatment of mild to moderate blastomycosis (9). This includes patients with skin lesions with or without osteoarticular involvement, some with chronic pulmonary blastomycosis, the occasional patient diagnosed with acute pulmonary blastomycosis, and others with focal involvement not including the CNS and with few or no systemic symptoms. Most cases of blastomycosis fall into this category. The usual dosage is 200 mg once or twice daily. When the daily dosage of itraconazole is 400 mg, best absorption is achieved by giving 200 mg twice daily. Itraconazole capsules require both food and acid for absorption; agents that decrease gastric acid must be avoided. If itraconazole suspension is used, it is given on an empty stomach and does not require acid for absorption. Fluconazole is not as effective as itraconazole for blastomycosis (10). However, if the patient is unable to tolerate itraconazole, fluconazole can be used; but the dosage should be 800 mg daily. There is little reported experience with voriconazole for the treatment of blastomycosis (11); because of this, voriconazole should not be a first-line agent for this infection. The echinocandins, caspofungin and micafungin, seem to have no activity against B. dermatitidis and should not be used. Amphotericin B is reserved for those patients who have severe infection with B. dermatitidis. This will include those with overwhelming pulmonary infection, CNS involvement, the rare patient who has widespread disseminated visceral as well as cutaneous involvement, and most patients who are immunosuppressed. The usual daily dosage of amphotericin B is 0.7 to 1 mg/kg. However, most clinicians now use a lipid formulation of amphotericin B at a dosage of 3 to 5 mg/kg daily. Either liposomal amphotericin B (AmBisome) or amphotericin B lipid complex (Abelcet) can be used. These agents help decrease the nephrotoxicity and infusion reactions inherent in the use of amphotericin B. With the exception of CNS infection, it is now uncommon for a patient to receive amphotericin B for the entire course of therapy. As soon as the patient has shown improvement and is able to take oral medications, it is appropriate to change to oral itraconazole, 200 mg twice daily. For patients with CNS blastomycosis, amphotericin B deoxycholate or a lipid formulation of amphotericin B is usually administered over a period of approximately 6 weeks (total dose of 2 g amphotericin B deoxycholate) before switching to an azole. Either itraconazole, 200 mg twice daily, or fluconazole, 800 mg daily, has been used for long-term treatment of CNS blastomycosis. The length of time required for treatment of blastomycosis depends on the extent of the infection, the immune status of the host, and the response

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to antifungal therapy. Acute pulmonary blastomycosis can be treated for 3 to 6 months, but chronic pulmonary infection will require 6 to 12 months of therapy. Although skin lesions often begin to resolve within the first month of therapy, treatment should continue for 6 to 12 months to achieve a mycological cure. Osteoarticular involvement requires therapy for at least a year and sometimes longer. Patients with CNS blastomycosis and immunosuppressed patients may require lifelong suppressive therapy with an azole. The decision about length of therapy in these patients is individualized based on their clinical response and state of immunosuppression. The response rates for itraconazole treatment of patients with pulmonary and cutaneous manifestation of blastomycosis are 90% to 95% (9). Relapses do occur and are usually related to inadequate length of therapy or poor patient compliance with the antifungal regimen. Generally, relapses can be treated the same as the initial infection with the exception that oral azole therapy should be prolonged to ensure eradication of the organism.

REFERENCES 1. Baumgardner DJ, Buggy BP, Mattson BJ, Burdick JS, Ludwig D. Epidemiology of blastomycosis in a region of high endemicity in north central Wisconsin. Clin Infect Dis. 1992;15:629-35. 2. Chapman SW, Lin AC, Hendricks KA, Nolan RL, Currier MM, Morris KR, et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect. 1997;12:219-28. 3. Pappas PG,Threlkeld MG, Bedsole GD, et al. Blastomycosis in immunocompromised patients. Medicine (Baltimore). 1993;72:311-25. 4. Gray NA, Baddour LM. Cutaneous inoculation blastomycosis. Clin Infect Dis. 2002;34: E44-9. 5. Meyer KC, McManus EJ, Maki DG. Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome. N Engl J Med. 1993;329:1231-6. 6. Sheflin JR, Campbell JA,Thompson GP. Pulmonary blastomycosis: findings on chest radiographs in 63 patients. AJR Am J Roentgenol. 1990;154:1177-80. 7. Areno JP 4th, Campbell GD Jr., George RB. Diagnosis of blastomycosis. Semin Respir Infect. 1997;12:252-62. 8. Chapman SW, Bradsher RW Jr., Campbell GD Jr., Pappas PG, Kauffman CA. Practice guidelines for the management of patients with blastomycosis. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:679-83. 9. Dismukes WE, Bradsher RW Jr., Cloud GC, Kauffman CA, Chapman SW, George RB, et al. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am J Med. 1992;93:489-97. 10. Pappas PG, Bradsher RW, Kauffman CA, Cloud GA,Thomas CJ, Campbell GD Jr., et al. Treatment of blastomycosis with higher doses of fluconazole. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1997;25:200-5. 11. Bakleh M, Aksamit AJ,Tleyjeh IM, Marshall WF. Successful treatment of cerebral blastomycosis with voriconazole. Clin Infect Dis. 2005;40:e69-71.

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Chapter 27

Candidiasis CAROL A. KAUFFMAN, MD

Key Learning Points 1. Candida species are part of the normal flora of the gastrointestinal and gernitourinary tracts and the skin in humans. 2. Candida species do not cause disease unless there are disruptions of the normal ecology of the areas they inhabit or defects in host defenses. 3. Candiduria almost always reflects colonization and not infection of the urinary tract and uncommonly requires antifungal therapy. 4. Mucocutaneous candidiasis can usually be treated with topical antifungal agents; focal invasive and disseminated candidiasis require treatment with systemic antifungal agents. 5. Candidemia should always be treated with an antifungal agent, vascular catheters should be removed or replaced, and therapy should continue for two weeks after the blood cultures become negative. 6. C. albicans is the most common species to cause infection and usually can be treated with fluconazole. 7. C. glabrata infections should be treated with an echinocandin, voriconazole, or amphotericin B, but not fluconazole. andida are small (2-6 µm) yeast-like organisms that reproduce by budding. Candida species normally colonize the human gastrointestinal and genitourinary tracts and the skin. These organisms generally cause no disease unless the normal ecology of the area they inhabit is disrupted. Infections occur with major perturbations in host defenses but also with alterations in the normal flora related to antibiotic use and breakdown

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Increasingly, Candida glabrata is found as the cause of candidemia and invasive candidiasis in hospitalized patients. Five agents are now available for treatment of candidemia and invasive candidiasis: fluconazole, voriconazole, caspofungin, anidulafungin, and amphotericin B. Lipid formulations of amphotericin B are less toxic than amphotericin B deoxycholate and are preferred if amphotericin B is to be used to treat invasive candidiasis. The echinocandins are fungicidal for all species of Candida, including C. glabrata and C. krusei, which are only moderately susceptible and resistant to fluconazole, respectively. A serum assay for beta-D-glucan may prove to be useful in the diagnosis of invasive candidiasis.

of natural barriers, such as might occur with catheter insertion or surgery. Candida albicans is the most common colonizing species, Candida glabrata is the second most common, and Candida tropicalis, Candida parapsilosis, and others are found less often. Each species has characteristics that affect treatment and outcomes (Table 27-1).

Epidemiology Given the ubiquity of Candida species, it should be no surprise that candidiasis is the most common opportunistic fungal infection. Several decades ago, the major groups at risk for serious Candida infections were those who had a hematologic malignancy, were neutropenic, or had received corticosteroids or cytotoxic agents. This has changed so that patients developing serious Candida infections now are more likely to be those who are in the intensive care unit and who are on broad-spectrum antibiotics, have central venous catheters in place, have had surgical procedures, require

Table 27-1 Characteristics of Candida Species That Cause Human Infection Species

Characteristics

Candida albicans Candida glabrata

Most common species; usually susceptible to fluconazole Increasingly isolated; often resistant to fluconazole; more common in older adults Responsible for outbreaks related to contaminated fluids; common in neonatal units; associated with central venous catheters Perhaps more virulent; more common in cancer patients Resistant to fluconazole; uncommon Resistant to amphotericin B; uncommon

Candida parapsilosis

Candida tropicalis Candida krusei Candida lusitaniae

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hemodialysis, are receiving parenteral nutrition, and have high APACHE (Acute Physiology and Chronic Health Evaluation) scores (1). Candida species are the fourth most common cause of nosocomial bloodstream infection, and the third most common among ICU patients (2). C. glabrata is increasingly found as a cause of candidemia and invasive candidiasis in hospitalized patients. Another group at high risk for Candida infections are patients who have AIDS. Before the introduction of effective antiretroviral therapy, candidiasis was the most common opportunistic infection in AIDS patients. The manifestations of disease in this population are almost entirely recurrent mucocutaneous infections, especially oropharyngeal candidiasis and esophagitis. These mucosal infections are linked directly to deficient cell-mediated immunity as reflected in low CD4 cell counts. Today, mucosal candidiasis is seen almost entirely in patients who have refractory HIV infection and in those who have never received medical care for AIDS.

Pathogenesis Candida species cause infection when they grow to great numbers on the mucous membranes they normally inhabit or when they enter areas of the body in which they normally do not live, such as blood and other sterile sites. Escape from the gastrointestinal tract occurs when the mucosa is disrupted as might occur with cytotoxic chemotherapy in a neutropenic patient, during a surgical procedure, or with bowel perforation. The skin is the source of infection when an indwelling catheter is in place, allowing the organism to gain access at the entry site. The genitourinary tract is not a common source for systemic invasion by yeasts; however, with obstruction of the urinary tract, bloodstream invasion can occur. Once Candida gain access to the bloodstream, widespread hematogenous dissemination occurs. The primary host defense against invasion by Candida species is phagocytosis and killing of the yeasts by neutrophils, monocytes, and macrophages. The usual pathological picture is that of many microabscesses in many different organs. Ironically, although T cells do not play a role in defense against invasive candidiasis, they are the major host defense in controlling Candida growth at mucosal surfaces. Persistent and recurrent infections of mucous membranes occur in patients who have deficient T-cell immunity, but it is unusual to see candidemia result from these infections.

Clinical Manifestations The manifestations of candidiasis vary from localized mucous membrane infection to life-threatening invasive disease. The host immune response is the critical determinant of both the extent and the outcome of infection.

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Mucocutaneous Infections Oropharyngeal candidiasis or thrush is characterized by the formation of white plaques on the buccal mucosa, palate, oropharynx, and tongue. The plaque-like material scrapes off easily with a tongue depressor revealing an erythematous, nonulcerated mucosa. In adults who wear upper dentures, a form of candidiasis termed denture stomatitis, is manifested by pain and erythema of the palate, but plaques are rarely noted. Thrush is seen in patients who have AIDS, leukemia, or received a transplant. It is also noted in those who use inhaled corticosteroids, have received radiation therapy to the head and neck area, and have been given broad-spectrum antibiotics. The appearance of thrush in a previously healthy individual with no known risk factors should raise the suspicion for HIV infection. Esophagitis may occur with or without oropharyngeal candidiasis. Patients with Candida esophagitis have substernal odynophagia as the prominent symptom. Almost always, the development of Candida esophagitis is related to immune dysfunction and not simply to local factors. Although seen most often in AIDS patients, esophagitis also occurs in patients with leukemia and in other immunosuppressed hosts. Candida species cause skin infection mostly in the intertriginous areas. The lesions are erythematous, frequently pustular, and pruritic. The presence of smaller satellite lesions helps differentiate candidiasis from tinea infections. A patient with intertriginous candidiasis should be checked for diabetes mellitus. However, most patients have no underlying medical problem but merely large folds of skin under which the organisms grow luxuriantly. Candida species also cause onychomycosis, and if fingernails are affected this is more likely to be caused by Candida than dermatophytes. Chronic mucocutaneous candidiasis is a rare syndrome; it is likely related to a specific T-cell defect to Candida and is characterized by thrush, vaginitis, onychomycosis, and hyperkeratotic skin lesions on the face, scalp, and hands. The lesions are disfiguring and recur quickly when antifungal therapy is stopped. Some patients have associated endocrinopathies, including hypoparathyroidism, hypothyroidism, and hypoadrenalism. Most patients have the initial onset of this disease in childhood.

Focal Invasive Infections Candida species have been noted to cause invasive infections in all organ systems, but the most common sites are the urinary tract, the abdomen, osteoarticular structures, and the eye. Candiduria is exceedingly common in hospitalized patients. Predisposing factors include indwelling urinary devices, diabetes mellitus, broad-spectrum antibiotics, and structural abnormalities (3). Candiduria is not synonymous with Candida urinary tract infection (UTI), and it is highly likely that most patients with candiduria are merely colonized. When Candida infection is

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present, the symptoms do not differ from those seen with bacterial cystitis or pyelonephritis. Development of a fungus ball, which is a mass of fungal hyphae, can cause obstruction of the collecting system; persistent infection and candidemia can ensue. Abdominal abscesses and peritonitis frequently contain Candida species in addition to bacteria. Acute necrotizing pancreatitis, bowel perforation, and anastomotic leaks after bowel surgery place the patient at increased risk for invasive candidiasis (4). The development of Candida peritonitis in patients on continuous ambulatory peritoneal dialysis usually occurs after previous episodes of bacterial peritonitis. The patient has fever, nausea, and abdominal pain, and the dialysate becomes cloudy. This is a difficult infection to treat and frequently leads to loss of the peritoneum for further dialysis. Osteoarticular infections follow hematogenous seeding of bones, especially intervertebral disk spaces, or direct inoculation with an intra-articular injection, a surgical procedure, or trauma. Patients who use intravenous drugs are also at risk for osteoarticular Candida infections. In the case of vertebral osteomyelitis, the symptoms of back pain and fever often occur weeks after an episode of fungemia (5). Sternal osteomyelitis occurs after median sternotomy and is manifested by pain, drainage from the surgical site, and few systemic symptoms (6). The manifestations of septic arthritis caused by Candida are generally less acute than those noted with bacterial joint infections. Prosthetic joint infections with Candida usually occur at the time of implantation and lead to increasing pain and joint dysfunction. Endophthalmitis arises from either hematogenous spread during an episode of fungemia (endogenous infection) or as a result of trauma or ophthalmic surgery, most often lens implantation (exogenous infection) (7,8). The symptoms include visual loss and pain in the eye. When lens implantation is accompanied by Candida infection, almost always the device must be removed. Hematogenous seeding leads initially to chorioretinitis; this is often asymptomatic. Without treatment, the infection progresses to involve the vitreous body at which point visual loss is common. At the chorioretinitis stage, characteristic white exudates are visible in the retina, and the diagnosis can be made by appearance alone. Once vitreitis occurs, it is difficult to visualize the retina, and vitreous aspiration is needed to help define the cause of the infection.

Candidemia and Disseminated Candidiasis Candidemia is the most obvious manifestation of disseminated Candida infection. Candida species obtained from a blood culture should never be considered a contaminant. Further studies to define the source and the extent of the infection should always be undertaken. Risk factors for candidemia include broad-spectrum antibiotics, central intravenous catheters, parenteral nutrition, renal failure, surgical procedures involving the gastrointestinal tract, neutropenia, and corticosteroid therapy. The attributable

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death from candidemia remains close to 40% despite new antifungal agents active against Candida (9). Patients can have septic shock and extensive visceral invasion with Candida with persistently negative blood cultures. The clinical picture of sepsis with disseminated candidiasis is indistinguishable from that caused by bacterial infection. The eyes, kidneys, liver, spleen, and brain are the most commonly affected sites; but virtually all organs have been noted to be involved. Clinical clues to the diagnosis of disseminated candidiasis include the appearance of painless, nonpruritic skin lesions on any area of the body. They usually are small pustules on an erythematous base but can be nodular or merely macular erythematous lesions. The development of chorioretinitis or endophthalmitis is a further clue for disseminated Candida infection (10). Chronic disseminated candidiasis, or hepatosplenic candidiasis, occurs almost entirely in leukemic patients who have had a previous episode of neutropenia, from which they have recovered (11). Daily high fevers, right upper quadrant pain, and nausea are the usual symptoms. The alkaline phosphatase level usually is elevated. On computed tomography (CT) scan, distinctive punched-out lesions are seen in liver, spleen, and sometimes kidneys. Biopsy of these lesions reveals microabscesses that contain budding yeasts.

Diagnosis Oropharyngeal and intertriginous candidiasis are generally diagnosed by clinical appearance. If uncertain, scraping the lesions and doing a potassium hydroxide preparation or a Gram stain on the material will show budding yeasts and pseudohyphae typically seen with Candida infections. The diagnosis of Candida esophagitis is often made presumptively when a patient at risk for this infection presents with odynophagia. A firm diagnosis is made by endoscopy, which shows plaque-like lesions and/or ulcerations; biopsy reveals budding yeasts and pseudohyphae in the mucosa. Endoscopy is also important to rule out other causes of esophagitis, such as herpes simplex and cytomegalovirus. The diagnosis of invasive candidiasis is more difficult. Clinical suspicion of Candida infection is essential and should be followed by a careful physical examination, seeking typical skin and retinal lesions. Culture of blood is a useful, if not very sensitive test. The automated blood culture systems used in most hospital laboratories have a sensitivity that is as high as that attained with the more labor-intensive lysis-centrifugation (Isolator tube) system. However, the sensitivity is still not high enough for clinicians to rely only on blood cultures to establish the diagnosis of invasive candidiasis. Growth of Candida species from a normally sterile body site indicates infection; but growth from sputum, urine in a patient with an indwelling bladder catheter, or an existing drainage tube does not establish infection. In almost all cases, growth of Candida species reflects colonization only.

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Growth of yeasts from blood or sterile body sites may take from 1 to 4 days, and species identification takes several days beyond that. Biopsy of lesions present in skin, bones, or other tissues should be done for culture and histopathologic examination. Material removed from pustular skin lesions at the bedside can be smeared on a slide and stained with a Gram stain; the presence of yeasts allows a rapid diagnosis. Punch biopsy of cutaneous lesions is also helpful; silver stains will reveal budding yeasts and pseudohyphae characteristic of Candida species. Previous attempts at developing a nonculture-based assay to detect Candida infections have failed. However, the new Fungitell assay, which tests for the presence in serum of βD-glucan and is a component of the cell wall of many different fungi, may prove to be useful for the earlier diagnosis of invasive fungal infections, including candidiasis (12). It is not specific for Candida and will likely be most useful in high-risk patients when used routinely to monitor changes in βD-glucan levels over time. Imaging studies, including CT scans, ultrasound, and magnetic resonance imaging, are helpful to define the extent of tissue invasion by Candida. In leukemic patients with presumed chronic invasive candidiasis, a CT scan showing the characteristic punched-out lesions in the liver and spleen is diagnostic (11).

Treatment Guidelines for the treatment of candidiasis have recently been published by the Mycoses Study Group and the Infectious Diseases Society of America (13). Randomly assigned, controlled trials have been done for mucocutaneous candidiasis in AIDS patients, candiduria, and candidemia in nonneutropenic patients. No trials have assessed therapy in patients who have focal invasive infections, such as peritonitis, endophthalmitis, and osteomyelitis. Localized infections of mucous membranes and skin are generally treated locally. Invasive candidiasis demands systemic antifungal therapy. Empirical treatment is commonly used for immunosuppressed patients who might have candidiasis, but in whom the diagnosis has not yet been established. Patients at the highest risk of infection are often given antifungal prophylaxis against Candida.

Mucocutaneous Infections Various creams, solutions, troches, and suspensions are available for treating mucocutaneous candidiasis. Clotrimazole lozenges, used 4 or 5 times daily, are simpler for patients with oropharyngeal candidiasis to take than nystatin suspension, commonly given as a swish and swallow regimen 4 times daily. Patients who have marked immunosuppression (AIDS patients

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with low CD4 counts, leukemics) and those who have denture stomatitis or are undergoing radiation therapy may not respond to local therapy. In these situations, oral fluconazole, 100 mg daily, is almost always effective. Azoleresistant thrush, although much less common now than noted before effective antiretroviral therapy became available, still occurs in patients with advanced AIDS. For these patients therapy with higher dose fluconazole, 400 to 800 mg daily, itraconazole suspension, 200 mg daily, or voriconazole, 200 mg twice daily, may be effective. Esophagitis cannot be treated with a local agent and requires systemic therapy. The usual therapy is fluconazole, 100 to 200 mg daily, for 14 to 21 days. Relief of symptoms occurs within 3 to 4 days for most patients; if the patient remains symptomatic on azole therapy, endoscopy should be done to ensure that the diagnosis is correct. For the patient who has Candida esophagitis unresponsive to fluconazole, other oral options are itraconazole suspension, 200 mg daily, or voriconazole tablets, 200 mg twice daily. Alternatively, other possibilities are intravenous amphotericin B, 0.3 to 0.5 mg/kg daily; caspofungin, 50 mg daily; anidulafungin, 100 mg daily; or micafungin, 150 mg daily. Patients who have chronic mucocutaneous candidiasis require lifelong suppressive therapy with oral azole agents.

Focal Invasive Infections The treatment of focal invasive infections varies according to the site of involvement and the species of Candida. Fluconazole has proven to be efficacious in the treatment of many different focal infections. The main drawback to the use of fluconazole is its restricted spectrum of activity; it is inactive against Candida krusei, which only rarely causes infection, and only modestly active against C. glabrata, which is an increasingly common cause of infection. For serious C. glabrata infections, fluconazole should not be used. Alternative agents are caspofungin, voriconazole, and amphotericin B. Additionally, for some serious and difficult-to-treat focal infections, treatment with amphotericin B or perhaps an echinocandin, which are fungicidal, should be used initially and followed by an azole agent. The treatment of UTI is complicated because of the difficulty in differentiating infection from colonization, which does not require treatment. Most patients with candiduria are not infected and are merely colonized. A suggested approach to the patient with candiduria is shown in Table 27-2. Many times, a simple maneuver, such as removing the indwelling catheter, will eliminate candiduria. For patients who do seem to have a Candida UTI, oral fluconazole is the preferred treatment (14). This agent achieves high concentrations in the urine and is simple to administer. Candida UTI should always be viewed as complicated and never treated with a short course of therapy. In the only blinded, randomly assigned, placebocontrolled treatment trial of candiduria, 2 weeks of fluconazole, 200 mg daily, was the regimen used.

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Table 27-2 An Approach to the Patient with Candiduria ● ●

●

●

●

Repeat urine culture to be sure not a contaminant. If repeat culture is positive and patient is asymptomatic: ● Assess predisposing factors (diabetes mellitus, antibiotics, indwelling catheters, GU tract abnormalities) and correct if possible. ● If patient remains asymptomatic, observe and do not treat. If repeat culture is positive and patient has mild symptoms suggesting lower urinary tract infection: ● Culture urine for bacteria and treat if found; check whether symptoms resolve. ● Assess predisposing factors as listed above and correct if possible. ● If bacterial infection not present and predisposing factors removed, observe clinical response and repeat urine culture to see if funguria has cleared. ● If symptoms and funguria persist, treat with fluconazole for 14 days. If repeat culture is positive and patient appears ill: ● Image the GU tract (ultrasound, CT scan) to be sure no obstruction present. ● If obstruction present, urology consult for options to relieve obstruction. ● Obtain blood cultures to look for fungemia. ● Correct predisposing factors when possible. ● Treat with fluconazole for 14 days. Repeat urine culture at end of therapy and several weeks after therapy has ended to verify that funguria has resolved.

Adapted with permission from: Kauffman CA, Hedderwick SA. Candida and other fungi. In: Yoshikawa TT, Ouslander JG, eds. Infection Management for Geriatrics in Long-Term Care Facilities. New York, NY: Marcel Dekker; 2002:449-72. Abbreviations: CT = computed tomography; GU = genitourinary.

The selection of an alternative agent to fluconazole arises most often when patients have C. glabrata UTI. Fluconazole can be tried initially, but failure is common. Other possible agents include intravenous amphotericin B deoxycholate, usually given as 1 to 3 doses only, and flucytosine, given orally at a dosage of 25 mg/kg 4 times daily. Flucytosine is an agent used almost entirely in combination with amphotericin B, but it can be used as sole therapy in this one circumstance. Other options include voriconazole or the echinocandins, but it is unclear if they will be effective. None achieve adequate concentrations in the urine, but it is possible that the concentrations attained in kidney tissue might be adequate to treat certain types of fungal infections. Bladder irrigation with amphotericin B should not be used; it eradicates only bladder colonization, requires that a catheter be placed into the bladder, and is associated with a high recurrence rate (15). Osteoarticular infections require months of therapy. Generally, intravenous amphotericin B, 0.7 mg/kg daily, or intravenous caspofungin, 50 mg daily, is given initially. This is followed with long-term therapy with an oral agent, such as fluconazole, 400 mg, or voriconazole, 200 mg twice daily (16). Fluconazole as primary therapy has been used successfully in patients with chronic osteomyelitis (7). Prosthetic joints infected with Candida almost always must be removed; a 2-stage arthroplasty procedure along with antifungal therapy has proved effective (17).

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Peritonitis associated with chronic ambulatory peritoneal dialysis can be treated with amphotericin B, fluconazole, or an echinocandin, depending on the species of Candida causing infection. For non-glabrata species, fluconazole is preferred. Intraperitoneal administration of amphotericin B is extremely irritating and should not be attempted. The catheter should be removed as soon as possible (18). Treatment of Candida eye infections varies with the extent of ocular involvement and whether the infection was acquired endogenously or exogenously. For infections associated with an intraocular lens implant, the implant should be removed if at all possible (19). Vitrectomy is usually done along with instillation of amphotericin B into the vitreous body. An antifungal agent that achieves adequate intravitreous concentrations should be given, such as fluconazole, 400 to 800 mg orally daily. For hematogenously acquired Candida eye infections, early lesions that involve only the choroid or retina can be treated effectively with systemic antifungal agents used to treat candidemia, including amphotericin B, caspofungin, fluconazole, or voriconazole. However, endophthalmitis with extension into the vitreous body require more aggressive therapy. This includes pars plana vitrectomy; instillation of amphotericin B into the vitreous body; and a systemic antifungal agent, such as fluconazole or voriconazole, that achieves adequate concentrations in the vitreous body (20). Therapy must be managed with an ophthalmologist who is experienced with fungal endophthalmitis.

Candidemia and Disseminated Candidiasis All patients with documented candidemia, even if only 1 blood culture bottle yields yeast, should receive an antifungal agent (13). The reason for this recommendation is the high rate of dissemination to major organs once Candida gains entrance to the bloodstream. Many antifungal agents are available for the treatment of candidemia (Table 27-3). These include fluconazole, caspofungin, anidulafungin, voriconazole, amphotericin B, and lipid formulations of amphotericin B. Micafungin presumably will also be effective but has not received FDA approval for this indication. Randomly assigned controlled clinical trials have been carried out primarily in nonneutropenic patient populations. In 4 different trials, it has been shown that fluconazole, voriconazole, and caspofungin are as effective as amphotericin B deoxycholate in the treatment of candidemia (13,21,22). No controlled trials have assessed the role of lipid formulations of amphotericin B for the treatment of candidemia; however, these agents can be viewed as having the same efficacy as amphotericin B deoxycholate but with less toxicity. An additional blinded randomly assigned trial showed that the combination of amphotericin B and fluconazole for the first 5 to 6 days of treatment cleared fungemia more quickly than fluconazole alone, but outcomes were no different between the 2 groups (23)

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Table 27-3 Treatment of Candidemia Antifungal Agents* ●

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●

Fluconazole, 800 mg loading dose; 400 mg daily IV or PO; preferred agent except for Candida glabrata and Candida krusei fungemia; safe; inexpensive Caspofungin, 70 mg loading dose; 50 mg daily IV; effective for all species; very few side effects; costly Anidulafungin, 200 mg loading dose; 100 mg daily IV; effective for all species; very few side effects; costly Voriconazole, 6 mg/kg bid loading dose; 3 mg/kg bid IV or PO; least experience to date; effective for all species; many drug interactions Amphotericin B deoxycholate, 0.7 mg/kg daily IV; effective for all species except Candida lusitaniae; most toxic agent; inexpensive; little role currently Lipid formulation amphotericin B (AmBisome or Abelcet), 3-5 mg/kg daily IV; effective for all species; less toxic than amphotericin B deoxycholate, but toxicity still occurs; very costly

Other Measures ● ● ● ●

Repeat blood cultures daily until no longer yield yeast Dilated eye examination should be performed by an ophthalmologist Remove or replace all intravascular catheters In patients who require central IV access, use peripheral site if at all possible for a few days to help clear the fungemia before replacing the central venous catheter

Length of Therapy ● ●

Two weeks after date of first negative blood culture If endophthalmitis present, treat until eye lesions resolved

* All are effective; choice will depend on the species of Candida, side effect profile, and cost. Abbreviations: bid = twice a day; IV = intravenous; PO = by mouth.

Fluconazole has been preferred for treatment of candidemia because it is as effective as amphotericin B and much safer. It is currently much less expensive than other agents approved for the treatment of candidemia. It should remain the treatment of choice for fungemia caused by C. albicans, C. parapsilosis, C. tropicalis, and most other species of Candida. However, fluconazole should not be used for C. glabrata or C. krusei fungemia. If C. glabrata is commonly isolated at a given hospital, a regimen other than fluconazole should be given as initial therapy until the species is identified. This will likely be caspofungin, which has the advantages of having fungicidal activity against all Candida species and having very few side effects. The echinocandins could readily become the first choice for treatment of candidemia if they were not so expensive. Candidemia has been shown to clear more quickly if all vascular catheters are removed or replaced as soon as possible (24). Daily blood cultures should be obtained to document clearing of the fungemia. Treatment should continue for 2 weeks after the date of the first negative blood culture. Chronic disseminated candidiasis is usually treated initially with a lipid formulation of amphotericin B, followed by long-term therapy with fluconazole (13). Fluconazole alone and caspofungin also may be effective.

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Treatment should continue until the lesions on CT scan have resolved; this usually requires months of therapy (11). Seriously ill patients who are at risk for disseminated candidiasis and who are febrile with no obvious source, may need to be treated before a fungal infection is documented. This approach is used in febrile neutropenic patients for whom outcomes of disseminated candidiasis are poor. Several different antifungal agents have been shown effective in randomly assigned, controlled trials in neutropenic patients with fever (25-27). Liposomal amphotericin B (AmBisome), caspofungin, or voriconazole could be used and will be effective against both Candida species and filamentous fungi that frequently cause infection in neutropenic patients. The decision about which of the aforementioned agents to use is usually based on the types of fungal infections seen at a given center, experience with the various agents, toxicity, and cost. The other group for whom this approach has been used is those in the ICU. However, the risk factors for candidiasis and the end points for stopping antifungal therapy are less defined in this group than in neutropenics, and controlled trials of empiric treatment have not been done. Fluconazole is the agent used most often because of its safety and cost; in the ICU there is no need to use an agent that will treat filamentous fungi as well as Candida species. However, if C. glabrata is a major cause of invasive candidiasis in a given ICU, fluconazole is not a good choice and an echinocandin is preferred. The use of antifungal prophylaxis to prevent infection in those at high risk for developing candidiasis has been proven effective in bone marrow transplant recipients and other immunosuppressed hosts (28,29). Fluconazole is the agent that has been used most often. However, the role of prophylaxis in patients in the ICU is controversial (30). The use of prophylaxis for all patients in the ICU is discouraged because of the potential for selecting those species that are resistant to fluconazole. Only those at highest risk of developing invasive infections should receive prophylaxis, but criteria establishing what constitutes highest risk have not been well defined among ICU patients. Several individual institutions have conducted blinded randomly assigned, controlled trials comparing fluconazole with placebo in ICU patients (31,32). However, it is unclear whether these studies are applicable to other ICU settings, and at this point prophylaxis is not recommended for ICU patients (13).

REFERENCES 1. NIAID Mycoses Study Group. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37:634-43. 2. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39:309-17. 3. Kauffman CA, Vazquez JA, Sobel JD, Gallis HA, McKinsey DS, Karchmer AW, et al. Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis. 2000;30:14-8. 4. Calandra T, Bille J, Schneider R, Mosimann F, Francioli P. Clinical significance of Candida isolated from peritoneum in surgical patients. Lancet. 1989;2:1437-40.

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5. Miller DJ, Mejicano GC. Vertebral osteomyelitis due to Candida species: case report and literature review. Clin Infect Dis. 2001;33:523-30. 6. Malani PN, McNeil SA, Bradley SF, Kauffman CA. Candida albicans sternal wound infections: a chronic and recurrent complication of median sternotomy. Clin Infect Dis. 2002;35:1316-20. 7. Thomas PA. Current perspectives on ophthalmic mycoses. Clin Microbiol Rev. 2003;16: 730-97. 8. Donahue SP, Greven CM, Zuravleff JJ, Eller AW, Nguyen MH, Peacock JE Jr., et al. Intraocular candidiasis in patients with candidemia. Clinical implications derived from a prospective multicenter study. Ophthalmology. 1994;101:1302-9. 9. Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis. 2003;37:1172-7. 10. Krishna R, Amuh D, Lowder CY, Gordon SM, Adal KA, Hall G. Should all patients with candidaemia have an ophthalmic examination to rule out ocular candidiasis? Eye. 2000;14 (Pt 1): 30-4. 11. Kontoyiannis DP, Luna MA, Samuels BI, Bodey GP. Hepatosplenic candidiasis. A manifestation of chronic disseminated candidiasis. Infect Dis Clin North Am. 2000;14:721-39. 12. Odabasi Z, Mattiuzzi G, Estey E, Kantarjian H, Saeki F, Ridge RJ, et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis. 2004;39:199-205. 13. Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis. 2004;38:161-89. 14. Sobel JD, Kauffman CA, McKinsey D, Zervos M, Vazquez JA, Karchmer AW, et al. Candiduria: a randomized, double-blind study of treatment with fluconazole and placebo. The National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis. 2000;30:19-24. 15. Drew RH,Arthur RR, Perfect JR. Is it time to abandon the use of amphotericin B bladder irrigation? Clin Infect Dis. 2005;40:1465-70. 16. Johnson MD, Perfect JR. Fungal Infections of the Bones and Joints. Curr Infect Dis Rep. 2001;3:450-460. 17. Phelan DM, Osmon DR, Keating MR, Hanssen AD. Delayed reimplantation arthroplasty for candidal prosthetic joint infection: a report of 4 cases and review of the literature. Clin Infect Dis. 2002;34:930-8. 18. Wang AY,Yu AW, Li PK, Lam PK, Leung CB, Lai KN, et al. Factors predicting outcome of fungal peritonitis in peritoneal dialysis: analysis of a 9-year experience of fungal peritonitis in a single center. Am J Kidney Dis. 2000;36:1183-92. 19. Kauffman CA, Bradley SF, Vine AK. Candida endophthalmitis associated with intraocular lens implantation: efficacy of fluconazole therapy. Mycoses. 1993;36:13-7. 20. Martínez-Vázquez C, Fernández-Ulloa J, Bordón J, Sopeña B, de la Fuente J, Ocampo A, et al. Candida albicans endophthalmitis in brown heroin addicts: response to early vitrectomy preceded and followed by antifungal therapy. Clin Infect Dis. 1998;27:1130-3. 21. Rex JH, Bennett JE, Sugar AM, Pappas PG, van der Horst CM, Edwards JE, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med. 1994;331:1325-30. 22. Caspofungin Invasive Candidiasis Study Group. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347:2020-9. 23. National Institute of Allergy and Infectious Diseases Mycoses Study Group. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis. 2003;36:1221-8. 24. Rex JH, Bennett JE, Sugar AM, Pappas PG, Serody J, Edwards JE, et al. Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group. Clin Infect Dis. 1995;21:994-6. 25. Walsh T J, Finberg RW,Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;340: 764-71. 26. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225-34.

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27. Walsh T J,Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351:1391-402. 28. Goodman JL,Winston D J, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326:845-51. 29. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant recipients. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1999;131:729-37. 30. Rex JH, Sobel JD. Prophylactic antifungal therapy in the intensive care unit. Clin Infect Dis. 2001;32:1191-200. 31. Pelz RK, Hendrix CW, Swoboda SM, Diener-West M, Merz WG, Hammond J, et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg. 2001;233:542-8. 32. Eggimann P, Francioli P, Bille J, Schneider R, Wu MM, Chapuis G, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med. 1999;27:1066-72. 33. Kauffman CA, Hedderwick SA. Candida and other fungi. In: Yoshikawa TT, Ouslander JG, eds. Infection Management for Geriatrics in Long-Term Care Facilities. New York, NY: Marcel Dekker; 2002:449-72.

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Chapter 28

Coccidioidomycosis CAROL A. KAUFFMAN, MD

Key Learning Points 1. Coccidioides thrives in a specific desert area in the southwest and is acquired through inhalation. 2. Most patients infected with coccidioidomycosis are asymptomatic. 3. Progressive pulmonary coccidioidomycosis is more common in older adults who also have diabetes mellitus or COPD. 4. Disseminated coccidioidomycosis occurs more commonly in dark-skinned races, patients who are immunosuppressed, and women in the last trimester of pregnancy. 5. Treatment of mild-to-moderate coccidioidomycosis can be with either itraconazole or fluconazole. 6. Severe infection should be treated with amphotericin B. 7. Coccidioidal meningitis requires life-long antifungal therapy.

Epidemiology Coccidioides is a dimorphic fungus that exists as a mold in the environment and as a spherule in vivo. It is recently verified that there are two species: Coccidioides immitis refers to isolates from California and Coccidioides posadasii to isolates from all other areas. Coccidioides species have the most restricted geographic region of all the endemic mycoses (1). The organism grows in southern California, the valleys of central California, Arizona, New Mexico, and western Texas in desert regions known as the lower Sonoran life zone. Areas of Central and South America that have this same ecology also support the growth of Coccidioides species. 541

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New Developments in the Management of Coccidioidomycosis ●

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The genus Coccidiodes is now thought to be comprised of two species; Coccidioides immitis refers to isolates from California and Coccidioides posadasii to isolates from elsewhere. Itraconazole and fluconazole are equivalent for treatment of chronic nonmeningeal coccidioidomycosis. The new expanded spectrum triazoles, voriconazole and posaconazole, can have a role to play in the treatment of disseminated and meningeal coccidioidomycosis, but more experience is needed before these agents can be recommended.

The wide dispersal of the organism leads to infection of most inhabitants of the endemic area before they reach adulthood. An important change in the epidemiology of coccidioidomycosis is the increase in infections in older adults. This is almost assuredly caused by the influx of older adults into the Sun Belt in their retirement years (2). These people, who were never exposed to C. immitis in their youth, are at risk to develop primary infection in their later years. Many of these older adults develop symptoms after returning home from the endemic area and seek medical care from their local physician who is frequently not familiar with the manifestations of coccidioidomycosis. Environmental cycles of rain and drought in the desert are important in the natural history of Coccidioides species and the epidemiology of human infection. Increased rain allows the organism to grow to greater numbers, and subsequent drought will facilitate increased dispersal when winds blow off the desert (3). Activities that involve disruption and aerosolization of desert soil can lead to outbreaks. And catastrophic events, such as earthquakes, have led to the occurrence of coccidioidomycosis in areas beyond those normally seen (4).

Pathogenesis The environmental or mold form of Coccidioides is composed of arthroconidia that are loosely connected, easily separated, and widely dispersed. Infection is acquired when the arthroconidia are inhaled into the alveoli. In the alveoli, the organism transforms into the spherule form. Spherules are large (20-80 um), thick-walled structures that contain hundreds of endospores. When filled, the spherule ruptures, releasing the endospores; each endospore is capable of forming a new spherule and continuing the infection in the host. The primary host defense against Coccidioides seems to be cell-mediated immunity (1). Patients with AIDS are at increased risk for infection, and when infection occurs, dissemination is the rule (5). Other risk factors for dissemination include hematologic malignancies, organ transplantation, and corticosteroid use (6,7). Neutrophils can have some role in containing infec-

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tion as they are present in most lesions. However, they cannot eliminate spherules. It is likely that many patients experience hematogenous dissemination, which usually is not associated with symptoms. Like several other endemic mycoses, in immunosuppressed patients, Coccidioides has the potential to reactivate years after the primary exposure to the organism. Dark-skinned races are at higher risk for dissemination and for severe infection than light-skinned individuals (8). The highest risk seems to be among African Americans, but Filipinos, Native Americans, and Hispanics are also at increased risk. The scientific basis for this predilection has yet to be determined. Another group at high risk of more severe coccidioidomycosis is women who are pregnant, especially those in the third trimester.

Clinical Manifestations Most persons with coccidioidomycosis have no symptoms or have mild symptoms suggesting a viral illness (9,10). This occurs mostly in children or young adults, and the diagnosis is rarely made at this time. Various pulmonary manifestations of disease can occur (Table 28-1). Patients with primary pulmonary coccidioidomycosis usually present with fever, fatigue, myalgias, and arthralgias. Nonproductive cough, anterior chest pain, and dyspnea can occur. Erythema nodosum occurs in as many as 25% of women and a smaller percentage of men and should bring to mind the possibility of coccidioidomycosis. Chest radiographs usually show a patchy pneumonitis, and hilar lymphadenopathy can be present. Symptoms can persist for weeks to a few months, but gradually resolve in almost all persons. Acute pulmonary coccidioidomycosis is often diagnosed as an atypical pneumonia occurring through viral, mycoplasma, or bacterial causes. Acute pulmonary histoplasmosis presents in a similar fashion, and travel and exposure history help differentiate the two fungal infections.

Table 28-1 Pulmonary Manifestations of Coccidioidomycosis Manifestation

Comment

Primary localized pneumonia Diffuse reticulonodular pneumonia Chronic fibronodular pneumonia Coccidioidoma Cavity formation

Generally self-limited and resolves without therapy Most common in immunocompromised patients

Pneumothorax Pleural effusion

Most often in older adults with COPD, diabetes; mimics tuberculosis Solitary nodule; must differentiate from carcinoma Usually peripheral and thin-walled; can remain asymptomatic or cause cough, hemoptysis Uncommon; occurs with rupture of cavity into pleural space Uncommon (10%); exudative; can be eosinophilic

Abbreviation: COPD, chronic obstructive pulmonary disease.

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When exposure to the organism is extensive or the host is immunosuppressed, acute overwhelming pneumonia can occur. Patients have high fevers, hypoxemia, and diffuse reticulonodular infiltrates on chest radiograph. This is a common manifestation of coccidioidomycosis in AIDS patients who have low CD4 counts. A small number of patients will have residual manifestations and subsequent complications after acute pulmonary infection. Coccidioidomas are pulmonary nodules remaining after the symptoms of infection have cleared. They can remain unchanged and visible on the chest radiograph for years. Cavitary lesions can persist for months to years, usually as solitary, thinwalled, peripheral lesions. Many of these will resolve, but for some patients, hemoptysis can occur, or the cavity can rupture into the pleural space. Chronic progressive pneumonia, often with cavitary lesions on chest radiograph occurs with increased frequency in those who are older and have chronic obstructive pulmonary disease (COPD) or diabetes mellitus (8). This form of coccidioidomycosis is similar to tuberculosis and other endemic mycoses, especially chronic cavitary pulmonary histoplasmosis. Less than 1% of patients with symptomatic coccidioidomycosis will develop symptoms of disseminated infection. The manifestations of extrapulmonary infection can be focal and related to one organ system, or they can be systemic. The sites involved most often are skin, subcutaneous tissues, osteoarticular structures, and meninges, but almost any organ can be affected. Cutaneous and subcutaneous lesions are one of the most common manifestations of disseminated coccidioidomycosis. The skin lesions are typically papular or pustular, can become plaque-like or verrucous, and can ulcerate and drain. They are common on the face. The cutaneous lesions mimic those of blastomycosis or squamous cell carcinomas. Subcutaneous abscesses become obvious when they form sinus tracts and drain. Osteoarticular infection is common. Osteomyelitis can occur contiguous to subcutaneous abscesses or in many bones that have been seeded through the hematogenous route. Vertebral involvement is common, but any bone can be involved. It is important to assess whether many osteoarticular structures are infected. A bone scan is a useful screening method, and magnetic resonance imaging studies will help define the extent of involvement of individual bony structures. The worst complication of disseminated coccidioidomycosis is meningitis. Meningitis can be the sole manifestation of dissemination, or it can be present along with dissemination to many different organs. The symptoms of meningitis can be dramatic when present with acute dissemination or subtle when the patient presents with isolated chronic meningitis. Symptoms include headache, confusion, behavioral changes, cranial nerve palsies, and signs of increased intracranial pressure. Coccidioidomycosis must be differentiated from meningitis caused by tuberculosis, cryptococcosis, histoplasmosis, and sarcoidosis. Cord involvement at any level can also occur causing back pain, weakness, or bowel and bladder dysfunction.

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Diagnosis The definitive diagnosis of coccidioidomycosis is made when the organism is grown in culture from involved tissues or body fluids. C. immitis and C. posadasii grow quickly and on most standard media. The exception is cerebrospinal fluid (CSF), which rarely yields the organism in patients with coccidioidal meningitis. It is important to warn laboratory personnel if coccidioidomycosis is a possible diagnosis as the mold form is highly infectious and a great risk for those working with it. Because Coccidioides is classified as a potential bioterrorism agent, clinical laboratories are obliged to send the mold to reference laboratories and not proceed with identification in the laboratory. Histopathological identification of the distinctive large spherules is extremely helpful in establishing an early diagnosis before culture evidence is available. Biopsy of involved tissue, cytological preparations from bronchoalveolar lavage fluid, potassium hydroxide stain (KOH) or calcofluor smears from sputum or purulent material from skin lesions or abscesses are all helpful in the early diagnosis of coccidioidomycosis. Serology is helpful in the diagnosis of coccidioidomycosis (11). A reference laboratory experienced in testing for coccidioidomycosis should always be sought. The diagnosis of acute coccidioidomycosis is best made with the appearance of IgM antibodies that are usually measured by an immunodiffusion (ID) assay. IgG antibodies measured by a complement fixation (CF) assay appear later and persist longer. The CF antibody titer can be used to follow the response to therapy. A decrease in the CF antibody titer or reversion to negative is associated with a good response; a stable high (>1:16) or increasing titer is a poor prognostic sign. A positive CF antibody test for Coccidioides in CSF is diagnostic of coccidioidal meningitis.

Treatment The Mycoses Study Group and the Infectious Diseases Society of America have published guidelines for the treatment of coccidioidomycosis (12). There is only one randomly assigned, blinded comparative trial that assessed the treatment of coccidioidomycosis (13). Most of the recommendations are based on open-label, non-randomly assigned, multicenter trials and anecdotal experience from experienced clinicians who practice in the area endemic for coccidioidomycosis (Table 28-2). Coccidioidomycosis differs from the other endemic mycoses in that either fluconazole or itraconazole can be used with similar efficacy. A blinded, randomly assigned comparison of fluconazole, 400 mg daily, and itraconazole, 200 mg twice daily, showed no overall difference between the two agents (13). However, for osteoarticular coccidioidomycosis, the response rate with itraconazole (70%) was significantly superior to the response rate with fluconazole (30%).

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Table 28-2 Recommended Treatment Regimens for Coccidioidomycosis Type of Infection

First-Line Therapy

Second-Line Therapy

Pulmonary

Mild, moderate Itraconazole 400 mg QD Amphotericin B 0.7 mg/kg/d (cavitary or localized) or fluconazole 400 mg QD AmBisome, 3-5 mg/kg/d or Abelcet 5 mg/kg/d* Severe (diffuse or AmBisome, 3-5 mg/kg/d or Amphotericin B 0.7-1 mg/kg/d progressive cavitary) Abelcet, 5 mg/kg/d until until stable, then change to stable, then change to itraconazole or fluconazole, itraconazole or fluconazole, 400 mg QD 400 mg QD Disseminated

Mild, moderate

Severe

Central nervous system

Itraconazole 400 mg QD or fluconazole 400 mg QD

Amphotericin B 0.7 mg/kg/d AmBisome, 3-5 mg/kg/d or Abelcet, 5 mg/kg/d* AmBisome 3-5 mg/kg/d or Amphotericin B 0.7-1 mg/kg/d Abelcet 5 mg/kg/d until until stable, then change to stable, then change to itraconazole or fluconazole, itraconazole or fluconazole, 400 mg QD 400 mg QD Fluconazole 800 mg QD Amphotericin B intrathecal or itraconazole 400 mg QD

Modified with permission from Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guidelines for the treatment of coccidioidomycosis. Clin Infect Dis. 2000;30:658-61. * Amphotericin B preparations are used only in the rare circumstance in which the patient is unable to tolerate azole antifungal agents or when the patient is pregnant. Abbreviations: QD, every day.

Most patients with acute pulmonary coccidioidomycosis do not require therapy with an antifungal agent. However, patients who have underlying immunosuppression, such as those who have a solid organ transplant, HIV infection, or are on corticosteroid therapy, and those who are pregnant should be treated. Consideration should be given for treatment of patients who are African American, Filipino, or Hispanic because of the high risk for dissemination in these populations. Healthy patients who continue to have symptoms for 3 to 4 weeks with no improvement, can be offered treatment. Therapy can be with either itraconazole, 200 mg twice daily, or fluconazole, 400 mg daily, except in pregnant women. Azoles are teratogenic; amphotericin B is the only safe antifungal agent for use in pregnancy. Severe diffuse pneumonia should be treated initially with amphotericin B, 0.7 mg/kg daily or a lipid formulation of amphotericin B, either AmBisome, 3 to 5 mg/kg/day, or Abelcet, 5 mg/kg/day. After alleviation, therapy can be changed to an oral azole. Patients who have chronic pulmonary coccidioidomycosis should always be treated; generally therapy with itraconazole, 200 mg twice daily, or fluconazole, 400 mg daily, is used. For those patients who have persistent cavitary lesions after adequate azole therapy, consideration for surgical removal is appropriate.

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Disseminated coccidioidomycosis must always be treated. Patients who are seriously ill should be treated initially with amphotericin B, 0.7 mg/kg/day. Lipid formulations of amphotericin B at a dosage of 3 to 5 mg/kg daily now are used more often to avoid the serious side effects noted with amphotericin B deoxycholate. Patients who have mild-to-moderate disease and are not immunosuppressed can be treated with either itraconazole, 200 mg twice daily, or fluconazole, 400 mg daily. There is little experience with the new azoles, but there are anecdotal reports of success with voriconazole and posaconazole for patients with disseminated coccidioidomycosis (14,15). The echinocandins seem to have no activity against Coccidioides species and should not be used to treat coccidioidomycosis. As might be expected, the most difficult form of coccidioidomycosis to treat is meningitis. In this case, fluconazole seems to be superior to itraconazole, most likely because of its superior penetration into the CSF. The dosage used by many clinicians is 800 mg daily although the initial studies reported on 400 mg daily (16). Itraconazole has been reported to be effective, but experience is limited (17). Voriconazole has also been used successfully in several patients with meningitis (18,19). As many as 20% of patients with meningitis will not respond to fluconazole or itraconazole. In this situation, amphotericin B administered by both the intravenous and intrathecal routes can be used (20). Before azoles, this was the recommended therapy. However, not surprisingly, intrathecal amphotericin B is poorly tolerated. Administration into the lumbar area frequently leads to arachnoiditis and does not effectively deliver drug to the basilar meninges. In the endemic area, amphotericin B is injected into the cistern directly or by means of a reservoir, but outside the endemic area, both neurologists and neurosurgeons are reluctant to do intracisternal injections. An intraventricular reservoir can be used for injections, but this method does not deliver drug as effectively to the basilar meninges. Coccidioidomycosis is the most difficult of the endemic mycoses to treat, and relapses are more common than with the other endemic mycoses. When treatment of acute pulmonary coccidioidomycosis is given, the length of therapy is usually 3 to 6 months. For chronic pulmonary, osteoarticular, and disseminated coccidioidomycosis, treatment should continue for minimum of 1, and often 2 years. Success rates with azole agents of approximately 70% are attainable in patients who have soft tissue infections. The response rates for chronic pulmonary infection are only 50% to 60%. Many African Americans with disseminated infection have recurrent relapses; lifelong therapy with an azole is often required for these patients. AIDS patients who have coccidioidomycosis should receive lifelong suppressive therapy with fluconazole to prevent relapse. Coccidioidal meningitis is fatal in almost all patients within 2 years of diagnosis if not treated. Treatment must be lifelong because the risk of relapse is so high (21).

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REFERENCES 1. Stevens DA. Coccidioidomycosis. N Engl J Med. 1995;332:1077-82. 2. Leake JA, Mosley DG, England B, Graham JV, Plikaytis BD, Ampel NM, et al. Risk factors for acute symptomatic coccidioidomycosis among elderly persons in Arizona, 1996-1997. J Infect Dis. 2000;181:1435-40. 3. Park B J, Sigel K,Vaz V, Komatsu K, McRill C, Phelan M, et al. An epidemic of coccidioidomycosis in Arizona associated with climatic changes, 1998-2001. J Infect Dis. 2005;191:1981-7. 4. Schneider E, Hajjeh RA, Spiegel RA, Jibson RW, Harp EL, Marshall GA, et al. A coccidioidomycosis outbreak following the Northridge, Calif, earthquake. JAMA. 1997;277: 904-8. 5. Woods CW, McRill C, Plikaytis BD, Rosenstein NE, Mosley D, Boyd D, et al. Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis. 2000;181:1428-34. 6. Blair JE, Logan JL. Coccidioidomycosis in solid organ transplantation. Clin Infect Dis. 2001;33:1536-44. 7. Blair JE, Smilack JD, Caples SM. Coccidioidomycosis in patients with hematologic malignancies. Arch Intern Med. 2005;165:113-7. 8. Rosenstein NE, Emery KW,Werner SB, Kao A, Johnson R, Rogers D, et al. Risk factors for severe pulmonary and disseminated coccidioidomycosis: Kern County, California, 1995-1996. Clin Infect Dis. 2001;32:708-15. 9. Crum NF,Lederman ER,Stafford CM,et al. Coccidioidomycosis. A descriptive survey of a reemerging disease. Clinical characteristics and current controversies. Medicine (Baltimore). 2004; 83:149-75. 10. Johnson RH. Coccidioidomycosis. Infect Dis Clin Pract. 1999;8:21-26. 11. Pappagianis D. Serologic studies in coccidioidomycosis. Semin Respir Infect. 2001;16:242-50. 12. Galgiani JN,Ampel NM, Catanzaro A, Johnson RH, Stevens DA,Williams PL. Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:658-61. 13. Galgiani JN, Catanzaro A, Cloud GA, Johnson RH,Williams PL, Mirels LF, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000;133:676-86. 14. Prabhu RM, Bonnell M, Currier BL, Orenstein R. Successful treatment of disseminated nonmeningeal coccidioidomycosis with voriconazole. Clin Infect Dis. 2004;39:e74-7. 15. Anstead GM, Corcoran G, Lewis J, Berg D, Graybill JR. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis. 2005;40:1770-6. 16. Galgiani JN, Catanzaro A, Cloud GA, Higgs J, Friedman BA, Larsen RA, et al. Fluconazole therapy for coccidioidal meningitis. The NIAID-Mycoses Study Group. Ann Intern Med. 1993;119:28-35. 17. Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med. 1990;112:108-12. 18. Cortez K J,Walsh T J, Bennett JE. Successful treatment of coccidioidal meningitis with voriconazole. Clin Infect Dis. 2003;36:1619-22. 19. Proia LA,Tenorio AR. Successful use of voriconazole for treatment of Coccidioides meningitis [Letter]. Antimicrob Agents Chemother. 2004;48:2341. 20. Stevens DA, Shatsky SA. Intrathecal amphotericin in the management of coccidioidal meningitis. Semin Respir Infect. 2001;16:263-9. 21. Dewsnup DH, Galgiani JN, Graybill JR, Diaz M, Rendon A, Cloud GA, et al. Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med. 1996;124: 305-10.

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Chapter 29

Histoplasmosis CAROL A. KAUFFMAN, MD

Key Learning Points 1. Histoplasmosis is acquired from the environment and is the most common endemic mycosis. 2. Most infections with H. capsulatum are asymptomatic. 3. Severe diffuse pneumonia occurs in patients with immune compromise and in healthy hosts with an intense exposure to H. capsulatum. 4. Chronic cavitary pulmonary and chronic progressive disseminated histoplasmosis are more common in older men and are both fatal unless treated. 5. Itraconazole is the antifungal agent of choice for the treatment of mild-to-moderate histoplasmosis. 6. Amphotericin B, usually a lipid formulation, should be given for severe histoplasmosis.

Epidemiology Histoplasma capsulatum is a dimorphic fungus that is a mold in the environment and a yeast in vivo. Histoplasmosis is the most common endemic mycosis, infecting hundreds of thousand of persons yearly. Infection is so common in the endemic area that most persons have been infected before adulthood. The organism is endemic in the Mississippi and Ohio River valleys, in many locations in Central America, and in focal areas of Southeast Asia and the Mediterranean basin (Figure 29-1). The mold phase of the organism grows to 549

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New Developments in the Management of Histoplasmosis ●

●

●

Patients receiving anti-TNF agents (Remicade, Humira, Enbrel) are at increased risk for severe disseminated histoplasmosis. AmBisome has been shown to be more efficacious than amphotericin B deoxycholate for the treatment of severe acute disseminated histoplasmosis in patients with AIDS. Stenting of the great veins and pulmonary arteries and veins has been shown to decrease obstructive symptoms in patients with fibrosing mediastinitis.

Figure 29-1 North and South American distribution of Histoplasma capsulatum.

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high concentrations in soil and caves rich in bird or bat guano. Exposure is related to activities in the environment that disperse the organism. Such activities include landscaping, cleaning debris from attics, bridges, or barns, tearing down old structures laden with guano, and spelunking (1). The largest outbreak caused infection in hundreds of thousands of persons exposed to the organism during an urban demolition project in Indianapolis (2). However, most cases are sporadic, and the exact exposure is unknown.

Pathogenesis Infection begins when the host inhales the microconidia of H. capsulatum into the alveoli. Neutrophils and macrophages phagocytize the organism, which quickly converts to the yeast phase; in this phase, the organism is able to survive within the macrophage. In this vehicle, H. capsulatum is spread to the hilar and mediastinal lymph nodes. This results in hematogenous dissemination throughout the reticuloendothelial system. After several weeks, specific cell-mediated immunity against H. capsulatum develops; the sensitized T cells activate the macrophages, empowering them to kill the organism (3). Histoplasmosis is the most pure example of the crucial importance of the cell-mediated immune system in host defense against fungi. The extent of disease is measured by the number of conidia that are inhaled and the immune response of the host. Healthy individuals can develop severe life-threatening infection if they are exposed to a huge burden of organisms as might occur when spelunking in a bat-infested cave. Conversely, a small inoculum can cause severe disseminated infection in a markedly immunosuppressed host, such as a patient with AIDS. Most infected persons have asymptomatic hematogenous dissemination; only rarely does this lead to symptomatic disseminated histoplasmosis. Latent infection is the rule in histoplasmosis, and the organism can reactivate years later if immunosuppression occurs (4). Reinfection can also occur in persons previously infected with H. capsulatum if they are exposed to a heavy inoculum of the mold.

Clinical Manifestations The vast majority of patients infected with H. capsulatum remain asymptomatic. Various different manifestations can occur in those who do have symptomatic infection (Table 29-1). Patients with acute pulmonary infection may not seek medical attention, and in those that do, the diagnosis is often not entertained. The usual symptoms are fever, chills, nonproductive cough, anterior chest discomfort, myalgias, arthralgias, and fatigue. The

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Table 29-1 Clinical Manifestations of Histoplasmosis Manifestations

Comments

Pulmonary histoplasmosis

Acute symptomatic Diffuse pneumonitis Chronic cavitary

Usually self-limited infection Immunosuppressed patients; point-source infection with large inoculum Patients with COPD; progressive respiratory insufficiency

Complications of pulmonary histoplasmosis

Granulomatous mediastinitis Fibrosing mediastinitis Pericarditis

Uncommon; persistent lymph node enlargement impinge on mediastinal structures Rare; excessive fibrosis obstructs major vessels and bronchi Self-limited; reaction to adjacent pulmonary infection; noninfectious

Disseminated histoplasmosis

Acute disseminated Chronic disseminated Central nervous system

Most common in immunosuppressed patients Older adults; progressive infection Isolated or with dissemination

Abbreviation: COPD, chronic obstructive pulmonary disease.

chest radiograph reveals a patchy lobar or multilobar nodular infiltrate (5). Most patients are initially treated for atypical pneumonia with antibiotics. Only when there is no response to this therapy or when the patient notes that others who were also involved in a specific outdoor activity have pulmonary symptoms, is the diagnosis of a fungal infection entertained. It is especially important to make the diagnosis of fungal infection quickly for those patients who had extensive exposure to the organism and developed severe pneumonia. These patients generally have high fevers, dyspnea, nonproductive cough, and prostration. Diffuse nodular infiltrates are noted on chest radiograph, and development of the adult respiratory distress syndrome can quickly ensue. Patients who are immunosuppressed also are more likely to have severe pulmonary infection with marked hypoxemia and diffuse infiltrates on chest radiograph. The usual host to develop chronic cavitary pulmonary histoplasmosis is an older adult who has chronic obstructive pulmonary disease. This form of histoplasmosis is progressive and fatal and mimics tuberculosis in almost all aspects. Patients usually manifest fever, fatigue, anorexia, weight loss, cough productive of purulent sputum, and hemoptysis (6). Chest radiographs show unilateral or bilateral upper lobe infiltrates and cavities, and fibrosis is seen in the lower lung fields. Besides tuberculosis, other chronic fungal pneumonias and nontuberculous mycobacterial infections must be differentiated from this form of histoplasmosis. Two complications of pulmonary histoplasmosis are especially problematic; these are granulomatous mediastinitis and fibrosing mediastinitis

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(6,7). Granulomatous mediastinitis is characterized by persistent mediastinal and hilar lymphadenopathy. Symptoms related to the presence of the enlarged nodes include dysphagia, chest pain, and nonproductive cough. The chest radiograph shows enlarged hilar and/or mediastinal nodes; computed tomography (CT) scan frequently reveals necrosis in the enlarged lymph nodes and impingement on mediastinal structures. Ultimately, most patients have resolution of the lymphadenopathy; fibrosing mediastinitis does not follow granulomatous mediastinitis. Fibrosing mediastinitis is a rare complication of pulmonary histoplasmosis. In this disease, excessive fibrosis that occurs in response to mediastinal histoplasmosis ultimately entraps the great vessels and/or bronchi. The symptoms are progressive and include dyspnea, cough, wheezing, and hemoptysis. Heart failure, pulmonary emboli, and superior vena cava syndrome are possible complications. In contrast to the preceding syndromes, acute Histoplasma pericarditis is a benign self-limited condition that occurs in those with acute pulmonary histoplasmosis. It is thought to be an inflammatory reaction to adjacent infection with H. capsulatum. Symptoms are those typical of pericarditis; the pericardial fluid is exudative, but rarely causes tamponade. Acute disseminated histoplasmosis is seen mostly in patients who are immunosuppressed. Typical patients include transplant recipients, those with hematological malignancies, AIDS patients whose CD4 counts are less than 150/µL (8), those on corticosteroids, and young infants. Patients receiving anti-tumor necrosis factor (TNF) agents are now known to be at risk for reactivation of intracellular pathogens, including H. capsulatum (9). Symptoms include chills, fever, malaise, anorexia, weight loss, and dyspnea; some patients have sepsis syndrome with adult respiratory distress syndrome and disseminated intravascular coagulation. Hepatosplenomegaly and skin and mucous membrane lesions are hints that this could be histoplasmosis. Diffuse pulmonary infiltrates are noted on chest radiograph, pancytopenia is common, and acute adrenal insufficiency can occur as the organism infiltrates the adrenal glands. Chronic progressive disseminated histoplasmosis is a fatal form of histoplasmosis that occurs mostly in middle-aged to elderly men who have no known immunosuppression (4). Symptoms include weeks to months of fever, night sweats, weight loss, and fatigue; the presentation can be that of fever of unknown origin. On physical examination, patients seem chronically ill, have hepatosplenomegaly, and can have painful ulcerations in the oral cavity. The symptoms and signs of adrenal insufficiency can appear with adrenal gland destruction. Increased erythrocyte sedimentation rate, pancytopenia, elevated alkaline phosphatase, and diffuse pulmonary infiltrates reflect widespread involvement typical of this disease. Central nervous system (CNS) histoplasmosis is uncommon. It can occur as a component of acute disseminated histoplasmosis or present as an isolated focal infection. The symptoms are headache, behavioral changes, and

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sometimes, focal neurological deficits. Signs of increased intracranial pressure can be prominent. The most common presentation is that of a chronic lymphocytic meningitis, but focal lesions can occur throughout the brain and the spinal cord and are best visualized with magnetic resonance imaging techniques.

Diagnosis Growth of the organism from tissue or fluid samples makes the definitive diagnosis of histoplasmosis (10). Most times this is confirmatory only because it can take up to 6 weeks for growth to occur. Probes specific for H. capsulatum confirm the identification of the organism as soon as growth occurs. For patients who have disseminated histoplasmosis, the yeast can be grown from cultures of blood; the lysis-centrifugation (Isolator tube) system is more sensitive than automated blood culture systems. Because culture-based methods are slow, identification of the organism in tissue or fluid samples should be pursued. The organisms appear as uniform, 2 to 4 µm oval budding yeasts. For patients with disseminated disease, biopsy samples from bone marrow, liver, lymph nodes, or lesions on the mucous membranes or skin usually reveal the organisms. Routine hematoxylin and eosin staining will not show the tiny yeasts, but methenamine silver or periodic acid Schiff stains will show the characteristic structure. In patients with severe acute dissemination, yeasts can be seen inside leukocytes on the peripheral smear. For patients with pulmonary histoplasmosis or granulomatous mediastinitis, biopsy of lung or lymph nodes can reveal the organism. Cytological examination of bronchoalveolar lavage fluid or sputum generally does not reveal the tiny yeasts. Serology plays an important role in the diagnosis of certain forms of histoplasmosis (10). Both complement fixation (CF) and immunodiffusion (ID) tests are available. The ID test detects both H and M antibodies and is slightly more specific than the CF test; both have a sensitivity of approximately 80%. False positive CF tests occur in patients with lymphoma, tuberculosis, sarcoidosis, and other fungal infections. Serology is generally not useful in immunosuppressed patients who cannot mount an antibody response. Patients with chronic cavitary pulmonary histoplasmosis and chronic progressive disseminated histoplasmosis almost always have positive results with both the CF and ID assays. Those with acute pneumonia can show a fourfold increase in CF titer or the appearance of an M band by ID. For patients with mediastinal lymphadenopathy, serological tests are suggestive, but not adequate to rule out tumor or other granulomatous processes as the cause of the lymphadenopathy. An enzyme immunoassay that measures the cell wall polysaccharide antigen of H. capsulatum in urine and serum has become extremely useful in the diagnosis of disseminated infection. Most of the published literature

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is on the use of this test in AIDS patients, but it is also useful in others, especially immunosuppressed patients, who have a high burden of organisms. The assay is less useful for pulmonary histoplasmosis, but can be positive in acute pulmonary infection. Testing for antigen is more sensitive in urine than in serum. Cross-reactivity can occur with blastomycosis.

Treatment Guidelines for the treatment of histoplasmosis have been published by the Mycoses Study Group and the Infectious Diseases Society of America (11). The guidelines are based primarily on open-label treatment trials of histoplasmosis in AIDS and non-AIDS patients and on retrospective and prospective reports from individual institutions (Table 29-2). Only one randomly assigned, blinded treatment trial, that was in AIDS patients, and

Table 29-2 Recommended Treatment Regimens for Histoplasmosis Type of Infection

First-Line Therapy

Second-Line Therapy

Pulmonary

- Mild, moderate - Severe diffuse

-

-

Itraconazole 200-400 mg QD Fluconazole 800 mg QD AmBisome 3-5 mg/kg/d or Amphotericin B 0.7 mg/kg/d Abelcet 5 mg/kg/d until stable, until stable, then itraconazole then itraconazole 200 mg BID 200 mg BID Chronic cavitary Itraconazole 200 mg BID Fluconazole 800 mg QD or Amphotericin B 0.7 mg/kg/d or lipid formulation 3-5 mg/kg/d Granulomatous Itraconazole 200 mg BID Amphotericin B 0.7 mg/kg/d or mediastinitis lipid formulation 3-5 mg/kg/d Fibrosing Itraconazole 200 mg BID mediastinitis (no evidence for effectiveness) Pericarditis Nonsteroidal anti-inflammatory Corticosteroids agents

Disseminated

- Mild, moderate Acute, chronic - Severe Acute, chronic - Central nervous system

Itraconazole 200 mg BID

Fluconazole 800 mg QD

AmBisome 3-5 mg/kg/d or Amphotericin B 0.7 mg/kg/d Abelcet 5 mg/kg/d until stable, until stable, then itraconazole then itraconazole 200 mg BID 200 mg BID AmBisome 3-5 mg/kg/d or Amphotericin B 0.7-1 mg/kg/d Abelcet 5 mg/kg/d until stable, until stable, then itraconazole then itraconazole 200 mg BID 200 mg BID or fluconazole or fluconazole 800 mg QD 800 mg QD

Modified with permission from Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis. 2000;30:688-95; and Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis. 2005;40:844-52. Abbreviations: BID, twice daily; QD, every day.

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one randomly assigned, blinded prophylaxis trial, also in AIDS patients, have been reported (12,13). In general, patients with severe histoplasmosis should be treated with amphotericin B or a lipid formulation of amphotericin B. Those with mild to moderate disease can be treated with an azole (14,15). The azole of choice is itraconazole; fluconazole should be considered a second-line agent (16,17). There is little experience with the use of voriconazole for the treatment of histoplasmosis (6). Currently, this agent cannot be recommended for the treatment of histoplasmosis. The echinocandins do not seem to have activity against H. capsulatum and should not be used. Most patients with acute pulmonary histoplasmosis do not require therapy and are frequently improving or have become asymptomatic before the diagnosis has been established. However, if the patient is still symptomatic after 4 weeks, therapy with itraconazole 200 mg daily for 6 to 12 weeks is recommended. Clearly, those patients who develop severe pulmonary symptoms related to acute exposure to H. capsulatum and immunosuppressed patients who have acute pulmonary histoplasmosis should be treated. In these patient populations, initial therapy should be with amphotericin B, 0.7 mg/kg/day. After a favorable response is noted, therapy can be changed to oral itraconazole. Treatment should continue until the infiltrate has resolved. Antifungal therapy is required for all patients with chronic pulmonary histoplasmosis. Itraconazole, 200 mg twice daily, for 12 to 24 months is the treatment of choice. When itraconazole capsules are used at a dosage of 400 mg daily, administration should be 200 mg twice daily with food. Agents that decrease gastric acid cannot be used with the capsular formulation. Itraconazole suspension is given between meals and does not require gastric acid for absorption. Based on anecdotal reports, patients with granulomatous mediastinitis are usually treated with a course of itraconazole, 200 mg twice daily, for 3 to 6 months. Not all patients will show benefit from this therapy. If obstructive symptoms persist, surgical resection of the enlarged lymph nodes has been noted to be beneficial. Fibrosing mediastinitis does not respond to antifungal therapy. The most effective treatment seems to be selective placement of stents in obstructed great vessels or bronchi (18). All patients with symptomatic disseminated histoplasmosis should receive antifungal therapy. Patients who have mild to moderate symptoms with acute disseminated disease and most patients who have the chronic progressive disseminated form of histoplasmosis can be treated with itraconazole, 200 mg twice daily. Immunosuppressed patients with moderate to severe disseminated histoplasmosis should be treated initially with amphotericin B, 0.7-1 mg/kg/day. For most patients, therapy can be changed to itraconazole after they become afebrile and are able to take oral medications. For those unusual patients whose entire course of therapy is carried out with amphotericin B deoxycholate, the total dose should be 35 mg/kg. It has been

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shown that liposomal amphotericin B (AmBisome) (3 mg/kg/d) is superior to amphotericin B deoxycholate (0.7 mg/kg/d) for initial therapy for AIDS patients with severe disseminated histoplasmosis (12). In a blinded, randomly assigned treatment trial, patients became afebrile sooner, the death rate was decreased, and toxicity was lessened in the liposomal amphotericin B group. In addition to improved effectiveness, the lipid formulation had less nephrotoxicity than amphotericin B deoxycholate. In general, most patients currently are treated with lipid formulation amphotericin B, either AmBisome or Abelcet, when more than a few days of therapy with amphotericin B are planned. CNS histoplasmosis should be treated initially with amphotericin B, usually a lipid formulation at 3 to 5 mg/kg daily for 6 to 12 weeks. After this, an oral azole agent should be given. Fluconazole, 800 mg daily, has been used successfully as has itraconazole, 200 mg twice daily (19). The duration of therapy for histoplasmosis varies with the type of disease. Those with acute pulmonary histoplasmosis are generally treated for 6 to 12 weeks. However, chronic histoplasmosis, both cavitary pulmonary and progressive disseminated forms, should be treated for at least 12 months and sometimes longer, depending on the clinical response. CNS histoplasmosis is treated for at least 12 months; some clinicians treat longer, depending on the clinical response to therapy. Patients who have AIDS should receive chronic suppressive therapy with itraconazole, 200 mg daily, after initial induction therapy. It is safe to discontinue suppressive therapy in those patients who have had restoration of their CD4 count to more than 200/µL for at least one year. Prophylaxis against histoplasmosis can be considered for AIDS patients with CD4 less than 150/µL who live in an endemic area in which there is a documented high attack rate (13). Acute histoplasmosis generally responds quickly to treatment with antifungal agents. However, patients who have chronic progressive disseminated or chronic cavitary pulmonary histoplasmosis respond more slowly. Patients with chronic cavitary pulmonary histoplasmosis frequently have progressive respiratory insufficiency despite antifungal therapy. Relapses are unusual in non-AIDS patients who have completed the prescribed course of antifungal therapy.

REFERENCES 1. Cano MV, Hajjeh RA. The epidemiology of histoplasmosis: a review. Semin Respir Infect. 2001;16:109-18. 2. Wheat J. Histoplasmosis. Experience during outbreaks in Indianapolis and review of the literature. Medicine (Baltimore). 1997;76:339-54. 3. Newman SL. Cell-mediated immunity to Histoplasma capsulatum. Semin Respir Infect. 2001;16:102-8. 4. Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am. 2003;17:1-19, vii. 5. Gurney JW, Conces DJ. Pulmonary histoplasmosis. Radiology. 1996;199:297-306. 6. Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med. 2004;25:129-44. 7. Davis AM, Pierson RN, Loyd JE. Mediastinal fibrosis. Semin Respir Infect. 2001;16:119-30.

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8. McKinsey DS, Spiegel RA, Hutwagner L, Stanford J, Driks MR, Brewer J, et al. Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: incidence, risk factors, and pathophysiology. Clin Infect Dis. 1997;24:1195-203. 9. Wood KL, Hage CA, Knox KS, Kleiman MB, Sannuti A, Day RB, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med. 2003;167:127982. 10. Wheat LJ. Laboratory diagnosis of histoplasmosis: update 2000. Semin Respir Infect. 2001;16:131-40. 11. Wheat J, Sarosi G, McKinsey D, Hamill R, Bradsher R, Johnson P, et al. Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:688-95. 12. U.S. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med. 2002;137:105-9. 13. McKinsey DS, Wheat LJ, Cloud GA, Pierce M, Black JR, Bamberger DM, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1999;28:1049-56. 14. Dismukes WE, Bradsher RW Jr., Cloud GC, Kauffman CA, Chapman SW, George RB, et al. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am J Med. 1992;93:489-97. 15. Wheat J, Hafner R, Korzun AH, Limjoco MT, Spencer P, Larsen RA, et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trial Group. Am J Med. 1995;98:336-42. 16. McKinsey DS, Kauffman CA, Pappas PG, Cloud GA, Girard WM, Sharkey PK, et al. Fluconazole therapy for histoplasmosis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis. 1996;23:996-1001. 17. Wheat J, MaWhinney S, Hafner R, McKinsey D, Chen D, Korzun A, et al. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeficiency Syndrome Clinical Trials Group and Mycoses Study Group. Am J Med. 1997;103:223-32. 18. Doyle TP, Loyd JE, Robbins IM. Percutaneous pulmonary artery and vein stenting: a novel treatment for mediastinal fibrosis. Am J Respir Crit Care Med. 2001;164:657-60. 19. Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis. 2005;40:844-52.

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Chapter 30

Aspergillosis JOSE A. VASQUEZ, MD

Key Learning Points 1. Aspergillosis remains a major cause of morbidity and mortality in immunosuppressed patients, especially in hematopoietic stem cell transplant (HSCT) recipients. It is the second most common cause of fungal disease in HSCT recipients, solid organ transplant recipients, and hematologic and oncologic malignancies. 2. Risk factors include neutropenia, chemotheraphy, graft versus host disease, immunosuppressive agents, and high-dose seroids. 3. Aspergillus infection can manifest in a variety of ways, ranging from colonization to life-threatening invasive disease. Moreover, the clinical manifestations are varied depending on the route of infection and the underlying disease. 4. The diagnosis of invasive aspergillosis continues to be a significant problem in the management of this infection. In fact, the diagnosis is frequently made using clinical manifestations and histopathologic analysis of affected tissue. 5. The early initiation of appropriate antifungal therapy is crucial in the management of this infection. Thus, efforts should focus on noninvasive studies to establish a putative diagnosis of invasive aspergillosis. 6. Recent studies by Herbrecht et al have demonstrated that therapy with voriconazole leads to improved survival when compared to amphotericin B in invasive aspergillosis, without the dose-limiting nephrotoxicity that is so commonly seen with amphotericin B. 559

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New Developments • Although newer diagnostic techniques and newer antifungals have improved the

prognosis of invasive aspergillosis, underlying immune dysfunction still remains one of the most important factors associated with morbidity and mortality. • Early and aggressive empiric antifungal therapy is an additional and essential link in managing invasive aspergillosis and subsequently improving survival. • Voriconazole may lead to greater survival when compared with amphotericin for invasive asperegillosis. • Posaconazole is indicated for prophylaxis against invasive aspergillosis in adults and adolescents who are immunocompromised due to hematopoietic stem cell transplant or graft versus host disease.

A

spergillus species are found worldwide and are ubiquitous in the environment. Aspergillosis encompasses a broad spectrum of diseases caused by members of the genus Aspergillus. The clinical manifestation and severity of the disease depends on the immunologic state of the patient. In the last decade, there have been significant advances in the diagnosis and treatment of invasive aspergillosis. However, invasive aspergillosis remains a major cause of illness and death in immunosuppressed patients (1,2). Lowered host resistance caused by such factors as underlying debilitating disease, neutropenia, chemotherapy, immunosuppressive agents, antimicrobial agents, and steroids predisposes the patients to colonization, invasive disease, or both. Additionally, aspergillosis is occasionally seen as an opportunistic pathogen in patients with bronchiectasis, carcinoma, sarcoidosis, or tuberculosis.

Epidemiology Aspergillus species are ubiquitous saprophytes found worldwide in nature. Aspergillus species are one of the most frequent organisms found in compost piles and readily isolated from the soil, air, water, and food. It is frequently isolated from hospital ventilation systems and hospital construction sites (3). In addition, it can also be found in 1% to 16% of respiratory secretions in normal hosts. There are approximately 600 recognized species of Aspergillus, of which A. fumigatus is the most frequent cause of disease in humans, followed by Aspergillus favus, Aspergillus niger and occasionally Aspergillus terreus, Aspergillus nidulans, Aspergillus glaucus (Table 30-1) (4,5). Aspergilli are molds that reproduce by means of spores termed conidia. Hyphae are septate and dichotomously branched. If the infection rapidly progresses the hyphae tend to be of even diameter, in indolent infections, the hyphae have bullous widened areas. Sporulation is rarely seen, but it grows well in stored hay or grain, decayed vegetation, and soil. Invasive infection is rare unless there is a marked immunodeficiency present.

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Table 30-1 Distribution of Aspergillus Species Aspergillus species

A. fumigatus A. flavus A. niger A. terreus A. versicolor A. nidulans A. oryzae A. glaucus

Isolation Frequency (%)

66 14 7 4 2 1 1 1

Republished with permission from Patterson TF. Aspergillosis. In: Dismukes WE, Pappas PG, Sobel JD, eds. Clinical Mycology. New York: Oxford University Press; 2003:221-40.

Aspergillus is the second most common cause of fungal disease in hematopoietic stem cell transplant (HSCT) recipients, solid organ transplant recipients, and hematologic and oncologic malignancies (5,6). In general, infection occurs in severely immunocompromised hosts, particularly in HSCT patients who develop graft-versus-host disease, patients who develop prolonged and profound neutropenia or patients with neutrophil dysfunction caused by corticosteroid therapy (Table 30-2) (5). Outbreaks in hospitals caused by renovations, new constructions, and ventilation systems have been frequently reported (2). Similarly, patients with chronic granulomatous disease can present with invasive aspergillosis, because of the inability of their phagocytes to generate microbicidal substrates. Less frequently, patients with alcoholic cirrhosis, collagen vascular diseases, and post-influenza infection are also at risk to develop invasive aspergillosis and even nonimmunocompromised hosts can infrequently develop disseminated aspergillosis (2). Table 30-2 Predisposing Factors for Invasive Aspergillosis ● ●

● ● ● ● ● ● ●

Neutropenia Transplantation ● Bone marrow transplant ● Liver transplant ● Lung transplant ● Heart transplant Graft-versus-host disease CMV infection/reactivation Corticosteroids (prednisone > 1 mg/kg/day) HIV (CD4 cell counts < 50/mm3) Chronic granulomatous disease Intravenous drug use Occasionally coexists with gram-negative bacterial pneumonia

Data from Patterson TF. Aspergillosis. In: Dismukes WE, Pappas PG, Sobel JD, et al. Clinical Mycology. New York: Oxford University Press; 2003:221-40; Marr KA, Carter RA, Crippa F, et al. Epdiemiologic and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34: 909-17; Gavalda J, Len O, San Juan R, et al. Risk factors for invasive aspergillosis in solid-organ transplant recipients: A case control study. Clin Infect Dis. 2005;41:52-9. Abbreviation: CMV, cytomegalovirus.

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Pathogenesis Aspergillus is acquired by inhalation of airborne spores; these spores (conidia) are small enough to reach alveoli or sinuses (5). Occasionally conidia in operating rooms can enter the implantation site of prosthetic valves. Exposure is universal, but disease is uncommon, because host factors are very important. Keeping immunocompromised hosts away from dusty hospital renovation or construction areas is useful, as is keeping potted plants out of their hospital rooms. Aspergillus species as with many other molds are considered angioinvasive pathogens. In other words, they have a tendency for vascular invasion, producing thrombosis, ischemia, infarction, and tissue necrosis (2). In compromised hosts, vascular invasion is paramount, leading to infarction, necrosis, edema, and hemorrhage in distal tissues. In infected tissues hyphae are abundant, even forming radially branching clusters in the tissue. In contrast, vascular invasion is not seen, and hyphae are sparse in tissue from patients with chronic granulomatous disease (CGD). Host defenses rely on phagocytes, not on antibodies or lymphocytes. Complement facilitates neutrophil damage to hyphae and monocyte killing of conidia. In addition, oxidation killing is important, because CGD patients have increased risk of infection (4,5). Most infections originate in the respiratory tract, then subsequently disseminates by means of the bloodstream to other tissues including other respiratory tract sites, central nervous system (CNS), kidneys, eyes, skin, liver, and spleen (1,3). Accordingly, the respiratory tract is the most commonly involved site (56%), followed by the CNS (6%), and the upper respiratory tract (sinuses) and skin (5%) (4). Multiorgan involvement or disseminated infection is found in approximately 20% of the patients (4). Prognosis depends on the type and severity of disease as well as the underlying immunological status of the patient (4,7). Invasion from a cutaneous source, such as central venous catheters, rarely occurs. The outcome of infection also varies depending on the site of infection and the status of the underlying immunosuppressive disease (Table 30-3) (4,5,8).

Table 30-3 Mortality Rates in Aspergillosis Underlying Disease/Infection

CNS or disseminated infection Bone marrow transplantation Respiratory tract Leukemia/lymphoma Overall mortality

Mortality Rate (%)

88 86 59 49 58

Data from Marr KA, Carter RA, Crippa F, et al. Epdiemiologic and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:909-17; Lin S, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis. 2001:32:358-66. Abbreviations: CNS, central nervous system.

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Clinical Manifestations Aspergillus infection can manifest in various ways, ranging from colonization to life-threatening invasive disease (Table 30-4) (2,5). Moreover, the clinical manifestations are varied depending on the route of infection and the underlying disease. The overall death rate depends on the underlying immunosuppressive state and can vary from 40% to 90% (4,5,8).

Ear Otomycosis is caused by the growth of mold in the external ear canal, which is common, but rarely invasive (9). Generally, the fungus grows as a saprophyte in debris and cerumen. Treatment is directed at the underlying cause, which is frequently chronic otitis externa and not the Aspergillus.

Paranasal Sinuses (Sinusitis) Acute paranasal sinusitis occurs primarily in patients with neutropenia (1,4). Sinusitis is initially indistinguishable from bacterial sinusitis and can actually coexist. In neutropenic patients mucosal invasion begins in the nasal mucosa or sinuses and can spread rapidly to contiguous structures, causing vascular invasion and necrosis. It rarely affects competent hosts, and when it does, the disease is indolent and granulomatous, and uncommonly becomes invasive. Manifestations include headaches, sinus pain, rapidly complicated by proptosis, and monocular blindness. This entity is also seen in patients with a history of allergic rhinitis, chronic nasal congestion, or recurrent sinusitis. Aspergillus or other molds can be found in the sinus mucosal secretions, along with eosinophils, granulocytes, and Charcot-Leyden crystals in a noninvasive form.

Table 30-4 Manifestations of Invasive Aspergillosis ● ●

●

●

● ● ●

Fever Pulmonary symptomatology ● Pleuritic chest pain—pleural rub ● Dry cough ● Dyspnea ● Hemoptysis, usually minor, occasionally catastrophic Chest radiograph: early can be normal, later followed by infiltrates-infarction, nodules-cavitation Focal neurologic lesions ● Seizures ● Focal neurologic deficits Systemic, multiorgan dysfunction Hemorrhagic skin lesions Negative blood cultures (~99%)

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In allergic fungal sinusitis, the natural course is poorly defined, and on occasion can form a fungus ball in the sinus cavities. Diagnosis is established by the identification of hyphae in tissue. However, in the high-risk patient, a presumptive diagnosis can be established by the identification of Aspergillus species from nasal or sinus cultures.

Endophthalmitis Ocular infection or endophthalmitis is generally produced by direct inoculation after either surgery or trauma, and can be followed by deep stromal invasion. Occasionally, endophthalmitis can be of hematogenous origin, as is seen in neutropenics or intravenous drug users with endocarditis.

Allergic Bronchopulmonary Aspergillosis Allergic bronchopulmonary aspergillosis (ABPA) is a chronic entity progressing from episodes of acute corticosteroid-responsive asthma to fibrotic end-stage lung disease. This is thought to be caused by a hypersensitivity reaction to Aspergillus in the bronchial tree without tissue invasion (10). Most patients have a history of preexisting asthma with fleeting pulmonary infiltrates caused by bronchial plugging. A set of defined criteria have been developed to assist in making the diagnosis: (a) episodic bronchial obstruction (asthma); (b) eosinophilia; (c) positive immediate (type 1) skin test to Aspergillus antigen; (d) elevated total IgE and IgG antibodies specific to A. fumigatus; (e) elevated serum IgE concentrations; (f) precipitating serum antibodies against Aspergillus antigens; (g) history of pulmonary infiltrates; and (h) episodic bronchial plugging that leads to central areas of saccular bronchiectasis (11). Patients occasionally give a history of expectorating brown mucous plugs that are microscopically positive for hyphae. Sputum cultures can be positive for Aspergillus in approximately two thirds of patients. Some patients experience no permanent damage, although others can develop steroid-dependent asthma or irreversible chronic obstructive pulmonary disease (COPD). Chest radiographs frequently reveal alveolar infiltrates, perihilar densities, atelectasis, and cavitary lesions. Infiltrates tend to be transient with a predilection for the upper lobes.

Aspergillomas (Fungus Balls) Aspergillomas consists of hyphal elements, fibrin, mucous, amorphous debris, hosts’ tissues, and a few inflammatory cells. They are generally seen in patients with preexisting cavities or underlying lung disease such as tuberculosis (TB), malignancy, sarcoidosis, histoplasmosis, bullous emphysema, or bronchiectasis (5).

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Clinically, 75% of patients present with hemoptysis, and in approximately 10% of patients it disappears spontaneously (12). The diagnosis is suspected in a high-risk patient with positive sputum cultures on chest radiograph. Aspergillomas tend to be solitary, average 3 to 5 cm, and consist of an intracavitary mass partially surrounded by a radiolucent crescent with walls of varying thickness. Sputum smears and cultures are only intermittently positive for Aspergillus, found in approximately 50% of patients. Serum Aspergillus precipitins are positive in approximately 90% of cases. Complications include spread to pleura, bronchopleural fistulas, bacterial lung abscess and superinfections and rarely, osteomyelitis that primarily affects the thoracic vertebrae.

Invasive Pulmonary Aspergillosis Invasive pulmonary involvement by Aspergillus species is characterized by fever, nonproductive cough or hemoptysis, tachypnea, and variable pulmonary infiltrates on radiograph, which can be unimpressive during neutropenia (2,4). Molds, such as Aspergillus species frequently invade blood vessels inducing pulmonary infarctions accompanied by chest pain, pleuritic rubs, and segmental pulmonary infiltrates (13). Chest radiographs can reveal one or many lesions that can be nodular or cavitary. A computed tomography (CT) scan of the chest is more sensitive than chest radiographs in detecting early infection and often reveals many ring-enhancing cavitary lesions that accompany relatively unimpressive nondiagnostic chest radiographs (14). A suggestive diagnosis can be made on the basis of a halo surrounding a denser consolidated area or crescent sign (14,15). In immunocompromised hosts, pulmonary aspergillosis can extend to involve the pericardium or disseminate hematogenously to cause endocarditis and CNS disease presenting as focal neurological disease, including seizures. A subacute or chronic form of invasive pulmonary aspergillosis presents as a slowly progressive necrotizing pulmonary lesion characterized by persistent antibiotic resistant fever, hemoptysis, and debilitation. This form of aspergillosis has been most often seen in patients with AIDS, diabetes, and chronic granulomatous disease (2,16).

Invasive Aspergillosis The incidence of invasive aspergillosis has increased greatly during the past 10 to 15 years (6). The increase is multifactorial and caused by new and more potent immunosuppressive regimens, greater number of immunocompromised patients, use of potent broad-spectrum antimicrobials, use of high-dose corticosteroids and increases in bone marrow and solid organ transplant recipients.

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If bone marrow function does not return, widespread dissemination to other organs can occur, primarily to other parts of lung, brain, liver, spleen, heart, and thyroid. Invasive aspergillosis must be strongly considered in the high-risk patient with neutropenia, fever, and pulmonary infiltrates that fail to respond to broad-spectrum antibacterial therapy (17). A frequent triad includes an HSCT patient who develops graft-versus-host disease, is put on high-dose steroids (prednisone 1 mg/kg/day), and develops cytomegalovirus (CMV) antigenemia (13,17). The manifestations of aspergillosis in CGD patients are different from those found in neutropenic patients. The symptoms are insidious and include fever, pulmonary infiltrates, increased erythrocyte sedimentation rate (ESR), and a chest radiograph with an area of pneumonia or many small nodular infiltrates. Spread to the thoracic spine, pleura, ribs, brain, and skin is not uncommon.

Aspergillosis of the Central Nervous System The central nervous system is one of the most frequent sites of infection, and has been estimated to occur between 10% to 20% of the time in invasive aspergillosis (1,4,5). Compromised host can have cerebral vessels occluded by Aspergillus, causing cerebral infarction with necrosis and occasionally hemorrhages. A brain abscess is the most common presentation. There are four primary types of CNS aspergillosis: meningitis, meningoencephalitis, single brain abscess, or many brain abscesses. Clinical symptoms include rapidly developing stroke syndrome, seizures, altered mentation, and progressive obtundation. On surgical intervention an area of necrosis with many hyphae surrounded by dense granulation tissue is frequently seen. Despite the newer antifungals, the death rate of CNS infection is still high, more than 80% (8). Recently, however, using the new azole, voriconazole, several investigators have been able to demonstrate response rates of approximately 25% (18,19).

Endocarditis Aspergilli can infect normal, damaged, or prosthetic valves. Aspergillus species can infect heart valves during surgery, or rarely during hematogenous dissemination in intravenous drug use (IVDU). Patients present with fever, cerebral emboli, heart failure, or conduction defects. Despite the endovascular focus of infection, the fungus is rarely cultured from blood (20). The manifestations are similar to those seen with bacterial endocarditis, and the diagnosis is frequently made postmortem.

Gastrointestinal tract The stomach, esophagus, small intestine, and colon are all frequent sites of infection (1). The lesions are caused by either direct invasion from the

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mucosal lining or hematogenous spread from invasive disease. The necrotic lesions tend to extend from the mucosa into the muscularis and produce gastrointestinal ulcerations, primarily in compromised host. Subsequently, vascular invasion with resultant thrombosis and infarction can result in gastrointestinal (GI) bleeds.

Cutaneous Aspergillosis Cutaneous infections are primarily seen in neutropenic, severely immunocompromised host, and are frequently a marker of disseminated disease. On occasion, they can also be seen in burns, intravenous (IV) sites, and surgical wounds (2,21). The resulting infection can be caused by either direct inoculation of Aspergillus from an environmental source or secondary to hematogenous dissemination (5,22). The lesion is classically a necrotizing skin ulceration, covered with a black eschar. For unknown reasons, the lesions tend to be seen more commonly in the lower extremities.

Aspergillus Osteomyelitis Aspergillus bone infection is uncommon, but is usually seen in either neutropenic patients IVDU, or in CGD patients (5,23). The infection begins by either contiguous spread to rib or vertebrae, or by hematogenous spread to vertebrae in compromised host (24). Occasionally, disc space infection with an associated epidural abscess can be seen.

Diagnosis The diagnosis of invasive aspergillosis continues to be a significant problem in the management of this infection. In fact, the diagnosis is frequently made using clinical manifestations and histopathologic analysis of affected tissue. Early recognition of the hosts at greatest risk (prolonged neutropenia, GVHD, corticosteroid usage, CMV antigenemia, etc.) is the key to early diagnosis and subsequent therapy. Definitive diagnosis of aspergillosis is extremely difficult, because there are no pathognomonic laboratory findings other than cultures of biopsy material from infected tissue and histopathology (Table 30-5) (2,5,13). The gold standard in establishing a Table 30-5 Problems with the Diagnosis of Aspergillosis ● ● ● ● ● ● ●

Nonspecific signs and symptoms Nonspecific laboratory parameters Difficulty establishing colonization versus invasion Blood cultures rarely positive (<1%) Need to establish tissue invasion—need biopsy if patients are thrombocytopenic Aspergilli are slow growers in vitro Non–culture-detection test still not available nor reliable

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diagnosis of invasive aspergillosis is the demonstration of tissue invasion caused by hyphae along with a positive culture for Aspergillus. The early initiation of appropriate antifungal therapy is crucial in the management of this infection. Thus, efforts have focused on noninvasive studies to establish a putative diagnosis of invasive aspergillosis. In a highrisk patient, especially with prolonged neutropenia, GVHD, high-dose steroids, and a positive culture from the nares, sputum, or bronchoalveolar lavage is predictive of invasive disease and strong enough evidence to initiate early presumptive antifungal therapy (Table 30-6). In the low-risk patient with CGD, HIV-infection or steroid use, tissue biopsy of an infected site is strongly encouraged before initiating antifungal therapy. The development of diagnostic criteria has been extremely difficult. Recently however, criteria for patients with hematologic malignancy, cancer, and bone marrow transplantation have been developed (17). Although the isolation of Aspergillus from tissue is the gold standard, and because fungal smears and cultures are frequently negative, noninvasive indirect evidence of invasive aspergillosis has been evaluated by serology. There are two testing methods currently available. The galactomannan enzyme-linked immunoabsorbent assay (ELISA) has been used in Europe for several years and uses a monoclonal antibody to galactomannan antigen (25). Galactomannan is a constituent of the Aspergillus cell wall found in the serum of patients with invasive disease. The current ELISA lowers the detection limit to 0.5 to 1.0 ng/mL of galactomannan in the serum. According to Maertens and colleagues, the reported sensitivity is approximately 90%, a specificity of 81% to 100%, and a positive predictive value of 80% (25). Serial monitoring increases the sensitivity of the assay and can detect disease before clinical suspicion. False positives can occur up to 10 days after the start of antifungal therapy and also in association with the use of certain antimicrobials such as piperacillin/tazobactam (26,27). Furthermore, a recent study has also demonstrated a decrease in the sensitivity of the galactomannan assay if the patient has been receiving either prophylactic or

Table 30-6 Criteria for Empiric Antifungal Therapy for Presumptive Invasive Aspergillosis ●

●

High-Risk patients—start treatment empirically if: ● Neutropenia ● Isolation of Aspergillus ● Fever ● Lung infiltrates or a compatible CT findings Low-Risk patients—biopsy and then start therapy if: ● Solid organ transplantation ● Oncologic malignancy ● CGD ● HIV-positive patients

Abbreviations: CGD, chronic granulomatous disease; CT, computed tomography.

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empiric antifungal therapy (28). In addition, it is also possible to use the assay as a therapeutic monitoring test of antifungal efficacy. The second nonculture detection assay is the Fungitell assay, an amebocyte lysis assay that detects the presence of (1-3) beta-D-glucan, a product of fungal cell walls of several fungal organisms, in the serum (29-31). It has been available in the United States since 2004. In prospective clinical trials, the assay has a sensitivity of 70% to 80% and a specificity of 80% to 98% (31). It is, however, considered a panfungal assay, because it is able to detect a broad spectrum of fungi including Fusarium, Trichosporon, Saccharomyces, Acremonium, in addition to Aspergillus and Candida species. Plain radiographs are frequently used as a means to establish the diagnosis. However, plain radiographs are often insensitive and miss subtle pulmonary findings. A high-definition CT scan of the thorax can be very beneficial in establishing the diagnosis of invasive pulmonary aspergillosis in the patient with a HSCT (15). This includes patients with completely normal chest radiographs. The high definition or spiral CT of the thorax can identify small nodules, cavities or infiltrates before the chest radiograph shows any abnormalities. The infiltrates are frequently nodular and peripherally located. During early infection, the nodule is surrounded by a halo, an area of intermediate attenuation (15). After approximately 1 week, the halo disappears, and the infiltrate becomes less defined, followed by the appearance of the crescent sign when cavitation takes place. Bronchoscopy with bronchoalveolar lavage and a transbronchial biopsy can detect approximately 50% of histology proven cases of aspergillosis. However, the use of invasive procedures in patients that are thrombocytopenic are frequently unable to be done. Histology of infected tissue demonstrates angular (45º), dichotomously branching septate hyphae, which are characteristic for Aspergillus species. However, this can also be compatible with infection caused by other molds such as Fusarium, Scedosporium, and Zygomycetes (3). Recently, molecular diagnostic assays, specifically PCR (polymerase chain reaction), DNA fingerprinting, and DNA probes have been used in an attempt to use noninvasive testing for the diagnosis of invasive aspergillosis (32,33). The assays are very sensitive and specific, rapid and reproducible, and are able to detect small amounts of fungal DNA, even though growth can be delayed 1 to 2 weeks or does not grow at all. Unfortunately, these studies are still in the early stages of development.

Treatment The management and prognosis of aspergillosis depends on the specific form of disease and the degree of immune suppression. (Initial doses of the various agents are shown in Table 30-7.) For more than 45 years, amphotericin B deoxycholate was the mainstay of antifungal therapy for aspergillosis. Recent

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Table 30-7 Treatment of Aspergillosis Agent

Initial Dose

Comments

Voriconazole

6 mg/kg IV BID × 2 doses, followed by 4 mg/kg IV BID 400 mg PO BID × 2 doses, followed by 200 mg PO BID 70 mg IV × 1 dose, followed by 50 mg IV QD 0.8 – 1.25 mg/kg/d, IV

Considered first-line therapy

Caspofungin acetate Amphotericin B deoxycholate

Itraconazole

200 mg TID for 4 d, then 200 mg BID, PO

Amphotericin B colloidal dispersion Liposomal amphotericin B Amphotericin B lipid complex

4-6 mg/kg/d, IV

1-5 mg/kg/d, IV 5 mg/kg/d, IV

Approved for patients with refractory disease Considered first-line therapy but high failure rate; significant interaction with cyclosporine Useful if a patient is eating and not receiving cytochrome P-450 inducers; significant interaction with cyclosporine; levels should be measured to ensure adequate absorption Less nephrotoxic than amphotericin B deoxycholate Less nephrotoxic than amphotericin B deoxycholate Less nephrotoxic than amphotericin B deoxycholate

Abbreviations: BID, twice daily; d, day; IV, intravenous; PO, orally; QD, daily; TID, three times daily.

studies by Herbrecht and coworkers have demonstrated therapy with voriconazole lead to improved survival when compared to amphotericin B in invasive aspergillosis, without the dose-limiting nephrotoxicity that is so commonly seen with amphotericin B (19). Furthermore, guidelines for the management of aspergillosis have been published by the Infectious Diseases Society of America (34).

Allergic Bronchopulmonary Aspergillosis The goal of therapy should include relief of bronchospasm, reversal of the parenchymal infiltration, and preservation of lung structure and function. Corticosteroids have been the mainstay of therapy for many years, however, steroid use has many pitfalls. The recommended dosage is 0.5 mg/kg/day during exacerbations until the chest radiograph clears, and for at least 3 months (34). Afterwards, if stable, the steroid dose should be tapered over a period of 3 months if possible. A study conducted by the Mycosis Study Group demonstrated that itraconazole (Sporanox) 200 mg twice daily has been successfully used to decrease airflow obstruction episodes and decrease exacerbations without the use of steroid therapy (35).

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Aspergilloma In most situations, most patients do not require any form of therapy. Aspergillomas can be treated by surgical resection. However, this approach can cause significant illness and death and therefore should be reserved for patients who develop severe hemoptysis. Systemic antifungal therapy is rarely curative because of poor penetration of drug into the fungus ball (5).

Invasive Aspergillosis Therapy for invasive aspergillosis has recently changed dramatically (34). However, despite newer antifungal therapy, the death rates still range from 50% to 100%, depending primarily on the underlying disease and the site of infection. The current mainstay of therapy for invasive aspergillosis is now considered to be voriconazole (Vfend). The appropriate dose of voriconazole for aspergillosis is 6 mg/kg twice daily for 1 day, followed by 4 mg/kg twice daily. A recently published randomly assigned, multicenter study compared conventional amphotericin B and voriconazole as initial therapy for invasive aspergillosis (19). This pivotal study in patients with invasive aspergillosis demonstrated that initial therapy with voriconazole led to better responses and improved survival with fewer serious side effects, specifically renal insufficiency and infusion-related toxicity. Voriconazole is one of the newer lipophilic triazole antifungals, structurally related to fluconazole (35-38). It exhibits excellent in vitro activity against a broad range of fungi, including Candida albicans, non-albicans Candida species, Aspergillus, Fusarium, Scedosporium apiospermum, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and various dermatophytes. Its oral bioavailability is greater than 95%, with nonlinear kinetics caused by first-pass metabolism. The drug undergoes extensive hepatic metabolism by three cytochrome P-450 enzymes and is metabolized primarily by means of the liver. Less than 2% of the drug is excreted unchanged in the urine. Voriconazole can decrease the elimination of drugs metabolized by cytochrome P-450 enzyme (CYP) 3A4, although inducers can decrease plasma concentrations of voriconazole, and inhibitors of 3A4 can increase levels of voriconazole. Voriconazole increases exposure to warfarin, sirolimus, tacrolimus, cisapride, quinidine, ergot alkaloids, cyclosporine, digoxin, midazolam, or triazolam, and phenytoin plasma concentrations. Administration with carbamazepine, barbiturates, phenytoin, rifampin, and rifabutin reduce voriconazole levels. Adverse events include skin rashes in approximately 10% to 18% of patients; elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and alkaline phosphatase in 4% to 20% of patients; and transient visual disturbances, which are described in approximately 20% to 33% of patients.

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Amphotericin B (deoxycholate or lipid preparations) continues to be alternative antifungal agents for invasive aspergillosis (36,39). Amphotericin B deoxycholate can be administered parenterally at a dosage varying from 1.0 to 1.5 mg/kg/day for a total dose of 1.5 to 4.0 g. Many Aspergillus species are relatively insensitive to amphotericin B, thus results are poor. In addition, A. terreus is considered intrinsically resistant to the polyenes (40). Its adverse events includes nephrotoxicity, which occurs in approximately 30% to 40% of patients receiving parenteral amphotericin B, given the long duration of therapy required in most patients and hence, predictable nephrotoxicity. Electrolyte abnormalities include the depletion of potassium and magnesium and are seen in almost 100% of patients. Infusion-related toxicity occasionally occurs in the form of acute reactions approximately 30 to 45 minutes after beginning infusion. Typically, chills, fever, and tachypnea can be present. Liver function abnormalities include elevations in aminotransferases in approximately 10% of patients. Thrombocytopenia and normocytic normochromic anemia can occasionally be detected after 7 to 10 days of therapy. If therapy lasts for more than 1 week, it is essential to monitor the complete blood count (CBC) with differential three times a week while the patient is on therapy. The lipid preparations of amphotericin B, which facilitate the administration of much higher doses of amphotericin with fewer side effects, have also shown encouraging results in studies of refractory aspergillosis (41). The three amphotericin B lipid preparations (Amphotec, Abelcet, AmBisome) are Food and Drug Administration (FDA) approved. All seem to deliver higher concentrations of the drug with a theoretical increase in therapeutic potential and decreased nephrotoxicity. Although all are lipid formulations of amphotericin B, the different formulations are not interchangeable, and dosages can vary (Table 30-7) (36). Although significantly fewer than with conventional amphotericin B, the lipid preparations still have important side effects (42). Nephrotoxicity, although less than with d-amphotericin B, is still present in approximately 15% to 25% of patients. Infusion-related toxicity is also seen and includes fever, chills, rigors, nausea, vomiting, hypertension, tachycardia, and hypoxia. Elevations in hepatic aminotransferases, alkaline phosphatases, and serum bilirubin can occasionally occur. Itraconazole (Sporanox) is also approved for use in aspergillosis, but has met with limited use, although it has shown efficacy in patients with aspergilloma, chronic necrotizing pulmonary aspergillosis, ABPA, and invasive aspergillosis (36). Itraconazole is a synthetic lipophilic-triazole antifungal agent. It has less effect on human sterol metabolism and does not decrease cortisol or testosterone levels, as is seen with ketoconazole. In-vitro itraconazole exhibits activity against a broad spectrum of fungi, including Candida albicans and many non-albicans Candida species, C. neoformans, C. immitis, H. capsulatum, B. dermatitidis, and Aspergillus species. Both the oral solution and injection contain itraconazole solubilized by hydroxypropyl-beta-cyclodextrin as a molecular inclusion complex. The dosage for aspergillosis is 100 to 300

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mg given orally twice daily. In severe life-threatening infections, the loading dose is 200 mg three times a day for the first 3 days, followed by 200 mg twice daily. The oral bioavailability is maximized when the drug is taken with food, and acidic gastric pH bioavailability is approximately 55%. Itraconazole is extensively distributed into tissues especially the lungs, brain, kidneys, liver, spleen, bone, and muscle where the drug concentrations are two to three times higher than the corresponding plasma concentration. The compound is metabolized by the liver into many metabolites, including hydroxy-itraconazole, the major metabolite that possesses in-vitro activity similar to the parent compound. Renal excretion of parent drug is less than 1%. Antacids can reduce absorption of itraconazole. Edema can occur with coadministration of calcium channel blockers (e.g., amlodipine, and nifedipine). Itraconazole can decrease the elimination of drugs metabolized by CYP 3A4, although inducers can decrease plasma concentrations of itraconazole, and inhibitors of 3A4 can increase levels of itraconazole. Rhabdomyolysis has been reported with the coadministration of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (lovastatin or simvastatin). Nausea, vomiting, diarrhea, and abdominal discomfort are the more common side effects. High doses can produce hypertension, hypokalemia, or edema. It should be used cautiously in hepatic insufficiency. Monitor liver function test in patients with preexisting hepatic dysfunction. It should not be given in patients with creatinine clearance less than 30 mL/min. Concomitant use of itraconazole with quinidine, dofetilide, pimozide, cisapride, and HMG-CoA reductase inhibitors is contraindicated. Caspofungin, a semisynthetic water-soluble pneumocandin derived from the fermentation products of Glarea lozoyensis, is the first of the new family of antifungal compounds (43). These drugs are noncompetitive inhibitors of the synthesis of the enzyme glucan synthase, which produces beta-(1,3)-D-glucan, an essential component of the cell wall of susceptible fungi. Caspofungin possesses in-vitro activity against a broad range of fungi, including Candida albicans, many non-albicans Candida species and Aspergillus fumigatus, A. flavus, and A. terreus (44,45). The recommended dose is 70 mg IV loading dose, followed by 50 mg IV daily. Distribution instead of excretion or biotransformation is the primary mechanism influencing plasma clearance. There is minimal renal excretion and some hepatic metabolism by hydrolysis and N-acetylation. Less than 2% of dose is excreted unchanged in the urine. Caspofungin reduces tacrolimus levels by approximately 20%, although cyclosporine increases caspofungin levels by approximately 35%. Coadministration of both have led to transient increases in aminotransferases in approximately 10% of patients. In addition, coadministration of hepatic inducers and inducer/inhibitors (efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dexamethasone, and carbamazepine) can result in significant reductions in caspofungin levels. There is no antagonism or interaction with amphotericin B or azoles. The more common side effects include phlebitis/thrombophlebitis (11%-15%), liver function test abnormalities (AST, ALT, and alkaline phosphatase, 10%-13%),

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and infusion-related toxicity (10%). In patients with moderate hepatic insufficiency, after a loading dose of 70 mg, a daily dose of 35 mg should be used. Because there is minimal renal excretion, the daily dosage does not have to be modified for patients in renal failure. Caspofungin (Cancidas) was the first echinocandin compound approved for use in the treatment of invasive aspergillosis in patients who are refractory to, or intolerant of other antifungals (44,45). Many new drugs such as posaconazole, micafungin, and anidulafungin have demonstrated in-vitro activity against Aspergillus species and are being extensively evaluated (35,46-48). Posoconazole has an indication for prophylaxis of invasive Aspergillus infections in patients 13 years or older who are immunocompromised because of HSCT or GVHD. In the past, combination therapy has been occasionally used in patients with invasive aspergillosis. In one of the early clinical trials, the combination of high-dose amphotericin B (1.0-1.5 mg/kg) together with flucytosine, dosed to achieve a peak serum level of 30 to 60 µg/mL was associated with a higher survival rate (87%) in patients with leukemia and invasive aspergillosis (1,4,5). Other combinations included the addition of rifampin to amphotericin B because of reports demonstrating some degree of in-vitro synergistic activity with this combination of drugs. Most of the time however, the adverse events limited their combined use (1,4,5). The recent approval of new antifungals with different mechanisms of action have increased interest in the use of combination antifungals. Recent in-vitro and animal trials have suggested some in-vitro additive or synergistic effect with the combination of echinocandins (caspofungin, anidulafungin, micafungin) and either voriconazole or amphotericin B (49-51). Controlled clinical trials however, have not been undertaken. At this point in time, although frequently used in clinical practice, the use of combination antifungal therapy does not have any definitive research to unequivocally support its standardized use (52). Although the role of immunoadjuvants for invasive fungal infections has not been well studied, several anecdotal reports have occasionally demonstrated improved outcomes (4, 5). Future research using granulocyte colonystimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon to help augment host response to fungal infections can prove beneficial in managing these opportunistic pathogens and improving the outcome. Surgical therapy, either alone or in combination with antifungal chemotherapy can also be useful in selected patients with either localized pulmonary or CNS aspergillosis (14). Surgical excision can be useful in brain abscess and sinus infections caused by Aspergillus. In addition, valve replacement is mandatory in managing Aspergillus endocarditis. For patients with aspergilloma, surgery can be required if massive hemoptysis develops; otherwise patients can continue to be followed with close observation (2,5). Indications for surgery include diagnostic resection, disease reduction, and

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massive hemoptysis from a single lesion. Surgical resection however, does have risk such as hemorrhage and undetected multifocal aspergillosis. A crucial factor in optimizing therapy in any patient with invasive aspergillosis is the decrease or elimination of the immunosuppression whenever possible. The recent literature suggest that if patients are diagnosed and treated early with appropriate antifungal therapy, the response rates can reach 50% or greater (53).

Prevention Prevention of opportunistic fungal pathogens such as aspergillosis in highrisk patients continues to be an extremely difficult dilemma. In the hospital setting, the current recommendation is the use of HEPA filtration as well as rooms with high frequency air exchange and positive pressure. Although in clinical practice some physicians use antifungals agents with Aspergillus activity as primary prophylaxis agents, there are no current studies or recommendations to promote this practice on a routine basis (54). However, there are certain situations where these antifungal agents are currently used as secondary prophylaxis. For example, patients with a previous diagnosis of invasive aspergillosis who are going to undergo stem-cell transplantation, solid organ transplantation, or a period of prolonged granulocytopenia and immunosuppression should receive suppressive prophylaxis with either voriconazole 4 mg/kg twice daily, itraconazole 300 mg twice daily, posaconazole 200 mg thrice daily, or amphotericin B 1 mg/kg daily (54).

Summary Infections caused by Aspergillus species have become an extremely common cause of illness and death in the high-risk immunosuppressed host. In fact, aspergillosis has become one of the leading causes of death in HSCT recipients as well as solid organ transplant recipients. It is important to understand the difficulty in establishing a definitive diagnosis of aspergillosis because of the lack of laboratory tests and the broad spectrum of disease manifestations. In many cases, the clinician will have to rely on a high index of suspicion in the high-risk patient to initiate early and appropriate antifungal therapy. Recent clinical trials that have evaluated the new azole, voriconazole, in immunocompromised patients with invasive aspergillosis demonstrate that voriconazole has made a significant effect in decreasing the illness and death rate of this previously deadly infection. Because of the difficulty in establishing a correct diagnosis and the rapid and recent development in newer diagnostic techniques and new antifungals, it is of utmost

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importance for the primary care physician to obtain the opinion of an infectious disease consultant for any patient who can be suspected of having a diagnosis of aspergillosis. REFERENCES 1. Denning DW. Invasive Aspergillosis. Clin Infect Dis. 1998;12:781-805. 2. Patterson TF. Aspergillus species. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone; 2005:2958-72. 3. Latgé JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev. 1999;12:310-50. 4. Patterson TF, Kirkpatrick WR, White M, Hiemenz JW, Wingard JR, Dupont B, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore). 2000;79:250-60. 5. Patterson TF. Aspergillosis. In: Dismukes WE, Pappas PG, Sobel JD, eds. Clinical mycology. New York: Oxford University Press; 2003:221-40. 6. Marr KA, Carter RA, Crippa F,Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34:909-17. 7. Ribaud P, Chastang C, Latgé JP, Baffroy-Lafitte L, Parquet N, Devergie A, et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis. 1999;28:322-30. 8. Lin SJ, Schranz J,Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32:358-66. 9. Kaur R, Mittal N, Kakkar M, Aggarwal AK, Mathur MD. Otomycosis: a clinicomycologic study. Ear Nose Throat J. 2000;79:606-9. 10. Rosenberg M, Patterson R, Mintzer R, Cooper BJ, Roberts M, Harris KE. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med. 1977;86:405-14. 11. Patterson R, Greenberger PA, Radin RC, Roberts M. Allergic bronchopulmonary aspergillosis: staging as an aid to management. Ann Intern Med. 1982;96:286-91. 12. Kaufman L, Standard PG, Jalbert M, Kraft DE. Immunohistologic identification of Aspergillus spp. and other hyaline fungi by using polyclonal fluorescent antibodies. J Clin Microbiol. 1997;35:2206-9. 13. Wingard JR, Leather HL. Diagnosis and therapy of invasive aspergillosis in hematopoietic stem cell transplant recipients. Curr Treatment Options Infect Dis. 2003;5:517-27. 14. Caillot D, Casasnovas O, Bernard A, Couaillier JF, Durand C, Cuisenier B, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol. 1997;15:139-47. 15. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol. 2001;19:253-9. 16. Denning DW. Chronic forms of pulmonary aspergillosis. Clin Microbiol Infect. 2001;7 Suppl 2:25-31. 17. Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34:7-14. 18. Denning DW, Ribaud P, Milpied N, Caillot D, Herbrecht R, Thiel E, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis. 2002;34:563-71. 19. Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347:408-15. 20. Duthie R, Denning DW. Aspergillus fungemia: report of two cases and review. Clin Infect Dis. 1995;20:598-605. 21. Denning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis. 1990;12:1147-201. 22. Allo MD, Miller J, Townsend T, Tan C. Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med. 1987;317:1105-8. 23. van ‘t Wout JW, Raven EJ, van der Meer JW. Treatment of invasive aspergillosis with itraconazole in a patient with chronic granulomatous disease. J Infect. 1990;20:147-50.

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24. Vinas FC, King PK, Diaz FG. Spinal aspergillus osteomyelitis. Clin Infect Dis. 1999; 28:1223-9. 25. Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood. 2001;97:1604-10. 26. Adam O, Aupérin A, Wilquin F, Bourhis JH, Gachot B, Chachaty E. Treatment with piperacillintazobactam and false-positive Aspergillus galactomannan antigen test results for patients with hematological malignancies. Clin Infect Dis. 2004;38:917-20. 27. Machett M, Fyrfaro E,Viscoli C. Galactomannan in piperacillin-tazobactam: How much and to what extent. Antimicrob Agents Chemother. 2005;49:3884-5. 28. Marr KA, Laverdiere M, Gugel A, Leisenring W. Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis. 2005;40:1762-9. 29. Hiyoshi M,Tagawa S, Hashimoto S, Sakamoto C,Tatsumi N. Evaluation of a new laboratory test measuring plasma (1->3)-beta-D-glucan in the diagnosis of Candida deep mycosis: comparison with a serologic test. Kansenshogaku Zasshi. 1999;73:1-6. 30. Kami M,Tanaka Y, Kanda Y, Ogawa S, Masumoto T, Ohtomo K, et al. Computed tomographic scan of the chest, latex agglutination test and plasma (1AE3)-beta-D-glucan assay in early diagnosis of invasive pulmonary aspergillosis: a prospective study of 215 patients. Haematologica. 2000;85:745-52. 31. Ostrosky-Zeichner L, Alexander BD, Kett DH, Vazquez J, Pappas PG, Saeki F, et al. Multicenter clinical evaluation of the (1->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis. 2005;41:654-9. 32. Kami M, Fukui T, Ogawa S, Kazuyama Y, Machida U,Tanaka Y, et al. Use of real-time PCR on blood samples for diagnosis of invasive aspergillosis. Clin Infect Dis. 2001;33:1504-12. 33. Kawazu M, Kanda Y, Goyama S,Takeshita M, Nannya Y, Niino M, et al. Rapid diagnosis of invasive pulmonary aspergillosis by quantitative polymerase chain reaction using bronchial lavage fluid. Am J Hematol. 2003;72:27-30. 34. Stevens DA, Kan VL, Judson MA, Morrison VA, Dummer S, Denning DW, et al. Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:696-709. 35. Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Catanzaro A, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342:756-62. 36a. Rex JH, Stevens DA. Systemic antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone; 2005:50214. 36b. Hossain MA, Reyes GH, Ghannoum MA. Newer antifungal agents and treatment strategies. Rev Med Microbiol. 2001;12(suppl 1);S3-12. 37. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12:501-17. 38. DiDomenico B. Novel antifungal drugs. Curr Opin Microbiol. 1999;2:509-15. 39. Gallis HA, Drew RH, Pickard WW. Amphotericin B: 30 years of clinical experience. Rev Infect Dis. 1990;12:308-29. 40. Sutton DA, Sanche SE, Revankar SG, Fothergill AW, Rinaldi MG. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J Clin Microbiol. 1999;37:2343-5. 41. Wong-Beringer A, Jacobs RA, Guglielmo BJ. Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis. 1998;27:603-18. 42. Barriere SL. Pharmacology and pharmacokinetics of traditional systemic antifungal agents. Pharmacotherapy. 1990;10:134S-140S. 43. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362:1142-51. 44. Stone EA, Fung HB, Kirschenbaum HL. Caspofungin: an echinocandin antifungal agent. Clin Ther. 2002;24:351-77; discussion 329. 45. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis. 2003;36:1445-57. 46. Klepser ME. Future candidates in the search for new antifungal agents. Curr Treatment Options Infect Dis. 2003;5:489-94. 47. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12:40-79. 48. Vazquez JA. Anidulafungin: a new echinocandin with a novel profile. Clin Ther. 2005;27:657-73. 49. Cuenca-Estrella M. Combinations of antifungal agents in therapy—what value are they? J Antimicrob Chemother. 2004;54:854-69.

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50. Johnson MD, MacDougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH. Combination antifungal therapy. Antimicrob Agents Chemother. 2004;48:693-715. 51. Mukherjee PK, Sheehan DJ, Hitchcock CA, Ghannoum MA. Combination treatment of invasive fungal infections. Clin Microbiol Rev. 2005;18:163-94. 52. Viscoli C. Combination therapy for invasive aspergillosis [Editorial]. Clin Infect Dis. 2004;39:803-5. 53. Maertens J,Theunissen K,Verhoef G,Verschakelen J, Lagrou K,Verbeken E, et al. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005;41:1242-50. 54. Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2000;6:659-713; 715; 717-27; quiz 729-33.

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Part VIII

Skin, Bone, and Joint Infections

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Chapter 31

Septic Arthritis WILLIAM G. GARDNER, MD

Key Learning Points 1. The acutely swollen joint may be caused by many different infectious agents but may also be due to non-infectious causes such as crystalline arthropathy. 2. Establishing the microbial etiology of septic arthritis requires a multifaceted approach including evaluation of the clinical setting, age of the individual, predisposing factors or conditions, and diagnostic arthrocentesis for cell count and cultures. 3. A key factor on physical examination of the septic joint is severe pain on joint movement or weight bearing. 4. Appropriate and prompt antimicrobial therapy is essential in preserving function of the septic joint.

T

he acutely swollen joint presents the physician with a diagnostic and therapeutic challenge. The differential diagnosis is extensive including noninfectious causes of joint inflammation, reactive arthritis caused by infection at a site remote from the joint, and infections within the joint space (1,2). Septic arthritis, which is caused by direct invasion of the joint space by a pyogenic microorganism, can be difficult to differentiate from joint swelling of reactive or noninfectious origin. However, it is extremely important to establish a correct diagnosis and institute the proper therapy to ensure a satisfactory outcome. Unrecognized and untreated bacterial infection of the joint can lead to permanent injury and even death (3). Because it is often difficult to establish a specific diagnosis at an early point, empirical antimicrobial therapy can be necessary if the clinical setting suggests an infectious cause. 581

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New Developments in the Diagnosis and Treatment of Septic Arthritis ●

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An increasing proportion of cases of septic arthritis are due to Gram-negative bacteria. Kingella kingae is a common cause of septic arthritis in children under 5 years of age. The incidence of urogenital gonococcal infection is increasing. This may reverse the previously seen trend of a decrease in gonococcal joint infection. Empirical therapy for suspected Staphylococcus aureus septic arthritis must consider the increasing prevalence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).

Pathogenesis Joint infection most often results from the hematogenous spread of microorganisms to the joint from a primary site of infection elsewhere in the body. Several factors contribute to seeding of the joint, including the vascular nature of the synovial membrane and the absence of a limiting basement membrane (2). When bacteria reach the joint space, they prompt an intense inflammatory response with release of proteolytic enzymes from synovial lining cells and neutrophils. The inflammatory response is further enhanced by the production of cytokines, such as interleukin-1 and tumor necrosis factor (TNF). Additionally, the infecting bacteria release proteolytic enzymes and collagenases that, along with the host inflammatory response, damage the articular cartilage if not properly treated. Inoculum size and other virulence factors of specific bacteria are important in the pathogenesis of joint infection. For example, Staphylococcus aureus, a common pathogen in septic arthritis, has a predilection for infecting joints that is partly the result of its specific binding properties for collagen and articular cartilage. Recent studies have suggested that strains of S. aureus that produce certain types of capsular polysaccharides can cause septic arthritis more often than other strains (4,5). The capsular polysaccharide can protect the microorganism from phagocytosis and intracellular killing by macrophages. Microorganisms can also reach the joint space by inoculation at surgery, during joint aspiration or injection, and after trauma. The incidence of septic arthritis after intra-articular injections is low. Such arthritis can occur in patients with rheumatoid arthritis who receive intra-articular injections of corticosteroids for acute flare-ups of their arthritis (6). Septic arthritis also has been reported after arthroscopy, occurring in 0.12% of cases in one large series (7). In children, septic arthritis can result from extension of a contiguous focus of osteomyelitis into the joint. This is uncommon in adults, but septic arthritis can result from a contiguous cellulitis, abscess, or septic bursitis. Joint inflammation also can occur as a reactive arthritis caused by an infectious process at a site remote from the joint. Examples include Reiter

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syndrome, the arthropathies associated with enteric infections, and the chronic arthritis of Lyme disease. The list of infectious agents associated with reactive arthritis is steadily growing. The pathogenesis of joint inflammation associated with these agents is unclear. In some cases, intra-articular persistence of viable but nonculturable bacteria such as Chlamydia trachomatis can be responsible for ongoing inflammation. In others, only the bacterial antigens are found in synovial tissue, causing an immune-mediated arthritis. Recent studies suggest the distinction between infectious arthritis and reactive arthritis is less clear than previously thought (8). Several factors have been recognized as predisposing to septic arthritis, and these are listed in Table 31-1. Infections at extra-articular sites, such as urogenital or rectal Neisseria gonorrhoeae infection, can lead to bacteremia with subsequent infection of one or more joints. Preexisting joint disease, especially advanced rheumatoid arthritis, creates an excellent environment for bacterial growth if the bacteria are seeded during an intra-articular injection or through bacteremia (6). Often there is a history of blunt trauma preceding joint infection. This trauma can injure the vascular supply, allowing bacteria to enter the joint and establish an infection. Immunologic abnormalities (e.g., immunoglobulin deficiency, complement deficiency, phagocytic defect) are also important factors that predispose to septic arthritis, especially when the latter is caused by Neisseria (2).

Table 31-1 Predisposing Factors for Infectious Arthritis Chronic Serious Illness

Cancer Hepatic cirrhosis Diabetes mellitus Impaired Host Defense Mechanisms

Immunosuppressive drugs Hypogammaglobulinemia Complement deficiencies Disorders of chemotaxis or intracellular killing Previous Arthritis or Joint Damage

Rheumatoid arthritis Crystal-induced arthritis Severe osteoarthritis Extra-articular Infection Systemic Lupus Erythematosus Intravenous Drug Abuse Joint Trauma Intra-articular Injections

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Etiology Infectious arthritis can be caused by a wide variety of microorganisms including pyogenic bacteria, mycobacteria, fungi, and viruses. Additionally, noninfectious joint inflammation of various causes can mimic infectious arthritis and must be considered in the differential diagnosis. Several factors are important in determining the microbial cause of a case of septic arthritis, including the clinical setting, predisposing factors or conditions, and the age of the patient. Table 31-2 lists the relative frequency of several common bacterial causes of infectious arthritis in various age groups. In neonates and infants younger than 1 year of age, the most common bacterial causes of septic arthritis are S. aureus, group B streptococcus, and gram-negative bacilli (e.g., Escherichia coli). Haemophilus influenzae was a previously common agent in septic arthritis in children between the ages of 1 year and 5 years, but the widespread use of H. influenzae vaccine has decreased its frequency markedly. Kingella kingae has recently been found to be a common cause of septic arthritis in children younger than 5 years of age, accounting for nearly half of cases in some series (9). In children 5 to 15 years of age, S. aureus accounts for almost 50% of cases. N. gonorrhoeae should be considered a possible pathogen in sexually active adolescents and adults with arthritis. The incidence of urogenital gonococcal infections decreased between 1975 and 1997 with a subsequent decrease in disseminated gonococcal infection and arthritis. However, since 1997 the incidence of urogenital infection caused by N. gonorrhoeae has increased, especially among men who have sex with men, which can result in an increase in gonococcal joint infections (10,11). In the adult population, S. aureus is the most common bacterial agent of septic arthritis; however, in certain clinical settings or in persons with predisposing conditions, (Table 31-3) other microorganisms must be considered. This becomes important when selecting initial empirical antimicrobial therapy

Table 31-2 Etiology of Septic Arthritis by Age* Age (years) Microorganism

Staphylococcus aureus Streptococcus species† Streptococcus pneumoniae Haemophilus influenzae Neisseria gonorrhoeae Neisseria meningitidis Gram-negative bacilli‡

<1

1–5

5–15

15–50

>50

+++ ++ ++ + — — ++

+++ ++ ++ + — — ++

+++ ++ + + + + ++

++ + — — ++++ + +

++++ ++ + — + + ++

* Plus signs indicate the frequency of each pathogen, with “+” signifying an uncommon occurrence and “++++” signifying a very common occurrence. † Includes Streptococcus groups A and B, viridans streptococci, and micro-aerophilic Streptococcus species ‡ Includes Enterobacteriaceae and Pseudomonas aeruginosa.

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Table 31-3 Pathogens Associated with Specific Clinical Settings or Predisposing Conditions Clinical Setting or Predisposing Condition

Neonatal arthritis Adolescent or sexually active adult Elderly with urinary infection Immunocompromised adult Adult with alcoholism, rheumatoid arthritis, or immunoglobulin deficiency Intravenous drug user Animal bite wound Human bite wound History of tick bite Systemic lupus erythematosus Erythematous papulopustular skin lesions Arthritis following bacterial enteritis

Pathogen

Group B Streptococcus, Staphylococcus aureus Neisseria gonorrhoeae Escherichia coli, Proteus mirabilis S. aureus, Pseudomonas aeruginosa Other gram-negative bacilli Streptococcus pneumoniae P. aeruginosa, Serratia species Pasteurella multocida, S. aureus Eikenella corrodens, S. aureus Anaerobic bacteria Borrelia burgdorferi Salmonella species Neisseria gonorrhoeae, N. meningitidis Sterile reactive arthritis

for septic arthritis, because routine antistaphylococcal drugs do not inhibit some of these pathogens. In recent years, an increasing proportion of cases of septic arthritis have been caused by gram-negative bacilli. A particular factor or condition usually predisposes to the gram-negative infection. In individuals who abuse intravenous drugs Pseudomonas aeruginosa and Serratia species can be involved and can infect the sternoclavicular or sacroiliac joints (12). Aeromonas hydrophila can cause arthritis in those with acute leukemia. E. coli and Proteus mirabilis can be associated with septic arthritis in elderly people who have urinary infections (13). Salmonella arthritis is associated with systemic lupus erythematosus, especially in those who are chronic carriers of salmonella. Septic arthritis occurring after bite wounds from dogs or cats is often caused by Pasteurella multocida, whereas arthritis associated with human bites can be caused by Eikenella corrodens (14,15). Anaerobic bacteria are an uncommon cause of septic arthritis. When an anaerobic joint infection occurs, it is usually in a setting of chronic debilitating disease, posttraumatic infection, or total joint arthroplasty (16). Nearly half of all anaerobic joint infections are polymicrobic. Peptococcus species are the most common anaerobic bacteria associated with posttraumatic and postoperative anaerobic septic arthritis, whereas Bacteroides species are responsible for most cases of septic arthritis associated with chronic debilitating disease. A recent review of septic arthritis caused by Clostridium species indicated that prompt diagnosis and proper management with open arthrotomy promise a good outcome (17).

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Inflammatory arthritis can also be associated with viral infections. Such arthritis is usually polyarticular, which is in contrast with bacterial arthritis. For example, rubella in young women commonly causes a polyarthritis, usually beginning within 7 days of onset of the characteristic rash in this disease and persisting for several weeks. The arthritis of rubella usually involves the small joints of the hands and, less commonly, the wrists and knees. A similar arthritis can occur in women who have received a rubella vaccine. Other viral arthritis in adults include the arthritis associated with hepatitis B infection, which is related to antigen-antibody complexes. Joint inflammation usually occurs in the pre-icteric phase and resolves with the onset of jaundice. Men infected with the mumps virus can develop a polyarthritis similar to that of rubella infection in young women (18). Additionally, parvovirus B19 can cause a self-limiting polyarthritis, which is acute, symmetrical, involving the hands, wrists and knees, and lasting from 2 to 4 weeks (19). Several other viral infections have been associated with arthritis including infection with HIV, hepatitis A and C, and lymphocytic choriomeningitis virus (20).

Clinical Manifestations Generally, septic arthritis is divided into gonococcal and nongonococcal arthritis. In nongonococcal septic arthritis, it is extremely important to recognize the infection early and to begin treatment promptly to achieve a good outcome. In contrast, gonococcal arthritis usually runs a less virulent course. Nongonococcal arthritis is mono-articular in 80% to 90% of cases. Although the knee is the most commonly affected joint, any joint can be involved. The onset is usually abrupt, with fever and joint pain; however, fever can be absent in the elderly, in persons with severe underlying disease, and in those on corticosteroids. On examination, the affected joint is erythematous, warm, and swollen, with a significant effusion present in most cases. A key point in the diagnosis of nongonococcal arthritis is the severe pain that occurs with attempted movement of the joint or with weight bearing (2,21). Gonococcal arthritis usually has a much different clinical presentation than does nongonococcal arthritis, commonly taking the form of a polyarthritis that is often migratory with associated painful tenosynovitis. The knees, wrists, hands, and ankles are commonly affected. Fever and chills are common. Joint effusions, when present, are usually small and difficult to tap. The synovial fluid leukocyte count can be less than 50,000 cells/mm3, and synovial fluid cultures are usually negative. However, blood cultures and cultures of primary sites (e.g., urethra, cervix, rectum) are often positive for N. gonorrhoeae. Skin manifestations of disseminated gonococcal disease, which are present in two thirds of cases, are a key to diagnosis. The skin lesions, often noted on the

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extremities, begin as painful maculopapular lesions that become pustular with a central area of necrosis (12). The lesions are not specific for gonococcal infection and can occasionally be seen in cases of infection caused by other microorganisms, including S. aureus, N. meningitidis, group A Streptococci, and H. influenzae. However, in the right clinical setting, they are very helpful in supporting the diagnosis of gonococcal arthritis. The primary genitourinary infection in cases of gonococcal arthritis is often not clinically apparent, and patients can be completely asymptomatic. Disseminated gonococcal infection with arthritis occurs more often in women than in men and commonly occurs during menstruation or pregnancy (2). Untreated, gonococcal polyarthritis can either resolve spontaneously or settle into a single large joint, mimicking nongonococcal arthritis. On rare occasions a monoarticular arthritis caused by N. gonorrhoeae can develop in the absence of the preceding skin lesions and polyarthritis (22). In both of the aforementioned situations, the synovial fluid findings are similar to those in nongonococcal arthritis, with leukocyte counts in excess of 50,000 cells/mm3. Joint fluid cultures for N. gonorrhoeae are more likely to be positive, and blood cultures are usually negative. Generally, the higher the synovial fluid leukocyte count is, the more likely the culture is positive. Gonococcal monoarthritis usually responds well to appropriate antimicrobial therapy and percutaneous needle drainage. Open surgical drainage of the joint is rarely needed.

Diagnosis Septic arthritis must be considered in any patient presenting with one or more acutely swollen joints. As shown in Table 31-4, the differential diagnosis is broad and includes both infectious and noninfectious conditions. Several factors should be considered in making the diagnosis, including the age of the patient, the duration of symptoms, the presence of recent or remote trauma, the status of the patient’s immune system, and the possibility of infection at another site (2). Laboratory studies that can be helpful in establishing a diagnosis of septic arthritis include the peripheral blood leukocyte count, erythrocyte sedimentation rate, and C-reactive protein concentration. Although usually elevated in septic arthritis, each is nonspecific and can also be elevated in noninfectious inflammatory arthritis. Peripheral blood cultures are positive for the causative agent in 40% to 50% of cases of nongonococcal arthritis, but less than 10% of cases of gonococcal arthritis. If gonococcal arthritis is being considered, obtain cultures of the urethra, cervix, rectum, and pharynx using selective culture media for N. gonorrhoeae. If done correctly with selective media for N. gonorrhoeae, cultures of the primary site of infection are more likely to be positive than are cultures of blood or synovial fluid (22).

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Table 31-4 Differential Diagnosis of the Inflamed Joint Infectious Arthritis Nongonococcal arthritis Infective endocarditis Gonococcal arthritis Whipple’s disease Viral arthritis Lyme disease Postinfectious Arthritis Rheumatic fever Poststreptococcal arthritis Reactive Arthritis Reiter’s syndrome Postdysenteric reactive arthritis Crystal-Induced Arthropathy Gout Calcium pyrophosphate deposition disease Hydroxyapetite crystalline arthritis Endocrine Diseases Diabetic neuropathic arthropathy Hyperparathyroidism Hyperthyroidism Hypothyroidism Acromegaly Gastrointestinal Diseases Inflammatory bowel disease Primary biliary cirrhosis

Metabolic Disorders Hyperlipoproteinemia Hemochromatosis Alkaptonuria (ochronosis) Wilson’s disease Hematologic Diseases Sickle cell disease Hemophilia Leukemia Immunologic Diseases Rheumatoid arthritis Hypogammaglobulinemia Systemic lupus erythematosus Serum sickness Miscellaneous Disorders Psoriatic arthritis Behçet’s disease Osteoarthritis Amyloidosis Traumatic arthritis Familial Mediterranean fever Sarcoidosis Sweet’s syndrome Neuropathic joint disease Hemarthrosis

Synovial fluid examination is an essential component in the evaluation of an acutely swollen, inflamed joint with a clinically apparent effusion. Features of the synovial fluid examination in infectious arthritis compared with those in several noninfectious causes of joint swelling are listed in Table 31-5. The normal, noninfected joint has a scant amount of synovial fluid that is nonturbid, viscus, and contains fewer than 200 leucocytes/mm3. Joint effusions seen in osteoarthritis can have leucocyte counts up to 2,000 leucocytes/mm3 and are considered noninflammatory. The joint fluid in nongonococcal septic arthritis usually has a total leucocyte count that exceeds 50,000 leucocytes/mm3, with a predominance of neutrophils; however, the range is broad, and the cell count can be low early in disease. The cell count in gonococcal polyarthritis and noninfectious inflammatory arthritis is usually less than the 50,000 leukocytes/mm3 (23). The joint fluid should also be analyzed for crystals, because crystalline deposition disease can mimic septic arthritis. Polarized light microscopy can be helpful in differentiating gout (characterized by fine, tapered crystals with weakly negative birefringence) and calcium pyrophosphate deposition (broad rhomboid-shaped crystals with strongly positive birefringence) from

Low Low Low

Turbid

Turbid

Turbid

3000–50,000

3000–50,000

3000–50,000

10,000–50,000

Low

200–2000 >50,000

High

WBC* (cells/mm3)

Low

* Cell counts may vary widely

Nongonococcal septic arthritis Gonococcal polyarthritis Gout and pseudogout Rheumatoid arthritis Reactive arthritis

Osteoarthritis

Viscosity

Clear to mildly turbid Turbid, purulent Turbid

Appearance

Disorder

Table 31-5 Synovial Fluid Findings in Acute Arthritis

>70%

>70%

—

>90%

>90%

<30%

PMNs in WBC

Negative

Negative

Positive 75% Positive 75% Negative

Negative

Gram Stain

Negative

Negative

Positive 85%–95% Positive 25% Negative

Negative

Culture

Negative

Negative

Positive

Negative

Negative

Negative

Crystals

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septic arthritis. It is important to remember that the presence of crystals does not exclude infection, because septic and crystal-induced arthritis can occur simultaneously (24). Gram stain of the synovial fluid is positive in more than 65% of cases of nongonococcal septic arthritis (2). The Gram stain can be quite helpful in the presumptive identification of the etiologic microorganism and in the selection of the initial antimicrobial therapy in patients with suspected septic arthritis. Although exact identification by Gram stain alone is not possible, general categorization into gram-positive and gram-negative organisms narrows the choice of antimicrobial agents considerably. The Gram stain is especially helpful in cases in which antimicrobial therapy has been given before joint fluid analysis, yielding negative cultures. Gram stain should be interpreted by an experienced laboratory technician to avoid false-positive results from artifact or precipitated stain. The definitive laboratory examination for the diagnosis of infection and determination of appropriate antimicrobial therapy in suspected septic arthritis is synovial fluid culture. Cultures are positive in nearly all cases of nongonococcal septic arthritis unless the patient has been given an antimicrobial agent (2). In contrast to nongonococcal arthritis, synovial fluid cultures are positive in less than 25% of cases of gonococcal arthritis (25). Some investigators have used polymerase chain reaction (PCR) technology to diagnose infectious arthritis caused by fastidious microorganisms or microorganisms that are difficult to culture such as Kingella kingae and Borrelia burgdorferi (26). However, this technology is not readily available in the clinical setting and has several limitations, including a high incidence of false positive results (27). Radiographic studies are of limited value in the diagnosis of septic arthritis. The most common radiographic feature of the disease is periarticular soft tissue swelling. Joint space widening can be seen early in the disease as a result of an effusion. As the disease progresses and the articular cartilage is destroyed, the joint space becomes narrowed. Rarely, radiographic studies show adjacent bone disease. Computed tomography (CT) can help in identifying hip joint effusions (28). Magnetic resonance imaging (MRI) is also useful in detecting joint and tendon sheath effusions (29). However, these studies are expensive and usually unnecessary for diagnosis of septic arthritis. Technetium-99m bone scans, gallium-67 and indium-111 scans are usually positive in septic arthritis but are of limited value in distinguishing infectious from noninfectious joint disease (30). The patient with a chief report of joint pain presents a diagnostic challenge for the primary care physician. A systematic approach, beginning with a thorough medical history and comprehensive physical examination, is essential in establishing the correct diagnosis. Figure 31-1 is an algorithm that illustrates the approach to patients with joint pain with or without swelling. First, a clinical evaluation should be done to determine whether the result is more likely the result of a periarticular inflammation (e.g., ten-

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Joint pain and/or swelling

Yes Periarthritis?

Consider tendonitis, bursitis, cellulitis

No Arthritis

Polyarticular

Monoarticular

Infectious (see Table 31-8)

Noninfectious (see Table 31-8)

Inflammatory arthritis (see Table 31-7)

Degenerative arthritis (see Table 31-4)

Metabolic arthritis (see Table 31-4)

Figure 31-1 Algorithm for the diagnosis of joint pain and swelling.

donitis, bursitis, or cellulitis) or the result of a true arthritis. Although infection must always be considered, many cases of polyarticular arthritis have a noninfectious cause as shown in Table 31-4. Additionally, polyarticular inflammatory arthritis can be divided into those conditions that present with symmetrical arthritis and those that present with an asymmetrical arthritis as shown on Table 31-6. The major causes of acute monoarticular arthritis are listed in Table 31-7. It is important to recognize that there is considerable overlap among the causes of polyarticular and monoarticular disease. Figure 31-2 is an algorithm that illustrates the approach to patients with monoarticular arthritis, but it can also be applied to the patient with

Table 31-6 Differential Diagnosis of Acute Polyarticular Inflammatory Arthritis Symmetrical Rheumatoid arthritis Systemic lupus erythematosis Other connective tissue diseases Crystal deposition disease Hepatitis B Rubella Subacute bacterial endocarditis Rheumatic fever Hypersensitivity reactions Psoriatic arthritis

Asymmetrical Neisseria infection Lyme disease Sarcoidosis Henoch–Schönlein purpura Ankylosing spondylitis Reiter’s syndrome Enteropathic arthropathy Psoriatic arthritis Behçet’s syndrome Whipple’s disease

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Table 31-7 Differential Diagnosis of Acute Monoarticular Arthritis Infection Trauma Crystal-induced arthropathy Hemarthrosis Neuropathic joint Mechanical internal derangement Reactive (e.g., Reiter’s disease, enteric-associated diseases)

polyarthritis. If a joint effusion is present, arthrocentesis is indicated. In the absence of an effusion, especially in the patient with polyarthritis, gonococcal disease should be considered. Synovial fluid leukocyte counts greater than 50,000 cells/mm3 strongly support an infectious cause; however cell counts of this magnitude can be found occasionally in crystal-induced arthropathy.

Treatment The treatment of septic arthritis has three facets: antimicrobial therapy, drainage of the infected joint, and restoring normal function of the joint. Because the identity of the infecting pathogen is often unknown, selecting the initial antimicrobial therapy often must be empirical. However, important clues to the identity of the infecting pathogen can be found in the clinical history and physical examination. Predisposing factors and specific clinical settings (see Table 31-3) also can suggest a likely pathogen. Additionally, a Gram stain of aspirated synovial fluid is often helpful in separating gram-positive from gram-negative infection, and the morphology of the microorganism can suggest a specific bacterial species. The decision on whether or not to begin antimicrobial therapy depends on both clinical and laboratory findings. When a specific microorganism cannot be identified, empirical therapy must include one or more antimicrobial agents effective against the most likely pathogens for the patient’s age group. Once culture results become available, the clinical response should be assessed and antimicrobial therapy altered, if appropriate. Specific therapy, preferably with a single agent, should be selected. If the cultures are negative, noninfectious causes should be reconsidered. Single-drug therapy is sufficient for most infections, including those caused by staphylococci, most streptococci, Neisseria species, and most gram-negative bacilli. To achieve synergy, combination therapy is indicated for infections caused by Enterococcus faecalis and P. aeruginosa. Infections caused by viridans streptococci strains that are intermediately sensitive to penicillin also can respond better to combination therapy than to single-drug therapy (31). Most antibiotics achieve therapeutic levels in synovial fluid when given systemically in appropriate doses (32). The practice of injecting an antimi-

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Monoarticular arthritis

Acute onset?

No

Chronic monoarticular arthritis

Yes No Inflammatory process?

Infection unlikely

Yes

Effusion present?

No

Yes

No Observe

Yes Consider gonococcal disease Culture blood and other appropriate sites Begin empirical antimicrobial therapy

Perform arthrocentesis for cell count and differential, crystal analysis, Gram stain, and culture

Crystal analysis positive?

Clinical history and evaluation suggestive of infection?

Yes

Begin anti-inflammatory agents pending culture

No Gram stain positive?

No

Yes

Yes

Culture blood and other appropriate sites Begin empirical antimicrobial therapy

No Culture blood and other appropriate sites Antimicrobial therapy is dependent on clinical suspicion of infection

Culture blood and other appropriate sites Choose empirical antimicrobial therapy based on bacterial stain, morphology, and clinical setting

No Culture positive?

Synovial fluid leukocyte count >50,000 cells/mm3

Reevaluate based on clinical response Consider noninfectious causes

Yes Modify antimicrobial therapy as needed Repeat arthrocentresis as needed

Figure 31-2 Algorithm for the management of monoarticular arthritis.

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crobial agent directly into a joint is unnecessary and not recommended because it can lead to excessively high concentrations of antibiotic in the synovial fluid, increasing the inflammatory response. An exception to this is the use of amphotericin B in treating infectious arthritis caused by fungi, in which intraarticular injection of small doses of the drug has proven safe and effective (33). The optimal duration of antimicrobial therapy for septic arthritis is not well established and varies with the causative pathogen, the adequacy of host defenses, and the clinical response (21). Disseminated gonococcal infection with polyarthritis is usually cured with a 7- to 10-day course of antibiotic, whereas acute nongonococcal suppurative arthritis can require a longer duration of therapy. Infections caused by most streptococci and by H. influenzae usually respond to a 2-week course of antimicrobial therapy, whereas S. aureus and gram-negative bacillary infections are treated for 3 to 4 weeks. If staphylococcal bacteremia occurs, the risk of endocarditis or other metastatic infection often necessitates 4 to 6 weeks of parenteral therapy. The antimicrobial agents of choice for common pathogens causing septic arthritis are listed in Table 31-8. The prevalence of community-associated methicillinresistant S. aureus (CA-MRSA) is increasing in many communities. If S. aureus Table 31-8 Antimicrobial Agents of Choice for Common Pathogens That Cause Septic Arthritis Pathogen*

Drug Regimen†

Staphylococcus aureus

Nafcillin 2 g IV q6h

Staphylococcus epidermidis Methicillin-resistant S. aureus Streptococcus groups A, B, C, and G Enterococcus faecalis

Neisseria gonorrhoeae

Neisseria meningitidis Haemophilus influenzae beta-Lactamase negative beta-Lactamase positive Pseudomonas aeruginosa

Alternative Drugs**

Vancomycin, cefazolin, clindamycin Vancomycin 15 mg/kg IV q12h TMP-SMX Vancomycin 15 mg/kg TMP-SMX, doxycycline, IV q12h linezolid Penicillin G 2 MU IV q4h Vancomycin, cefazolin, erythromycin Penicillin G 2 MU IV q4h Vancomycin with (or ampicillin 2 g q6h) + gentamicin gentamicin 1 mg/kg IM/IV q8h Ceftriaxone 1 g IV q24h Spectinomycin, ciprofloxacin, or other quinolones Penicillin G 2 MU IV q4h Ceftriaxone Ampicillin 2 g IV q6h Ceftriaxone 2 g IV q24h Piperacillin 4 g IV q6h +/tobramycin 5–7 mg/kg IV

Cefuroxime, TMP-SMX TMP-SMX Ceftazidime with aminoglycoside or ciprofloxacin

IM = intramuscularly; IV = intravenously; MU = million units; TMP-SMX = trimethoprim–sulfamethoxazole. * Duration of drug regimen is determined by pathogen: 2 weeks for Streptococcus, Haemophilus, Neisseria, and Enterococcus species, and 3 weeks for Staphylococcus species and gram-negative bacilli. † Dose may vary with body weight and renal function. ** See Appendix for recommended doses in adults.

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is suspected or proven to be the causative agent, vancomycin should be used as initial empirical therapy. Vancomycin-resistant S. aureus occur but are rare and need not be considered. The second facet of treatment of septic arthritis is drainage of pus from the affected joint. Drainage decompresses the joint and removes inflammatory cells, degradative enzymes, and fibrinous debris. In nongonococcal suppurative arthritis, adequate drainage is essential for a satisfactory outcome (2). However, the effusions in septic arthritis caused by N. gonorrhoeae or N. meningitidis, are rarely large enough to require drainage, and these conditions usually respond well with antimicrobial therapy alone. When effusions are present, needle aspiration is almost always adequate and surgical drainage is rarely indicated. The efficacy of repeated needle aspiration compared with surgical arthrotomy in septic arthritis has long been a subject of debate. No prospective controlled studies have compared medical and surgical drainage. An early study by Goldenberg and coworkers indicated a better result with needle aspiration than with surgical drainage, but the difference was not statistically significant (34). However, the study did clearly show the importance of early therapy to good outcome. A subsequent retrospective analysis of several studies showed no significant difference in outcome with medical and surgical therapy but did confirm the importance of early diagnosis and treatment (35). It is very likely that the drainage method used on a joint effusion has little effect on outcome so long as the drainage procedure is effective in removing the effusion. If needle aspiration is selected as the technique for drainage, the affected joint should be aspirated at least daily until fluid no longer accumulates. Repeat cultures and leukocyte counts on the joint fluid are useful in monitoring response to therapy. The fluid should become sterile over 48 to 96 hours, and the leukocyte count should steadily decline. Positive synovial fluid cultures after 7 days of therapy and high synovial fluid leukocyte counts after 5 days are associated with a poor outcome (36). Therefore, if fluid continues to reaccumulate after 2 to 3 days of needle aspiration or there is worsening of systemic sepsis, surgical drainage should be considered. Recent advances in arthroscopic technique have made surgical drainage of infected joints more attractive and in most cases the preferred approach (37). Open surgical drainage usually is reserved for severe infections with loculated debris within the infected joint and for infections involving the shoulder and hip. Hip infections require open surgical arthrotomy to relieve the pressure on the intravascular structures completely and to prevent ischemic destruction of the epiphyseal plate or femoral head (38). In most other cases, arthroscopic drainage is preferable to repeated needle aspiration. Many surgeons insert a closed suction drainage system postoperatively to irrigate an infected joint and to deliver intra-articular antimicrobial agents. This practice has not proven beneficial and is probably unnecessary, because most systemically administered antimicrobials reach adequate

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levels in synovial fluid (32). If used, these irrigation systems should remain in place for no longer than 48 hours. The third facet of treatment of septic arthritis is restoration of normal function of the affected joint. During the initial presentation and early treatment period, any movement of the joint can be very painful. Immobilization during this phase of treatment alleviates pain; however, after adequate decompression and a response to initial treatment, passive motion should be initiated to prevent fibrous adhesions and permanent joint injury (39). Whenever possible, continuous passive motion is preferred to intermittent passive or active motion. When the inflammatory process is controlled, appropriate physical therapy can be required to ensure the return of normal joint function.

Outcome Several factors have been identified as important in influencing the outcome of septic arthritis. These include the causative microorganism, the duration of symptoms before the beginning of appropriate antimicrobial therapy, the adequacy of drainage of the infected joint, the particular joint or joints involved, and host factors of age and underlying disease (3,21,36). Generally gonococcal arthritis has a much better prognosis than does nongonococcal arthritis and rarely requires surgery. Arthritis caused by gramnegative or anaerobic bacteria has been associated with a poor outcome in some series but not in others (2,16,21); however, more important than the microbial cause is the presence of underlying disease, because most deaths of patients with septic arthritis occur in those with serious underlying or chronic disease (3,21). The overall death rate for nongonococcal septic arthritis is approximately 10%, but varies with the preceding factors (3). Delay in instituting appropriate antimicrobial therapy is associated with a poor outcome. The duration of symptoms before therapy is inversely related to outcome (36). The outcome is also related to the time required to sterilize the synovial fluid after therapy is begun. Patients in whom this requires more than 7 days have a poor outcome (36). Synovial fluid leukocyte response can also be used as a prognostic indicator, because those patients with persistently high synovial fluid leukocyte counts on repeated aspirations have a poor outcome (3).

REFERENCES 1. Fink CW. Reactive arthritis. Pediatr Infect Dis J. 1988;7:58-65. 2. Goldenberg DL, Reed JI. Bacterial arthritis. N Engl J Med. 1985;312:764-71. 3. Goldenberg DL, Cohen AS. Acute infectious arthritis. A review of patients with nongonococcal joint infections (with emphasis on therapy and prognosis). Am J Med. 1976;60:369-77. 4. Shirtliff ME, Mader JT. Acute septic arthritis. Clin Microbiol Rev. 2002;15:527-44. 5. Nilsson IM, Lee JC, Bremell T, Rydén C,Tarkowski A. The role of staphylococcal polysaccharide microcapsule expression in septicemia and septic arthritis. Infect Immun. 1997;65:4216-21.

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6. Goldenberg DL. Infectious arthritis complicating rheumatoid arthritis and other chronic rheumatic disorders. Arthritis Rheum. 1989;32:496-502. 7. Sherman OH, Fox JM, Snyder S J. Arthroscopy: No problem surgery. J Bone Joint Surg. 1986;68A: 256-65. 8. Kuipers JG, Köhler L, Zeidler H. Reactive or infectious arthritis. Ann Rheum Dis. 1999;58:661-4. 9. Lundy DW, Kehl DK. Increasing prevalence of Kingella kingae in osteoarticular infections in young children. J Pediatr Orthop. 1998;18:262-7. 10. Rompalo AM, Hook EW 3rd, Roberts PL, Ramsey PG, Handsfield HH, Holmes KK. The acute arthritis-dermatitis syndrome. The changing importance of Neisseria gonorrhoeae and Neisseria meningitidis. Arch Intern Med. 1987;147:281-3. 11. Centers for Disease Control and Prevention. Sexually transmitted disease surveillance 1999. Available at: http://www.cdc.gov/nchstp/dstd/Stats_Trends/1999SurvRpt.htm. 12. Roca RP,Yoshikawa TT. Primary skeletal infections in heroin users: a clinical characterization, diagnosis and therapy. Clin Orthop Relat Res. 1979:238-48. 13. Newman ED, Davis DE, Harrington TM. Septic arthritis due to gram negative bacilli: older patients with good outcome. J Rheumatol. 1988;15:659-62. 14. Ewing R, Fainstein V, Musher DM, Lidsky M, Clarridge J. Articular and skeletal infections caused by Pasteurella multocida. South Med J. 1980;73:1349-52. 15. Bilos Z J, Kucharchuk A, Metzger W. Eikenella corrodens in human bites. Clin Orthop Relat Res. 1978:320-4. 16. Fitzgerald RH Jr., Rosenblatt JE,Tenney JH, Bourgault AM. Anaerobic septic arthritis. Clin Orthop Relat Res. 1982:141-8. 17. Gredlein CM, Silverman ML, Downey MS. Polymicrobial septic arthritis due to Clostridium species: case report and review. Clin Infect Dis. 2000;30:590-4. 18. Gordon SC, Lauter CB. Mumps arthritis: a review of the literature. Rev Infect Dis. 1984;6: 338-44. 19. Woolf AD, Campion GV, Chishick A,Wise S, Cohen BJ, Klouda PT, et al. Clinical manifestations of human parvovirus B19 in adults. Arch Intern Med. 1989;149:1153-6. 20. Rynes RI, Goldenberg DL, DiGiacomo R, Olson R, Hussain M, Veazey J. Acquired immunodeficiency syndrome-associated arthritis. Am J Med. 1988;84:810-6. 21. Rosenthal J, Bole GG, Robinson WD. Acute nongonococcal infectious arthritis. Evaluation of risk factors, therapy, and outcome. Arthritis Rheum. 1980;23:889-97. 22. Gelfand SG, Masi AT, Garcia-Kutzbach A. Spectrum of gonococcal arthritis: evidence for sequential stages and clinical subgroups. J Rheumatol. 1975;2:83-90. 23. McCutchan HJ, Fisher RC. Synovial leukocytosis in infectious arthritis. Clin Orthop Relat Res. 1990;256:226-30. 24. Baer PA,Tenebaum J, Fam AG. Coexistent septic and crystal arthritis. Report of four cases and literature review. J Rheumatol. 1986;13:3. 25. O’Brien JP, Goldenberg DL, Rice PA. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine (Baltimore). 1983;62:395-406. 26. Yagupsky P. Diagnosis of Kingella kingae arthritis by polymerase chain reaction analysis [Letter]. Clin Infect Dis. 1999;29:704-5. 27. Stahl HD, Hubner B, Seidl B, Liebert UG, van der Heijden IM,Wilbrink B, et al. Detection of multiple viral DNA species in synovial tissue and fluid of patients with early arthritis. Ann Rheum Dis. 2000;59:342-6. 28. Hendrix RW, Fisher MR. Imaging of septic arthritis. Clin Rheum Dis. 1986;12:459-87. 29. Beltran J, Noto AM, McGhee RB, Freedy RM, McCalla MS. Infections of the musculoskeletal system: high-field-strength MR imaging. Radiology. 1987;164:449-54. 30. Tumeh SS. Scintigraphy in the evaluation of arthropathy. Radiol Clin North Am. 1996;34: 215-31, ix. 31. Johnson CC,Tunkel AL. Viridans streptococci and groups C and G streptococci. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone; 2000:2167-83. 32. Nelson JD. Antibiotic concentrations in septic joint effusions. N Engl J Med. 1971; 284:349-53. 33. Downs NJ, Hinthorn DR, Mhatre VR, Liu C. Intra-articular amphotericin B treatment of Sporothrix schenckii arthritis. Arch Intern Med. 1989;149:954-5. 34. Goldenberg DL, Brandt KD, Cohen AS, Cathcart ES. Treatment of septic arthritis: comparison of needle aspiration and surgery as initial modes of joint drainage. Arthritis Rheum. 1975;18: 83-90.

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35. Broy SB, Schmid FR. A comparison of medical drainage (needle aspiration) and surgical drainage (arthrotomy or arthroscopy) in the initial treatment of infected joints. Clin Rheum Dis. 1986;12:501-22. 36. Ho G Jr., Su EY. Therapy for septic arthritis. JAMA. 1982;247:797-800. 37. Jackson RW. The septic knee—arthroscopic treatment. Arthroscopy. 1985;1:194-7. 38. Wilson N, DiPaola M. Acute septic arthritis in infancy and childhood: 10 year experience. J Bone Joint Surg. 1986;68B:584-7. 39. Salter RB. The biologic concept of continuous passive motion of synovial joints. The first 18 years of basic research and its clinical application. Clin Orthop Relat Res. 1989:12-25.

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Chapter 32

Prosthetic Joint Infection ANTHONY R. BERENDT

Key Learning Points 1. Rates of infection vary from 0.5 to 2%. 2. Infections may be caused by virulent pathogens or skin commensals. 3. Clinical features of infection include: “start up pain”, delayed wound healing, and a history that the joint was “never right”. 4. Multiple well-obtained intra-operative samples are recommended for identification of the pathogen. 5. Treatment should be multidisciplinary and includes surgical debridement, potential removal the implant, antibiotic therapy, and rehabilitation. 6. Patients with joint replacements should have prompt treatment of infections elsewhere in the body to reduce risks of bacteremia and spread to the implant.

P

rosthetic joint infections are uncommon. As such they can seem, at face value, to be of little relevance to the primary care physician. However they are devastating conditions for patients to experience, coming as they do as complications of procedures that are usually remarkably effective in relieving pain and enhancing quality of life. It is therefore all the more problematic that when infection does complicate joint replacement, it causes considerable illness and is very difficult to eradicate without combinations of surgery and prolonged antibiotic use. The gap between preoperative expectation and postoperative reality is difficult for many patients and health care workers to adjust to and contributes to the illness of the patients. This

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New Developments in the Diagnosis and Treatment of Prosthetic Joint Infection ●

●

New diagnostic tests include use of polymerase chain reaction (PCR) for detection of microbial DNA. Protocols that use initial intravenous (IV) therapy followed by oral therapy (often with fluoroquinolone-rifampin combination) have shown good rates of success in selected patients.

and the high economic costs for health care providers and systems makes it important for all physicians to have a basic understanding of the condition. For the primary care physician specifically, there are important potential roles in raising early suspicions of prosthetic joint infection, in long-term antibiotic prescribing and supervision, and in providing support and advocacy for patients in their journey through often complex and demanding treatment programs.

Epidemiology Infection can arise through operative contamination or by hematogenous spread and can present early or late. Published rates, which vary from 0.5% and 2% but are sometimes higher (1,2), are sensitive to case definition and the duration and carefulness of follow-up (3). Risk factors for infection include the following (1): ●

●

●

●

A history of previous surgery on the joint. This likely reflects the technical difficulties in carrying out revision surgery or primary joint replacement after other procedures. A history of cancer past or present. Probably caused mainly by the immunosuppressive effect of chemotherapy and the locally compromising effect of radiotherapy, but other elements can be relevant. A score greater than 1 in the National Nosocomial Infections Surveillance (NNIS) system, which awards one point for each of prolonged surgery, a poor wound score, or an American Society of Anesthesiology score of over 1. A history of superficial wound infection. Anatomic barriers are disrupted by joint replacement, so that what seems to be superficial infection can easily progress to deep infection. Furthermore some apparently superficial infections are in fact the presentation of deep infection.

Other risk factors include the presence of significant hematoma. Although all joint replacements will have some associated hematoma, persistent drainage from the wound for more than 5 days after surgery is indicative of a deep

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collection and a greatly increased risk of superficial and deeper infection (4). Although many other individual factors have been quoted as important risks, these have not been identified through less rigorous methodology.

Pathophysiology and Etiology Two separate elements come together in the pathogenesis of prosthetic joint infection. First, the implant has effects on local innate immunity that make the implant more liable to infection than would be the case for native structures. These effects include complement depletion in the vicinity of the implant and inhibition of phagocytosis by foreign material. For this reason, the inoculum required to set up infection is greatly reduced, and some organisms not normally considered to be pathogenic become important causes of prosthetic joint infection. Thus prosthetic joint infections are caused not only by virulent pathogens such as Staphylococcus aureus, β-hemolytic Streptococci and Enterobacteriaceae, but also by skin commensals such as coagulase-negative Staphylococci, Corynebacteria, and Propionibacterium (for review see reference 5). Second, prosthetic joint infections are characterized by adherence of organisms to the implant and other biomaterials. The resulting multicellular adherent consortium is known as a biofilm, and it comprises one or more microbial species enmeshed in a polysaccharide glycocalyx (6). Organisms in the adherent state display a phenotype of relative resistance to many antibiotics, although they remain genetically susceptible and identifiable as such on conventional laboratory testing. The impairment of antibioticrelated killing is accompanied by a simultaneous inhibition of host-related killing. The inability of the host to kill the infecting organisms leads to chronic suppuration. Collections of pus and granulation tissue can form next to the implant and eventually track through adjacent tissue planes or surgical scars to produce collections or sinuses. In addition, the inflammatory response activates recruit osteoclastic cells. Bone resorption at the interface between implant and bone leads to loosening and eventual mechanical failure of the prosthesis.

Clinical Manifestations Prosthetic joint infection therefore presents in various ways. Early and late presentations have already been referred to. Another useful distinction is between acute and chronic infection. Acute infection, which is here defined as infection associated with an acute inflammatory response, most commonly occurs in the early postoperative period as a wound infection. It can, however, present late because

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of the bacteremic spread of infection to the joint. The clinical manifestations of acute infection include fever, systemic illness, signs of wound infection if the surgical wound has not yet healed (purulence in the wound or purulent discharge from it, erythema, swelling, and pain), and painful limitation of movement of the joint. Although there is no consensus definition of chronic infection, it is a useful concept as it implies a different level of urgency in treatment, and different treatment protocols. Implants with a history of infection exceeding 2 weeks are likely to behave, from a prognostic point of view, as chronically infected. Any joint replacement with an established sinus, mechanical loosening, or where infection recurred after treatment is unequivocally chronically infected, even if there is an acute flare at the time of presentation. Sinuses usually develop down old drain sites or surgical scars. Rarely, sinus formation occurs into more distant sites, such as the ischiorectal area (7) or pelvis (8). They can produce substantial amounts of purulent or serous drainage, requiring management with dressings or even a stoma bag to collect the drainage. Any or all of the appearance, drainage, excoriation of skin, offensive smell, or the need to modify or restrict activities can be highly distressing for patients. The natural history of loosening is a progressive, painful deterioration in prosthesis function. In early loosening, the joint feels stiff or painful only for a few minutes at a time when first moved after a period of rest or sleep. As loosening progresses, this start-up pain becomes more severe and prolonged. The joint becomes constantly painful and later, irritable even on minor movement. Finally, gross mechanical failure, with migration of one or both components, dislocation, or fracture of the cement mantle, can occur. Chronic infections can have significant effects on the patient’s general health. Fever is rare, but loss of well-being, fatigue, and some weight loss are commonplace. Indeed, it is often not until after the infection has successfully been treated that some patients appreciate the extent of the illness associated with a chronic infection.

Diagnosis There is no single, simple test that identifies infection. Clinical features are start-up pain, a history of delayed wound healing, a history that the joint was “never right,” or more overt signs of infection. Although C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated, this finding is neither specific nor sensitive in chronic infections. In very active cases there can be an associated anemia of chronic disease and/or hypoalbuminemia. Plain radiographs can show periprosthetic lucency indicating loosening; fracture of cement or bone; gross migration or dislocation of components; and soft tissue swelling. However these changes do not distinguish septic

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from aseptic cause. The same is true of technetium-99 (99Tc) bone scanning. Other isotope scans (leukocyte or antibody scans) are not reliably reproducible in their performance between different centers. Culture of joint fluid and joint tissues has been widely investigated (9). Aspiration of the joint is more reliable for high burdens of infection, and false-negative results can occur in chronic, low-grade disease. Tissue samples allow improved diagnostic yield on culture, and histological examination of peri-prosthetic tissue. There are good criteria for identifying infection according to the numbers of polymorphs present in the tissues (10). Enhanced diagnostic methods under scrutiny at present include the use of sonication to dislodge biofilms from the surface of the prosthesis (11), and broad-range polymerase chain reaction (PCR) for detection of microbial DNA (12). These methods are gaining increasing currency but are not yet standard, and in some hands, have been inferior to culture (13). They can substantially alter our concept of the apparently noninfective causes of prosthesis loosening (aseptic loosening) if it transpires that many implants can be shown to have associated microbes. At present, it is reasonable to restrict our consideration of infection to those clinically obvious presentations described here, but one additional entity can be included. Many studies have demonstrated that the isolation of organisms from many well-taken intra-operative samples is diagnostic of infection (14), with a high correlation with the characteristic histologic changes (15). These diagnostic results are sometimes obtained from cases undergoing revision surgery with no previous suspicion of infection and with no macroscopic evidence of infection at surgery. Surgeons are therefore encouraged routinely to send many different samples at revision surgery to pick up these clinically inapparent cases, as well as to rule infection in or out confidently when the level of suspicion is higher. For this reason, antibiotics should routinely be withheld from patients for at least 2 weeks before revision surgery, unless with the express agreement of the surgeon.

Treatment Treatment should be multidisciplinary, because for success, many different elements must be encompassed. These include surgical debridement of infected soft tissue, potential removal of the implant and subsequent reconstruction, antibiotic choice and administration, management of medical and psychological illness, and rehabilitation (Table 32-1). The role of the primary care physician as part of a multidisciplinary team is outlined in Table 32-2. Acute infections that arise in the context of a soundly fixed implant can sometimes be treated successfully with debridement and retention of the prosthesis. There has been increasing confidence in this approach since the studies by Zimmerli and colleagues of the use of fluoroquinolone-rifampin

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Table 32-1 Treatment Options for Prosthetic Joint Infection Treatment Option

Usual Indication for Consideration of Option

Do nothing

No reconstructive option; patient unwilling to have surgery; unable to tolerate antibiotics, or already proved to be ineffective in controlling symptoms Acute infection, soundly fixed prosthesis

Debridement and retention Suppress with antibiotics alone Excision arthroplasty One-stage revision Two-stage revision Fusion (knee) Amputation

No reconstructive option; morbidity of excision unacceptable No reconstructive option, but symptoms of infection unacceptable Medically fit patient with sensitive pathogen (consider also if very high anesthetic risk) More resistant or unknown pathogens Complex reconstruction required Patient and surgeon preference; reconstruction impossible or high risk Severe symptoms, reconstruction impossible

Problems

High failure rate No alleviation of symptoms

Long-term antibiotics can be required High failure rate Antibiotic intolerance Inferior functional outcome Greater rate of recurrence Morbidity Cost of two operations Technically difficult; disability from rigid leg Morbidity, disability, and body image

Table 32-2 Roles of the Primary Care Physician in Management of Prosthetic Joint Infection Role

Rationale

Prompt referral if infection suspected Prompt treatment of infection in other body sites Consider prophylaxis for dental treatment and obtain specialist advice if need be Ensure no antibiotics for at least 2 weeks prior to revision surgery Partnership working with specialist hospital team

Prognosis for acute infection adversely affected by delay Reduce risk of bacteremic or local spread

Advocacy and support

Prevention of hematogenous infection, balanced against risk of anaphylaxis Allows most reliable ruling in or out of chronic, sometimes occult, infection Patient can need outpatient parenteral antibiotic therapy, prolonged oral antibiotics, or reevaluation for suspected relapse or recurrence Patient needs expert, often complex, management; psychological illness and disability can be significant

combinations in device-related infections. Initially in an animal model, using subcutaneous Teflon cages infected with staphylococci to mimic a biomedical device-related infection (16,17), this work has shown that the combination of ciprofloxacin and rifampin can be curative for an infected foreign body. This has been extrapolated to the clinical situation in many contexts

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including case series (18,19) and a randomized controlled trial of prosthesis retention comparing ciprofloxacin and rifampin with ciprofloxacin monotherapy (20). The positive results of these studies have led to the proposal of a specific protocol for the retention of implants acutely infected with staphylococci (21). No randomly assigned comparative study of intravenous versus oral antibiotic therapy has been made, so treatment regimens vary substantially about the duration of intravenous therapy. Many units still give 6 weeks of intravenous therapy according to antimicrobial sensitivity patterns, with subsequent oral follow-up. Using protocols of a period of intravenous therapy (can be given as outpatient parenteral therapy) followed by oral follow-up with fluoroquinolone-rifampin combinations, high rates of arrest of infection have been achieved (22,23). However it is important to recognize that in some studies at least, time is of the essence, with a narrow window, for S. aureus in particular, for the delivery of the debridement and the antibiotic therapy after the onset of symptoms (24). Other studies have suggested that the prognosis of infections treated with S. aureus remains particularly poor (25), although this can reflect variations in the antibiotic regimens used, the host status, or inherent differences in the likelihood of success when comparing hip and knee replacement. Given this, the primary care physician needs to be alert to the possibility of infection. Because early hospital discharge after joint replacement is the norm in most health care systems, most acute infections will present in the primary care setting. The temptation to give empiric antibiotics if deep infection is suspected should be resisted until after evaluation by the surgeon. Should a referral to the surgical team result in advice simply to give empiric antibiotics without secondary care review, it is perfectly appropriate for the primary care physician to challenge this and ask for a justification. How can deep infection requiring timely treatment be ruled out, how will the causative organism(s) be identified once empiric therapy has been initiated, and what effect will delay of diagnosis and treatment of deep infection have on the longer term outcome? The orthopedic surgeon should be able to give rational responses to these questions. Chronic infections are yet more complex entities to treat. Although their established nature means that time is no longer of the essence in their management, there is a greater variety of treatment options needing individual tailoring to the needs, expectations, and status of the patient. There is more likely to be a history of previous infection and failed management; mechanical loosening of the implant; and a compromised soft tissue envelope caused by both previous surgeries and sinus-tract formation. Experience also suggests that in most cases, there will be significant levels of anxiety, depression, and/or anger directed at previous or present health care providers, which relate to the uncertainty of the prognosis, fear of future pain and disability, and the iatrogenic nature of the condition. These variations and difficulties make it essential to assess the individual patient’s physical and psychological illness and to set realistic expectations for the future management.

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Removal of the implant, known as excision arthroplasty, can be an end point of treatment in its own right or can be a prelude to reconstruction. In the hip, it is possible to function acceptably, in many cases, through the establishment of a Girdlestone pseudarthrosis. However most other major joints cannot produce pseudarthroses with acceptable levels of comfort and function. In areas such as the knee and ankle, weight bearing after resection would be bone-on-bone, and intolerably painful. In the shoulder and elbow, there are issues of potential gravitational traction on nerves and soft tissues and poor function caused by lack of mechanical stability. If reconstruction is carried out after excision, this can be done in a single stage or two. In a two-stage procedure, all infected and foreign material is removed at the first operation, and a new joint is implanted, using antibiotic-loaded cement, several weeks later. Single-stage exchange has no such interval, with the new joint inserted immediately after the debridement. Elements of the two approaches can be combined; for example, there is increasing interest in the use of articulating antibiotic-loaded spacers, which support the soft tissues, maintain some mobility, and maintain limb length while providing locally high levels of antibiotic. These can be quite complex, and there are anecdotal reports of occasional patients needing no further reconstruction. Single-stage exchange has success rates of approximately 80% to 85% (26,27); two-stage exchange has success rates of more than 90% (28,29). Fusion and amputation represent end-stage procedures. Although fusion preserves the distal part of the limb, this can produce new disability. For example in the knee, fusion leads to leg rigidity, which impedes sitting in cars, trains, buses, airplanes, and theater seats. Even amputation is no panacea, with possible sequelae of a range of stump problems, and a threat to independent living for older patients.

Prevention In response to high-infection rates, Charnley devised the laminar flow enclosure and body exhaust suits. This achieved reductions in rates that are equivalent to those caused by the deployment of antibiotics; in the landmark MRC trial that established this, the effects of ultraclean air and antibiotics were additive (30). The surgeon also takes other measures to reduce the risk of infection, including meticulous attention to technique and the avoidance of unnecessary tissue trauma; elimination of surgical dead spaces; insistence on good theatre discipline; and correction of preoperative comorbidities. Prophylactic antibiotics have been shown to reduce infection rates. Patients with joint replacements should have prompt treatment of infections elsewhere in the body to reduce risks of bacteremia and spread. Prophylaxis for dental work is controversial (31,32), but it is recommended by some expert bodies and should be strongly considered for those with

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new or loose implants, and prompt treatment is advised in all patients with prosthetic joints who develop overt dental infection.

Summary Prosthetic joint infection is a formidable problem. The primary care physician can contribute to its management by acting on clinical suspicion with prompt referral back to the original surgeon, who should possess or have access to appropriate skills; by participating in the long-term management plan; and by ensuring, through advocacy and support, that the needs and wishes of the whole patient are being appropriately considered at all times.

REFERENCES 1. Berbari EF, Hanssen AD, Duffy MC, Steckelberg JM, Ilstrup DM, Harmsen WS, et al. Risk factors for prosthetic joint infection: case-control study. Clin Infect Dis. 1998;27:1247-54. 2. Ridgeway S,Wilson J, Charlet A, Kafatos G, Pearson A, Coello R. Infection of the surgical site after arthroplasty of the hip. J Bone Joint Surg Br. 2005;87:844-50. 3. Reilly J, Noone A, Clift A, Cochrane L, Johnston L, Rowley DI, et al. A study of telephone screening and direct observation of surgical wound infections after discharge from hospital. J Bone Joint Surg Br. 2005;87:997-9. 4. Saleh K, Olson M, Resig S, Bershadsky B, Kuskowski M, Gioe T, et al. Predictors of wound infection in hip and knee joint replacement: results from a 20 year surveillance program. J Orthop Res. 2002;20:506-15. 5. Zimmerli W,Trampuz A, Ochsner PE. Prosthetic-joint infections. N Engl J Med. 2004; 351:164554. 6. Gristina AG, Costerton JW. Bacterial adherence and the glycocalyx and their role in musculoskeletal infection. Orthop Clin North Am. 1984;15:517-35. 7. Briggs RD, McLauchlan J, Davidson AI. Late infection of a total hip prosthesis presenting as an ischiorectal abscess. Br J Surg. 1979;66:291-2. 8. Gasiunas V, Plénier I, Hérent S, May O, Senneville E, Migaud H. [Transabdominal removal of femoral and acetabular components of a severely protruded and infected hip arthroplasty with urinary tract complications]. Rev Chir Orthop Reparatrice Appar Mot. 2005;91:346-50. 9. Barrack RL, Harris WH. The value of aspiration of the hip joint before revision total hip arthroplasty. J Bone Joint Surg Am. 1993;75:66-76. 10. Athanasou NA, Pandey R, de Steiger R, Crook D, Smith PM. Diagnosis of infection by frozen section during revision arthroplasty. J Bone Joint Surg Br. 1995;77:28-33. 11. Tunney MM, Patrick S, Gorman SP, Nixon JR,Anderson N, Davis RI, et al. Improved detection of infection in hip replacements. A currently underestimated problem. J Bone Joint Surg Br. 1998;80:568-72. 12. Tunney MM, Patrick S, Curran MD, Ramage G, Hanna D, Nixon JR, et al. Detection of prosthetic hip infection at revision arthroplasty by immunofluorescence microscopy and PCR amplification of the bacterial 16S rRNA gene. J Clin Microbiol. 1999;37:3281-90. 13. Panousis K, Grigoris P, Butcher I, Rana B, Reilly JH, Hamblen DL. Poor predictive value of broadrange PCR for the detection of arthroplasty infection in 92 cases. Acta Orthop. 2005;76:341-6. 14. Atkins BL, Athanasou N, Deeks JJ, Crook DW, Simpson H, Peto TE, et al. Prospective evaluation of criteria for microbiological diagnosis of prosthetic-joint infection at revision arthroplasty. The OSIRIS Collaborative Study Group. J Clin Microbiol. 1998;36: 2932-9. 15. Pandey R, Drakoulakis E,Athanasou NA. An assessment of the histological criteria used to diagnose infection in hip revision arthroplasty tissues. J Clin Pathol. 1999;52:118-23. 16. Widmer AF, Frei R, Rajacic Z, Zimmerli W. Correlation between in vivo and in vitro efficacy of antimicrobial agents against foreign body infections. J Infect Dis. 1990;162:96-102. 17. Blaser J,Vergères P,Widmer AF, Zimmerli W. In vivo verification of in vitro model of antibiotic treatment of device-related infection. Antimicrob Agents Chemother. 1995; 39:1134-9.

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18. Widmer AF, Gaechter A, Ochsner PE, Zimmerli W. Antimicrobial treatment of orthopedic implantrelated infections with rifampin combinations. Clin Infect Dis. 1992;14:1251-3. 19. Jacquier A, Champsaur P, Vidal V, Stein A, Monnet O, Drancourt M, et al. [CT evaluation of total HIP prosthesis infection]. J Radiol. 2004;85:2005-12. 20. Zimmerli W,Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279:1537-41. 21. Zimmerli W, Ochsner PE. Management of infection associated with prosthetic joints. Infection. 2003;31:99-108. 22. Berdal JE, Skråmm I, Mowinckel P, Gulbrandsen P, Bjørnholt JV. Use of rifampicin and ciprofloxacin combination therapy after surgical debridement in the treatment of early manifestation prosthetic joint infections. Clin Microbiol Infect. 2005;11:843-5. 23. Marculescu CE, Berbari EF, Hanssen AD, Steckelberg JM, Harmsen SW, Mandrekar JN, et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis. 2006;42:471-8. 24. Brandt CM, Sistrunk WW, Duffy MC, Hanssen AD, Steckelberg JM, Ilstrup DM, et al. Staphylococcus aureus prosthetic joint infection treated with debridement and prosthesis retention. Clin Infect Dis. 1997;24:914-9. 25. Deirmengian C, Greenbaum J, Lotke PA, Booth RE Jr., Lonner JH. Limited success with open debridement and retention of components in the treatment of acute Staphylococcus aureus infections after total knee arthroplasty. J Arthroplasty. 2003;18: 22-6. 26. Wroblewski BM. One-stage revision of infected cemented total hip arthroplasty. Clin Orthop Relat Res. 1986:103-7. 27. Callaghan JJ, Katz RP, Johnston RC. One-stage revision surgery of the infected hip. A minimum 10-year followup study. Clin Orthop Relat Res. 1999:139-43. 28. Haleem AA, Berry DJ, Hanssen AD. Mid-term to long-term followup of two-stage reimplantation for infected total knee arthroplasty. Clin Orthop Relat Res. 2004:35-9. 29. Kraay MJ, Goldberg VM, Fitzgerald SJ, Salata MJ. Cementless two-staged total hip arthroplasty for deep periprosthetic infection. Clin Orthop Relat Res. 2005;441:243-9. 30. Lidwell OM, Lowbury EJ, Whyte W, et al. Effect of ultraclean air in operating rooms on deep sepsis in the joint after total hip or knee replacement: A randomised study. Br Med J (Clin Res Ed). 1982;285:10-4. 31. American Dental Association. Antibiotic prophylaxis for dental patients with total joint replacements. J Am Dent Assoc. 2003;134:895-9. 32. Jacobson JJ, Schweitzer S, DePorter DJ, Lee JJ. Antibiotic prophylaxis for dental patients with joint prostheses? A decision analysis. Int J Technol Assess Health Care. 1990;6:569-87.

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Chapter 33

Osteomyelitis JASON H. CALHOUN, MD REBECCA A. BRADY, PHD MARK E. SHIRTLIFF, PHD

Key Learning Points 1. Osteomyelitis is progressive and results in the inflammatory destruction of bone, in bone necrosis, and in new bone formation. 2. Osteomyelitis is predominantly of bacterial origin. 3. The most determinate diagnostic tool for osteomyelitis is isolation of the causative pathogen through bone, blood, or joint culture. 4. Radiologic evaluation of osteomyelitis can be used to support or refute clinically suspected disease, but no radiologic technique can confirm or rule out the presence of osteomyelitis. 5. Appropriate treatment of osteomyelitis includes drainage, debridement, obliteration of dead space, wound protection, stabilization if necessary, and specific antimicrobial coverage. 6. Most cases of long-bone osteomyelitis are posttraumatic or postoperative.

O

steomyelitis is commonly characterized by infection of the cortical and/or medullary portions of the bone. The term osteo refers to bone and the term myelo to the marrow cavity, both of which are involved in the disease. Osteomyelitis is progressive and results in the inflammatory destruction of bone, bone necrosis, and new bone formation. Although there are many etiologic microorganisms, osteomyelitis is predominantly of bacterial origin.

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New Developments • Magnetic resonance imaging (MRI) is becoming the radiographic test of choice to

detect osteomyelitis. • New treatment options for methicillin-resistant Staphylococcus aureus (MRSA),

such as linezolid, daptomycin, and tigecycline, hold promise for treatment of osteomyelitis. Studies with these agents are ongoing. • Hyperbaric oxygen (HBO) therapy may facilitate healing in patients with vascular insufficiency in areas of borderline-normal cutaneous oxygen tension.

Etiology For the purpose of discussing the cause of osteomyelitis, the Waldvogel staging system (Table 33-1) is used because it is based on the cause of the infection (1-3). His staging system describes 3 categories of osteomyelitis: 1) hematogenous osteomyelitis, 2) osteomyelitis with a contiguous focus, and 3) osteomyelitis associated with a vascular insufficiency. Additionally, each category can be either acute or chronic.

Acute Osteomyelitis Acute Hematogenous Osteomyelitis Hematogenous osteomyelitis occurs primarily in infants and children. In these cases, the disease most often begins in the tibial and femoral metaphyses, because the anatomy and histology of the long-bone metaphyses make them susceptible to infection (4). There are no functionally active phagocytic cells in the lining of the afferent loops of these metaphyseal capillaries, and blood flow through them slows considerably and becomes more turbulent (5). For these reasons, any obstruction of the capillary ends can lead to avascular necrosis. Because children bear the greatest amount of mechanical stress on their epiphyseal growth plates, they are at greater risk than adults or infants for trauma in this area. When minor trauma occurs in an infant, it may cause a small hematoma or bone necrosis, which can be invaded by an infecting pathogen. The targets of infection are the large sinusoids that form from the terminal vessels of the growth plates. At the onset of hematogenous osteomyelitis, the acute infection is focal. Subsequently, many cumulative physiological factors in the host add to the Table 33-1 Osteomyelitis: Waldvogel Classification ● ● ● ● ●

Hematogenous osteomyelitis Osteomyelitis caused by contiguous focus of infection No generalized vascular disease Generalized vascular disease Chronic osteomyelitis (necrotic bone)

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extension of the infection by compromising the medullary circulation. These factors include leukocyte breakdown, increased bone pressure, decreased pH, and decreased oxygen tension. In addition, the coordinated expression of the particular virulence factors of the infecting microbial species also determines the disease progression and severity. As it progresses, the infection swells laterally through haversian and Volkmann canal systems, perforating the bony cortex and lifting the periosteum from the surface of the bone. At this point in the progression of the disease, the periosteal and endosteal circulations are lost, leaving large segments of dead cortical and cancellous bone. In infants, because capillaries extend across the growth plate, infection can spread into the epiphysis and the joint space. In children older than 1 year of age, the capillaries no longer penetrate the growth plate, and therefore the epiphysis and joint space are protected from spreading infection. However, because the growth plate in adults has been resorbed completely, infection can pass into the joint space. A single pathogenic species is most commonly recovered from bone cultures of hematogenous osteomyelitis, and Staphylococcus aureus is the most commonly isolated organism (6). Although normally described as a disease of children, hematogenous osteomyelitis has been reported in older age groups. In adults, hematogenous osteomyelitis usually occurs in the vertebrae or in the bones of the wrist and ankle. It is thought that vertebral osteomyelitis begins with an infected embolus within the vertebral body. The resulting ischemia and infarction lead to bone destruction and the infection’s spread into the contiguous disk space. The lumbar vertebral bodies are the most common sites of infection in vertebral osteomyelitis, followed by (in order of frequency of infection) the thoracic and cervical vertebrae. The infection can spread rapidly in the axial skeleton by means of the abundant venous networks of the spine. Commonly, patients with vertebral osteomyelitis have a history of chronic skin infections, urinary tract infections, and intravenous drug use. The osteomyelitis in such cases is typically monomicrobial, with S. aureus again being the most frequent pathogen (1-3).

Acute Osteomyelitis Secondary to a Contiguous Focus of Infection with Normal Vascularity Contiguous osteomyelitis occurs when bacteria are introduced exogenously into bone by trauma or the extension of an adjacent soft tissue infection. The most common factors that contribute to contiguous osteomyelitis are open fractures, joint infections, and soft tissue infections. Traumatic injury often deprives the bone and surrounding tissues of blood flow, providing a good environment for the survival of bacteria. Another important source of contiguous osteomyelitis is an infection that originates from surgical contamination, including that of hardware and joint prosthetic devices. The most common site of contiguous osteomyelitis is the tibia, and the most common cause is trauma (6). This is because the midportion of the tibia lacks

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dense vascularity and has little surrounding soft tissue, which limits its degree of protection and recovery from injury. Bone necrosis, soft tissue damage, and loss of bone stability often result from contiguous osteomyelitis. Unlike hematogenous osteomyelitis, many species of organisms are often isolated from the infected bone in contiguous osteomyelitis, with S. aureus and Staphylococcus epidermidis the most prevalent pathogens. Also isolated are gram-negative bacilli and anaerobic microorganisms.

Acute Osteomyelitis Secondary to a Contiguous Focus of Infection with Generalized Vascular Insufficiency Neuropathy, ischemia, and immunopathy are the 3 pathophysiologic factors responsible for infection in the diabetic foot (7, 8). Neuropathy and vascular compromise make the feet of diabetic individuals more susceptible to minor trauma (e.g., skin ulceration, tissue breakdown) and, along with immunopathy, set the stage for infection (8). One third of diabetic foot infections that require hospitalization are accompanied by osteomyelitis; in such cases, the small bones of the feet are the most common sites of infection. A delayed inflammatory response, stemming from poor tissue perfusion, predisposes the bone to infection in these patients. The disease begins in a claudicated area of traumatized skin. Most often, the infection gains entry through a cutaneous portal (e.g., a diabetic foot ulcer), which leads to cellulitis. Although it is only a local infection, the cellulitis can spread contiguously to tendons, a joint capsule, or bone. However, only when the infection penetrates the medullary cavity can the resulting condition be diagnosed as osteomyelitis. Osteomyelitis is present if a diabetic foot ulcer extends to the bone. Many aerobic organisms are isolated from the infected bone in such cases. Additionally, because of the ischemic environment, anaerobic organisms are often isolated from the infected bone as well. Chronic Osteomyelitis Although the pathogenesis of acute and chronic osteomyelitis are similar, some characteristics that are unique to each of these 2 states of infection distinguish them from one another. Pathologic features of chronic osteomyelitis are the presence of necrotic bone, the formation of new bone, and the exudation of polymorphonuclear leukocytes joined by large numbers of lymphocyte histiocytes, and occasionally plasma cells. The hallmark of chronic osteomyelitis is infected dead bone within a compromised soft tissue envelope. The cause of the infection is variable: Pathogenic organisms can reach the bone through hematogenous seeding, open trauma, or contiguous spread. Once the infection is established, an involucrum of fibrous tissue and chronic inflammatory cells forms around the granulations and dead bone. After the infection is contained, there is a decrease in vascularization of the infection site, and the metabolic demands of an effective inflammatory response cannot be satisfied. The revascularization and resorption of the dead bone and scar tissue are similarly affected. The process of resorption eventually subsides, and the haversian

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canals are sealed by scar tissue. The bacteria responsible for the infection are enclosed in a biofilm. A biofilm may be defined as a microbe-derived sessile community characterized by cells that are attached to a substratum, interface, or each other, are embedded in a matrix of extracellular polymeric substance, and exhibit an altered phenotype with respect to growth, gene expression, and protein production (9). Once in this state, the bacteria have a greatly reduced metabolic activity, and the host immune system and antimicrobial agents are incapable of clearing the infection. The coexistence of infected, nonviable tissues and an ineffective host response leads to chronicity of the infection. The nidus of persistent contamination must be removed before the infection can regress. New bone formation is another characteristic of chronic osteomyelitis. New bone develops from the surviving fragments of periosteum, endosteum, and cortex in the region of the infection and is produced by a vascular reaction to the infection. The newly forming bone may extend outward from the periosteum and along the intact periosteal and endosteal surfaces, thereby surrounding the dead bone and forming an involucrum. This involucrum is irregularly shaped and contains openings through which pus may permeate into the surrounding soft tissues, forming a sinus tract that allows pus to travel from the involucrum to the skin surface. The involucrum may increase in density gradually and form part or all of a new bone shaft. Depending on the size of the affected bone and the duration of the infection, the amount and density of the new bone may increase progressively for weeks or months. New endosteal bone may proliferate and obstruct the medullary canal. Once the sequestrum has been removed surgically, the remaining cavity may be filled with new bone, especially in children. In adults, however, the cavity may persist or may be filled with fibrous tissue that connects with the skin surface through a sinus tract.

Clinical Manifestations Local findings that lead to the diagnosis of osteomyelitis are often absent in neonates (10). When present, these local findings include edema and decreased motion of a limb. A joint effusion adjacent to the site of bone infection is present in 60% to 70% of cases of osteomyelitis. In contrast with infants, children with hematogenous osteomyelitis have fever of abrupt onset, irritability, lethargy, and local signs of inflammation that are typically present for 3 weeks or fewer from the time that the bone infection began. Although there may be a minimal increase in temperature, systemic toxicity is absent in 50% of children with hematogenous osteomyelitis. Children with the disease have reports referable to the involved bone, such as pain for 1 to 3 months’ duration in the affected limb. Infants with hematogenous osteomyelitis usually have normal soft tissue that envelops the infected bone and are capable of an efficient immune response to the infection.

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In hematogenous vertebral osteomyelitis in adults, the clinical signs of soft tissue extension often dominate the findings at presentation and may lead to misdiagnosis and improper treatment, unless the possibility of osteomyelitis is considered. Patients with hematogenous vertebral osteomyelitis present with vague symptoms and signs that include dull, constant back pain, spasms of the paravertebral muscles, point tenderness over the involved vertebral body, and no (or only a low-grade) fever. There is localized pain and tenderness of the involved bone segments in at least 90% of cases (11). The pain, usually of insidious onset, progresses slowly over a period from 3 weeks to 3 months. An acute clinical presentation of chills, swelling, and erythema over the involved bone is seen occasionally. The clinical features of osteomyelitis with a contiguous force and normal vascularity include low-grade fever, local pain, draining sinuses, tenderness, and erythema over the involved bone. The infection usually manifests within 1 month after the inoculation of one or more organisms by means of trauma, surgery, or soft tissue infection. The patient is often afebrile and frequently has loss of bone stability, bone structure, and soft tissue damage. In patients who have vascular disease, the clinical features are more subtle and are usually associated with foot ulcers, which render this form of bone infection difficult to diagnose. Patients can present with an apparently localized process that includes an ingrown toenail, a perforating foot ulcer, cellulitis, or a deep-space infection. Furthermore, concurrent peripheral neuropathy often blunts the patient’s perception of pain. Fever and toxicity are frequently absent. There are no exact criteria for defining the transition from acute to chronic osteomyelitis. The hallmark of chronic osteomyelitis is the presence of dead bone as exemplified by the presence of sequestrum (1-3). Involucrum, local bone loss, persistent drainage, and/or sinus tracts are the common features of chronic osteomyelitis. Patients with chronic osteomyelitis present with chronic pain and drainage. Fever is usually of a low grade or absent. The erythrocyte sedimentation rate (ESR) is often increased, reflecting chronic inflammation; however, the leukocyte count is usually normal. Squamous cell carcinoma and amyloidosis are complications of chronic osteomyelitis that take many years to develop.

Classification Osteomyelitis can be classified by duration, pathogenesis, location, extent, and host status. Osteomyelitis is currently classified according to the Waldvogel (Table 33-1) or the Cierny-Mader (Table 33-2) system (1-3,12). Although the Waldvogel system remains the most popular classification system, it is limited to the cause of the infection and does not lend itself well to the identification of different clinical features of the disease for diagnosis and treatment. For this reason, the Cierny-Mader classification system is used

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Table 33-2 Cierny-Mader Staging System Anatomic Type ● ● ● ●

Stage Stage Stage Stage

1: 2: 3: 4:

Medullary osteomyelitis Superficial osteomyelitis Localized osteomyelitis Diffuse osteomyelitis

Physiologic Class ● ●

●

A Host: Normal host B Host: Systemic compromise (Bs)* ● Local compromise (Bl)* ● Systemic & local compromise (Bls)* C Host: Treatment worse than the disease

* See Table 33-3 for a list of systemic or local factors that affect immune surveillance, metabolism, and local vascularity.

in this chapter as a model for discussion of the diagnosis and treatment of osteomyelitis. It is based on the anatomy of the bone infection and the physiology of the host and allows the staging of long-bone osteomyelitis and the development of comprehensive treatment guidelines for each stage of the disease. The Cierny-Mader classification is based on the status of the disease process, regardless of cause, localization, or chronicity. The anatomical categories of osteomyelitis in the Cierny-Mader system are medullary, superficial, localized, and diffuse. Stage 1, or medullary osteomyelitis, denotes an infection that is confined to the intramedullary surfaces of the bone (e.g., hematogenous osteomyelitis, infection of intramedullary rods). Stage 2, or superficial osteomyelitis (a true contiguous-focus infection of bone), occurs when an exposed, infected, or necrotic surface of bone lies at the base of a soft tissue wound. Stage 3 or localized osteomyelitis is usually characterized by a full-thickness cortical sequestration that can be removed surgically without compromising bone stability. Stage 4, or diffuse osteomyelitis, is a process that involves all structural components of the bone; its arrest usually requires an intercalary resection of the bone. Diffuse osteomyelitis includes infections in which there is loss of bone stability, either before or after débridement. According to the Cierny-Mader system, the patient is classified as an A, B, or C host (Tables 33-2 and 33-3): An A host represents a patient with normal physiologic, metabolic, and immunologic capabilities; a B host is either systemically compromised, locally compromised, or both; and a C host is a patient in whom the illness of treatment is worse than that of the disease itself. The terms acute and chronic osteomyelitis are not used in this staging system, because areas of macronecrosis must be removed regardless of the acuity or chronicity of an uncontrolled infection. The stages of osteomyelitis in the Cierny-Mader system are dynamic and may be altered by treatment or by changes in the host.

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Table 33-3 Systemic or Local Factors that Affect Immune Surveillance, Metabolism, and Local Vascularity Systemic (Bs)

Local (Bl)

Malnutrition Renal, hepatic failure Diabetes mellitus Chronic hypoxia Immune disease Malignancy Extremes of age Immunosuppression or neuropathy Immune deficiency

Chronic lymphedema Venous stasis Major vessel compromise Arteritis Extensive scarring Radiation fibrosis Small vessel disease Complete loss of sensation Tobacco abuse

Diagnosis It is important that the physician recognize the clinical signs of osteomyelitis in its earliest stages. Most presentations of osteomyelitis, such as radiographic features or draining sinus tracts, are late complications of the disease. Osteomyelitis crosses from the more easily treated acute form to the difficult-to-treat chronic form when the bone dies, which usually occurs 10 days into the infection. When osteomyelitis is first discovered through radiographic manifestations, the diagnosis is already late and the treatment is more costly and difficult. Making the diagnosis at an early stage gives the patient the best opportunity for full recovery.

Culture and Microbiology The most determinate diagnostic tool for osteomyelitis is isolation of the causative pathogen through bone, blood, or joint culture (13-15). With stage 1 hematogenous osteomyelitis, a blood or joint culture can eliminate the need for a bone biopsy when radiographs and nucleotide scans show evidence of osteomyelitis. It should be noted that only 50% of patients with hematogenous osteomyelitis have positive blood cultures; however, for all other stages of the disease, it is necessary to obtain a bone culture from débridement surgery or deep bone biopsy to make a diagnosis. Sinus tract culture should not be used as a diagnostic technique because it has proven a poor indicator of gram-negative infection (16). Antimicrobial treatment of osteomyelitis should be based on susceptibility tests of culture isolates. If possible, the cultures should be made before any antibiotic is given and after the patient has ceased receiving antibiotic therapy for 24 to 48 hours. Furthermore, both fungi and mycobacteria should be considered pathogens in immunocompromised patients. In osteomyelitis that occurs after a footpuncture wound, Pseudo-monas aeruginosa is the most commonly found organism.

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Hematologic Findings In acute osteomyelitis, there is leukergy (the clumping of leukocytes that accompanies some inflammations and infections), increased ESR, and increased C-reactive protein (CRP) level and leukocyte count before treatment is begun (17-19). In cases of chronic disease, the leukocyte count rarely exceeds 15,000 cells/mm3 and is most often normal. The ESR, CRP level, and leukocyte count may decrease with appropriate treatment; but they often increase after débridement surgery. Return of the ESR and CRP to normal during the course of therapy is a favorable prognostic sign.

Imaging Studies Radiologic evaluation of osteomyelitis can be used to support or refute clinically suspected disease; no radiologic technique can confirm or rule out the presence of osteomyelitis absolutely. Because the radiologic approaches and techniques used for investigating osteomyelitis are numerous and diverse, there is confusion about which is most effective. It is difficult to interpret changes on plain radiography in early stage 1 osteomyelitis. In particular, radiographic changes often lag behind the evolution of infection by at least 2 weeks because 30% to 50% loss in bone density is often required to reach a level of bony destruction that can be visualized (20). The first radiographic changes to occur are soft tissue swelling, periosteal thickening, and focal osteopenia; however, these findings are subtle and often missed. The most diagnostic changes are delayed and occur in association with an indolent infection of several months’ duration. It should be remembered that at the beginning of antibiotic therapy, the patient shows clinical improvement before radiographic improvement is evident. In stage 2 osteomyelitis, the outer cortex of the bone is involved. In these cases there is evidence of periosteal thickening and/or sclerosis. Osteomyelitis of stages 3 and 4 may be more evident than the disease in its earlier stages; soft tissue swelling, osteopenia, lytic changes, and sclerosis are all characteristic findings. Small and large sequestra also may be present. Because of the degree of sclerosis and nonspecific radiographic changes, it is often difficult to estimate the scope of the infection by visualization on films. Therefore, the physician must carefully evaluate the disease clinically and possibly surgically as well. Sensitivity and specificity are only 70% and 50%, respectively, making this technique often unreliable (8-9). Although it is the least sensitive diagnostic technique, plain radiography is the most informative technique when there is a clinical suspicion of osteomyelitis. Ultrasound is another option, but it is only able to diagnose soft tissue infection surrounding the bone making this imaging technique of limited use. Radionuclide scans, computed tomography (CT), and magnetic resonance imaging (MRI) are often used to diagnose osteomyelitis in cases in which it is ambiguous and to determine the extent of bone and soft tissue

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infection. In most cases, these diagnostic tests are not required for osteomyelitis of the long bones. Radionuclide scans are widely used, and these help to identify areas of inflammation better than radiography alone. This method also has the benefit of being useful for suspected implant infections as well, because there are no issues with metallic scatter like MRI or CT. The technetium-99m (99mTc) methydiphosphonate scan demonstrates increased isotope accumulation in areas of osteoblastic activity and increased vascularity (21). Sensitivity and specificity of osteomyelitis detection for this method range from 69% to 100% and 38% to 94%, respectively. However, any event leading to bone injury leads to a positive scan, causing false diagnoses. Falsepositive rates have been reported from 0% to 64% in reported series (22) and high rates can be attributed to cases of new bone formation, fracture healing, heterotopic ossification, arthritis, and local minor trauma (23). A second class of radiopharmaceuticals used for the evaluation of osteomyelitis includes gallium-67 (67Ga) citrate and indium-111 chloride; both become bound to transferrin, which leaks from the blood into areas of inflammation. These scans also show increased isotope uptake in malignant tumors and in areas in which polymorphonuclear leukocytes or macrophages are concentrated. Because they do not show bone detail well, these scans do not readily distinguish between bone and soft tissue inflammation. Three-phase 99m Tc methydiphosphonate scans help resolve this problem. Another radionuclide technique exploits indium-111 (111In) labeled leukocytes, in which patient leukocytes are isolated, labeled with 111In, and injected back into the patient. These radiolabeled leukocytes will accumulate in regions of acute infection, causing it to be a sensitive method (except in most cases of chronic osteomyelitis) and the radionuclide technique of choice for diagnosing and localizing acute osteomyelitis in the limbs (22-25). Although its sensitivity is 86%, its specificity is only 12% (26). Also, these scans are positive in approximately 40% of patients with acute osteomyelitis and in 60% of patients with septic arthritis. Chronic osteomyelitis, bony metastases, and degenerative arthritis often yield negative scans. However, this method works well in cases of suspected prosthetic implant infection when combined with bone marrow imaging with 99mTc sulfur colloid marrow scintigraphy because leukocyte uptake around prostheses may be caused by surgery. When an accumulation of leukocytes is seen, coupled with noncongruent bone marrow patterns and absent marrow uptake, an infection is likely. 99mTc hexamethylpropylene amine oxime leukocytes ( 99mTc HMPAO WBCs) are also used to overcome the problems with 111In leukocytes, such as the 24-hour delay required for imaging, high levels of radiation in the spleen, and limited injection dose. The combination of these 2 scans leads to a sensitivity of 100% and a specificity of 94% (26). CT may be useful in the diagnosis of osteomyelitis by measuring the increased marrow density that occurs early in the infection (27). CT is also useful in identifying areas of devitalized bone and reveals the involvement of

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surrounding soft tissues, particularly in cases of vertebral osteomyelitis. In a difficult infection, the CT scan may assist in selecting the most appropriate surgical approach (28). MRI has become the most useful diagnostic tool for identifying and determining the extent of musculoskeletal sepsis (29-30). The spatial resolution of MRI makes it useful in differentiating bone from soft tissue infections. MRI displays greater anatomic detail than does radionuclide scanning and has greater specificity for abnormalities than do either CT or radiography. Moreover, MRI does not expose patients to ionizing radiation. The sensitivity and specificity to detect cases of osteomyelitis are between 68% to 100% and 50% to 100%, respectively (31-32). In cases of vertebral osteomyelitis, MRI is particularly valuable and has a sensitivity and specificity of 96% and 92%, respectively (33). The main disadvantage of MRI is its poor resolution of the cortex, which could yield many false-negative results in cases of isolated cortical infection (34). Initial MRI screening usually consists of both T1- and T2-weighted spin echo pulse sequences. In a T1-weighted study, edema and fluid are dark, whereas fat (including the fatty marrow of bone) is bright. In a T2-weighted study, the reverse is true. The typical appearance of osteomyelitis is of a localized area of abnormal marrow with a decreased signal intensity (darker appearance) on T1-weighted images and increased signal intensity on T2weighted images. Occasionally, however, there also may be a decreased signal intensity on T2-weighted images. Cellulitis is seen as a diffuse area of intermediate signal intensity on T1-weighted images of soft tissue and as an increased signal intensity on T2-weighted images of the same tissue. Because it may be difficult to differentiate infection from neoplasm on the basis of MRI alone, further clinical and radiographic confirmation may be necessary.

Osteomyelitis with Vascular Insufficiency For patients with vascular disease, the diagnosis of osteomyelitis can become a challenge because of coexisting clinical effects. It is essential, however, that the physician recognizes osteomyelitis in its early stages to arrest the infection and prevent amputation caused by complications of peripheral vascular disease. Clinical evaluation is the most important step in diagnosing osteomyelitis in patients with vascular disease. Any ulcer or skin laceration near a bony area of the foot that has persisted for more than 1 to 2 weeks should be considered a risk factor for underlying osteomyelitis. When the bone can be visualized, treatment of osteomyelitis can begin immediately and be adjusted when culture results are known. In all other cases, radiographic evidence is necessary to confirm the existence of the disease. Patients with both osteomyelitis and vascular disease often have radiographs that show patchy bone destruction, a periosteal reaction, and illdefined bone margins. CT scans, although more sensitive, are less useful than radiographs for identifying infections of the foot bones because of the

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small amount of bone and adjacent soft tissue in the extremities. Radionuclide scans yield positive findings in cases of both soft tissue and bone inflammation. Consequently, a positive scan may indicate only a soft tissue infection. In studies of patients with osteomyelitis with complicating soft tissue infections of the foot, MRI proved to be diagnostically better than plain radiography, bone scanning, 67Ga scanning, and leukocyte scanning (35). MRI is also useful in distinguishing areas of neuropathy, which are identified by a low signal intensity on all pulse sequences within bony structures and soft tissue. This contrasts with osteomyelitis, in which marrow gives a high signal intensity on all pulse sequences except for T1weighted sequences. Because of their high cost, MRI studies should be reserved for patients who have a questionable diagnosis of osteomyelitis.

Vertebral Osteomyelitis The most common radiographic feature of vertebral osteomyelitis is faint lucency at the edge of the affected vertebral body, with loss of clear demarcation of the cortical margin. MRI is the simplest and most effective method for determining osteomyelitis of the spine. Involvement of the vertebral bodies, discs, and paravertebral region is detected easily. Disease-induced changes in MRI scans include increased enhancement on T1-weighted images and increased intensity on T2-weighted images. Consistently, infection has been associated with an early decreased intensity of the vertebral marrow on T1-weighted images and an enhanced intensity of the same area with gadolinium-enhanced contrast studies. Significant changes on T2weighted images also have been shown to be early signs of infection.

Treatment Many factors must be considered in determining the appropriate course of treatment of the patient with osteomyelitis and especially the effect that treatment will have on the patient. If curative measures will adversely affect the patient’s quality of life, simple suppression of the disease with oral antibiotic therapy may be preferred. If the patient is a good surgical candidate, foreign material and sequestra must be removed. Appropriate treatment of osteomyelitis includes adequate drainage, thorough débridement, obliteration of dead space, wound protection, stabilization if necessary, and specific antimicrobial coverage. If the patient is a compromised host, an effort should be made to correct or alleviate the host’s defect(s).

Medical Management After cultures are obtained from a patient with osteomyelitis, a parenteral antimicrobial regimen is begun to eliminate the clinically suspected pathogens (Table 33-4). Once the causative pathogen has been identified,

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the specific classes of antimicrobial drugs for its eradication can be selected through appropriate methods of sensitivity testing (36). Most experts prefer bacteriocidal over bacteriostatic therapy (with the exception of clindamycin); and, with the exception of acute osteomyelitis, antimicrobial therapy by itself is rarely curative. Cure usually requires surgery, and most experts use parenteral therapy in adults and with chronic osteomyelitis to ensure high concentrations of drug at the infected site. Stage 1, or hematogenous osteomyelitis, in children usually can be treated with antimicrobial drugs alone (37). Antibiotic therapy without surgery is possible because children’s bones are very vascular and children have an effective immune response to infection. It is recommended that children with osteomyelitis initially receive 2 weeks of parenteral antibiotic therapy followed by an oral antibiotic regimen. Oral therapy should be given for 4 to 6 weeks. Because the quinolone class of antimicrobial drugs has been shown to cause articular damage in young animals, this class of drugs should not be used in pediatric patients. Stage 1 osteomyelitis is more refractory to therapy in adults than in children and is usually treated with antimicrobial drugs and surgery. The patient is given 4 weeks of appropriate parenteral antimicrobial therapy, dating from the initiation of therapy or after the last major débridement surgery. For methicillin-susceptible S. aureus (MSSA) and Streptococcus species, the antimicrobial agent initially chosen should be clindamycin, nafcillin, or cefazolin. Clindamycin may the drug of first choice for sequential intravenous or oral therapy because of its excellent bone penetration and bioavailability. If the initial medical management fails and the patient is clinically compromised by a recurrent infection, medullary and/or soft tissue débridement is necessary in conjunction with another 4-week course of antibiotic therapy. As noted earlier, an infected intramedullary rod can cause stage 1 osteomyelitis. If the bone is stable, the rod can be removed. The patient is given a 4-week course of antibiotic therapy beginning at the time of rod removal. If the bone is unstable, the patient is given suppressive oral antibiotic therapy until bone stability is achieved. Once stability is achieved, the rod is removed and the patient is given a 4-week course of antibiotic therapy, again beginning at the time of rod removal. Stage 2, or superficial osteomyelitis, occurs when an exposed infected, necrotic surface of bone lies at the base of a soft tissue wound. After superficial bone débridement and soft tissue treatment, the patient is given 2-week parenteral antimicrobial therapy beginning after the last major débridement surgery. Without adequate débridement, most antibiotic regimens fail no matter the duration the therapy. Even when all necrotic tissues have been débrided adequately, the remaining bed of tissue must be considered contaminated with the causative pathogen(s). Consequently, it is important to give the patient at least 4 weeks of antibiotic treatment. The arrest rate for stages 3 and 4 osteomyelitis with such treatment is approximately 90% (10).

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Table 33-4 Initial Choice of Antibiotics for Therapy of Osteomyelitis* Organism

Antibiotics of First Choice

Alternative Antibiotics

MSSA

Nafcillin or oxacillin 2 g IV q4h for 4-6 wk

●

Cefazolin 2 g IV q8h for 4-6 wk ● Penicillin-intolerant patient: ● Vancomycin 15 mg/kg IV q12h for 4-6 wk ● Clindamycin 900 mg q8h for 4-6 wk ● Linezolid 600 mg IV or PO MRSA and MRSE Vancomycin 15 mg/kg IV q12h for 4-6 wk for 6 wk (platelet count should be checked weekly if this drug is given over 14 days ● TMP/SMX DS (if tested susceptible) 2 tablets q12h for 4-6 wk ● Levofloxacin (if tested susceptible) 500-750 mg PO/IV q24h with or without rifampin 600 mg/day for 4-6 wk ● Cefazolin 2 g q8h IV or Streptococcus Penicillin G 2 million units IV (Groups A, B, q4h or ampicillin 2 g IV q4h Ceftriaxone 1-2 g IV q24h for and viridans for 4-6 wk 4-6 wk ● Penicillin intolerant patient: streptococci) ● Vancomycin 15 mg/kg IV q12h for 4-6 wk ● Clindamycin 900 mg q8h for 4-6 wk** Enterococcus Ampicillin 2 g IV q4h for Vancomycin 15 mg/kg IV q12h and streptococ4-6 wk plus gentamicin for 4-6 wk plus (optional) cus with MIC 1 mg/kg IM q8h for 1-2 wk gentamicin 1 mg/kg IM q8h > 0.5 µg/mL for 1-2 wk ● Ciprofloxacin 750 mg PO Enteric bacteria Ceftriaxone 1-2 g IV q24h for 4-6 wk (if tested susceptible) q12h for 4-6 wk ● Levofloxacin 750 mg PO (if tested susceptible) q24h for 4-6 wk ● Based on susceptibility ESBL-producing Imipenem/cilastatin 500 mg IV enteric bacteria q6h or Meropenem 1 g IV q8h results for 4-6 wk ● Piperacillin 4 g IV q6h or Pseudomonas Cefepime 2 g IV q12h ● Imipenem/cilastatin 500 mg aeruginosa IV q6h or Meropenem 1 g IV q8h for 4-6 wk ● Ciprofloxacin 750 mg PO q12h for 4-6 wk * Adult doses. ** Clindamycin resistant group B streptococci has been increasingly found in certain geographic areas Abbreviations: h = hour; ESBL = extended-spectrum beta-lactamase; IM = intramuscular; IV = intravenous; MIC = minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus; MRSE = methicillin-resistant Staphylococcus epidermidis; MSSA = methicillin-susceptible Staphylococcus aureus; PO = by mouth; q = every; TMP/SMX DS = trimethoprim/sulfamethoxazole double-strength; wk = week.

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Hospital lengths of stay for osteomyelitis have been decreased in recent years by the development of outpatient catheters and oral antibiotic therapy. Intravenous therapy can be given on an outpatient basis with longterm intravenous access catheters, such as Hickman or Groshong catheters (38,39). In addition to outpatient intravenous therapy, oral therapy with quinolones for gram-negative organisms is used for adult patients with osteomyelitis (40,41). The second-generation quinolones (e.g., ciprofloxacin, ofloxacin) have poor activity against Streptococcus, Enterococcus, and anaerobic bacteria. The third-generation quinolones (e.g., levofloxacin, gatifloxacin) have excellent activity against Streptococcus but provide minimal coverage of anaerobic organisms. None of the quinolones provides reliable coverage of Enterococcus. The currently available quinolones provide variable coverage of S. aureus and S. epidermidis, and resistance to the secondgeneration quinolones is increasing. MSSA should be covered with another oral antimicrobial agent, such as clindamycin or amoxicillin-clavulanate. Before being moved to an oral antimicrobial regimen, the patient should be given 2 weeks of parenteral antibiotic therapy; it is important to ascertain whether the organisms isolated from the patient’s infection are sensitive to the oral regimen. The patient must be compliant with treatment and have close outpatient follow-up. A combination of parenteral and oral antibiotic therapy has been used in some situations. Osteomyelitis caused by MSSA has been treated successfully with the combination of a semisynthetic penicillin and rifampin, and osteomyelitis caused by methicillin-resistant S. aureus (MRSA) has been treated successfully with a combination of vancomycin and rifampin. New treatment options for MRSA include linezolid, daptomycin, and tigecycline. Studies in osteomylitis treatment with these agents are ongoing.

Surgical Management Surgical management of osteomyelitis can be very challenging. The principles of surgically treating any infection are equally applicable to the treatment of infection in bone. These include adequate drainage, extensive débridement of all necrotic tissue, obliteration of dead spaces, adequate soft tissue coverage of the treated bone, restoration of an effective blood supply, and stabilization of the patient. The goal of débridement in osteomyelitis is to leave healthy, viable bone tissue and conditions that can lead to the rapid formation of new bone. However, even when all necrotic tissue has been débrided adequately, the remaining bed of tissue must be considered to be contaminated with the etiologic pathogen. The challenge in treating osteomyelitis compared with that of an infection of soft tissue alone is the need for bone débridement. In cases of chronic osteomyelitis, débridement is essential for cure. Adequate débridement may leave the large-bone defect known as a dead space. To arrest the disease and maintain the integrity of the bone, appropriate management of

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any dead space created by débridement surgery is mandatory. The goal of dead-space management is to replace dead bone and scar tissue with durable, vascularized bone tissue. Allowing the bone to become revascularized is the best way to ensure the arrest of the infection in osteomyelitis. Complete wound closure should be attained whenever possible. Cancellous bone grafts allow the filling of the dead space that remains after débridement surgery with tissue that allows revascularization (42). These grafts also can be placed beneath local or transferred tissues where soft tissue reconstruction is necessary. Careful preoperative planning is critical to conserving the patient’s limited cancellous bone reserves. Open cancellous grafts are useful when a free tissue transfer is not a treatment option and when local tissue flaps are inadequate. Antibiotic-impregnated acrylic beads may be used to sterilize and to maintain dead space temporarily (43,44). The beads are usually removed within 2 to 4 weeks and then replaced with a cancellous bone graft. The antibiotics most commonly used in impregnated beads are vancomycin, tobramycin, and gentamicin. Local delivery of antibiotics (e.g., amikacin, clindamycin) into dead space has been accomplished with an implantable pump. If pathologic movement of bone is present at the site of infection, measures must be taken to achieve permanent stability of the affected skeletal unit. Stability may be achieved with plates, screws, and rods, and/or an external fixator. External is preferred to internal fixation because of the tendency of medullary rods to become secondarily infected and thereby extend the original bone infection. An Ilizarov external fixator allows bone reconstruction of segmental defects and difficult infected nonunions (45,46). This external fixation method is based on the theory of distraction histogenesis, whereby bone is fractured in the metaphyseal region and slowly lengthened. The growth of new bone in the metaphyseal region pushes a segment of healthy bone into the defect left by surgery. The Ilizarov method also may be used to compress nonunions and to correct malunions. Infected pseudoarthroses with segmental osseous defects also may be treated by débridement and microvascular bone transfers. Vascularized bone transfer is a useful procedure for treating infected segmental osseous defects of long bones of more than 3 cm length. Vascularized bone transfers can be performed 1 month or more after the successful treatment of a bone infection. Adequate soft tissue coverage of the bone is necessary to arrest osteomyelitis. Small soft tissue defects may be covered with a split-thickness skin graft. Local tissue flaps or free flaps may be used to fill dead space (47,48). Although local muscle flaps are useful because of their ease of placement, they are often of limited use because of the locality of the bone infection in osteomyelitis. For areas such as the distal tibia, microsurgical implantation of a muscle flap is necessary. In the presence of a large soft tissue defect or with an inadequate soft tissue envelope, local muscle flaps and free vascularized muscle flaps may be placed in a 1- or 2-stage procedure.

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Local and free muscle flaps, when combined with antibiotic therapy and surgical débridement of all nonviable osseous and soft tissue, have a success rate of from 66% to 100% in chronic osteomyelitis (49). Local muscle flaps and free vascularized muscle transfers alleviate the local biological environment by bringing in a blood supply important to host-defense mechanisms, antibiotic delivery, and osseous and soft tissue healing.

Special Treatments Osteomyelitis with Vascular Insufficiency Determination of the vascular status of the tissue at the infection site is crucial in the evaluation of patients in whom osteomyelitis is accompanied by vascular insufficiency. Although several methods can be used to determine the vascular status of such patients, measuring cutaneous oxygen tension and pulse pressure is the most commonly used method. Cutaneous oxygen tensions are measured with a modified Clark electrode that is applied to the skin surface. The results provide guidelines for determining the location of adequately perfused tissue. The tensions recorded in this manner are also helpful for predicting the benefit of local débridement surgery and in selecting surgical margins at which healing can be expected to occur. Revascularization, if possible, or hyperbaric oxygen therapy facilitates healing in areas where oxygen tensions are of borderline normality. Historically, treatment pressures of both 2.0 and 2.4 atmosphere absolute (ATA) have been used, with treatment times varying from 2 hours at the lower pressure to 90 minutes at 2.4 ATA. Treatment pressure and duration are the same for monoplace and multiplace chambers. Now the higher pressure of 2.4 ATA is almost universally used. Because experimental evidence suggests that twice-per-day hyperbaric oxygen (HBO) treatments interfere with bone healing (50-52), if used HBO treatment should be provided on a once-per-day basis for the treatment of osteomyelitis. The patient who has osteomyelitis with vascular insufficiency may be managed with suppressive antibiotic therapy, local débridement surgery, or ablative surgery. The choice of treatment is based on tissue oxygen perfusion at the infection site, extent of the osteomyelitis, and patient preference. The patient can be offered long-term suppressive antibiotic therapy when a definitive surgical procedure might lead to unacceptable illness or disability or in cases in which the patient refuses local débridement or ablative surgery. However, even with suppressive antibiotic therapy, amputation of the involved bone may ultimately be necessary. Local débridement surgery and a 4-week course of antibiotic therapy may be used for the patient who has osteomyelitis in bone that is amenable to débridement. Unless good tissue oxygen tensions are present, the wound fails to heal and ultimately requires an ablative procedure. As noted earlier, hyperbaric oxygen therapy facilitates healing in areas of borderline-normal oxygen tension.

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The patient with extensive osteomyelitis and poor tissue oxygen perfusion usually requires some type of ablative surgery. Digital and ray resections; transmetatarsal amputations; midfoot disarticulations; and Chopart, Lisfranc, and Syme amputations (amputation of the foot with retention of the heel pad) permit the patient to ambulate without a prosthesis. The level of amputation is measured by the vascularity and potential viability of the tissues proximal to the site of infection. Hyperbaric oxygen therapy facilitates healing if surgery is done in or through areas of low oxygen tension as measured cutaneously. When infected bone is transected surgically, the patient is given 4 weeks of antibiotic therapy. Two weeks of antibiotic therapy are given when the infected bone is excised completely, but some residual soft tissue infection remains. When amputation is done proximal to a site of bone and soft tissue infection, the patient should be given from 1 to 3 days of antibiotic therapy.

Vertebral Osteomyelitis Biopsy and débridement cultures dictate the choice of antibiotic(s) to be used in treating vertebral osteomyelitis. Antibiotic therapy is given for 4 to 6 weeks and is dated from the initiation of therapy or from the last major débridement surgery. Open surgical treatment is usually necessary only in cases in which the patient develops an extension of an original infection (e.g., paravertebral or epidural abscess, when medical management fails, when bone instability is likely to occur). The neurological status of the patient must be monitored closely in such cases. Surgical fusion of the involved vertebrae is usually not required, because bone fusion occurs spontaneously within 1 to 12 months after appropriate antibiotic therapy. The frequency of a successful outcome for patients treated with bed rest alone is not substantially different from that for ambulatory patients stabilized with a cast, corset, or brace.

Prevention Most cases of long-bone osteomyelitis are posttraumatic or postoperative. With the increasing number of accidents and orthopaedic procedures done, it is unlikely that infection rate will decrease. Patients with diabetes mellitus can prevent osteomyelitis by minimizing foot trauma and preventing foot ulcers (8) (see Diabetic Foot Infection chapter). This includes education about proper foot care, including daily inspection of the feet. Daily foot washing and use of moisturizing creams are necessary to avoid breaking the skin. Furthermore, patients should avoid activities that might cause unnecessary trauma to vasculitic neuropathic feet. This includes walking barefoot or wearing improperly fitted shoes. The only way to reduce the frequency of contiguous-focus osteomyelitis in diabetic patients is to prevent the development of diabetic foot ulcers or aggressively prevent diabetic foot ulcers from involving bone through treatment of the infection, wound care, and the off-loading of pressure points.

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Acknowledgments The authors thank Gordon Christensen, MD, and M. M. Manring, PhD, for their help in the preparation of this manuscript.

REFERENCES 1. Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. 3. Osteomyelitis associated with vascular insufficiency. N Engl J Med. 1970;282:316-22. 2. Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects (second of three parts). N Engl J Med. 1970;282:260-6. 3. Waldvogel FA, Medoff G, Swartz MN. Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med. 1970;282:198-206. 4. Trueta J, Morgan JD. The vascular contribution to osteogenesis: Studies by the injection method. J Bone Joint Surg Br. 1960;42B:97-109. 5. Hobo T. Zur Pathogenese de akuten haematatogenen Osteomyelitis, mit Beruckishtigun der Vitalfarbungslehre. Ada School Med Univ Imp Kioto. 1922;4:l-29. 6. Mader JT,Wilson KJ. Comparative evaluation of cefamandole and cephalothin in the treatment of experimental Staphylococcus aureus osteomyelitis in rabbits. J Bone Joint Surg Am. 1983;65:507-13. 7. Caputo GM, Cavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med. 1994;331:854-60. 8. Calhoun JH, Cantrell J, Cobos J, Lacy J, Valdez RR, Hokanson J, et al. Treatment of diabetic foot infections: Wagner classification, therapy, and outcome. Foot Ankle. 1988;9:101-6. 9. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15:167-93. 10. Ish-Horowicz MR, McIntyre P, Nade S. Bone and joint infections caused by multiply resistant Staphylococcus aureus in a neonatal intensive care unit. Pediatr Infect Dis J. 1992;11:82-7. 11. Cierny G 3rd. Chronic osteomyelitis: results of treatment. Instr Course Lect. 1990;39:495-508. 12. Cierny GI, Mader JT, Penninck JJ. A clinical staging system for adult osteomyelitis. Contemp Orthop. 1985;10:17-37. 13. Perry CR, Pearson RL, Miller GA. Accuracy of cultures of material from swabbing of the superficial aspect of the wound and needle biopsy in the preoperative assessment of osteomyelitis. J Bone Joint Surg Am. 1991;73:745-9. 14. Mader JT, Calhoun JH. Osteomyelitis. In: Mandell GL, Douglas RG, Bennett JE Jr., eds. Principles and Practice of Injections Diseases. New York, NY: Churchill Livingstone; 1995:1039-51. 15. Cierny G 3rd, Mader JT. Approach to adult osteomyelitis. Orthop Rev. 1987;16:259-70. 16. Mackowiak PA, Jones SR, Smith JW. Diagnostic value of sinus-tract cultures in chronic osteomyelitis. JAMA. 1978;239:2772-5. 17. Otremski I, Newman RJ, Kahn PJ, Stadler J, Kariv N, Skornik Y, et al. Leukergy—a new diagnostic test for bone infection. J Bone Joint Surg Br. 1993;75:734-6. 18. Roine I, Faingezicht I, Arguedas A, Herrera JF, Rodríguez F. Serial serum C-reactive protein to monitor recovery from acute hematogenous osteomyelitis in children. Pediatr Infect Dis J. 1995;14:40-4. 19. Unkila-Kallio L, Kallio MJ, Eskola J, Peltola H. Serum C-reactive protein, erythrocyte sedimentation rate, and white blood cell count in acute hematogenous osteomyelitis of children. Pediatrics. 1994;93:59-62. 20. Butt WP. The radiology of infection. Clin Orthop Relat Res. 1973:20-30. 21. Rosenthall L, Lisbona R, Hernandez M, Hadjipavlou A. 99mTc-PP and 67Ga imaging following insertion of orthopedic devices. Radiology. 1979;133:717-21. 22. Wheat J. Diagnostic strategies in osteomyelitis. Am J Med. 1985;78:218-24. 23. Datz FL, Jacobs J, Baker W, Landrum W, Alazraki N, Taylor A Jr. Decreased sensitivity of early imaging with In-111 oxine-labeled leukocytes in detection of occult infection: concise communication. J Nucl Med. 1984;25:303-6. 24. Propst-Proctor SL, Dillingham MF, McDougall IR, Goodwin D. The white blood cell scan in orthopedics. Clin Orthop Relat Res. 1982:157-65. 25. Howie DW, Savage JP,Wilson TG, Paterson D. The technetium phosphate bone scan in the diagnosis of osteomyelitis in childhood. J Bone Joint Surg Am. 1983;65:431-7. 26. Palestro CJ, Roumanas P, Swyer AJ, Kim CK, Goldsmith SJ. Diagnosis of musculoskeletal infection using combined In-111 labeled leukocyte and Tc-99m SC marrow imaging. Clin Nucl Med. 1992;17:269-73.

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27. Kuhn JP, Berger PE. Computed tomographic diagnosis of osteomyelitis. Radiology. 1979;130:503-6. 28. Seltzer SE. Value of computed tomography in planning medical and surgical treatment of chronic osteomyelitis. J Comput Assist Tomogr. 1984;8:482-7. 29. Tehranzadeh J,Wang F, Mesgarzadeh M. Magnetic resonance imaging of osteomyelitis. Crit Rev Diagn Imaging. 1992;33:495-534. 30. Modic MT, Pflanze W, Feiglin DH, Belhobek G. Magnetic resonance imaging of musculoskeletal infections. Radial Clin North Am. 1986;24:247-58. 31. Kothari NA, Pelchovitz DJ, Meyer JS. Imaging of musculoskeletal infections. Radiol Clin North Am. 2001;39:653-71. 32. Tehranzadeh J,Wong E,Wang F, Sadighpour M. Imaging of osteomyelitis in the mature skeleton. Radiol Clin North Am. 2001;39:223-50. 33. Modic MT, Feiglin DH, Piraino DW, Boumphrey F, Weinstein MA, Duchesneau PM, et al. Vertebral osteomyelitis: assessment using MR. Radiology. 1985;157:157-66. 34. Erdman WA,Tamburro F, Jayson HT, Weatherall PT, Ferry KB, Peshock RM. Osteomyelitis: characteristics and pitfalls of diagnosis with MR imaging. Radiology. 1991;180:533-9. 35. McAndrew PT, Clark C. MRI is best technique for imaging acute osteomyelitis [Letter]. BMJ. 1998;316:147. 36. Ericsson HM, Sherris JC. Antibiotic sensitivity testing: Report of an international collaborative study. Acta Pathol Microbiol Scand [B]. 1971;217:1. 37. Tetzlaff TR, McCracken GH Jr., Nelson JD. Oral antibiotic therapy for skeletal infections of children. II. Therapy of osteomyelitis and suppurative arthritis. J Pediatr. 1978;92:485-90. 38. Couch L, Cierny G, Mader JT. Inpatient and outpatient use of the Hickman catheter for adults with osteomyelitis. Clin Orthop Relat Res. 1987:226-35. 39. Hickman RO, Buckner CD, Clift RA, Sanders JE, Stewart P, Thomas ED. A modified right atrial catheter for access to the venous system in marrow transplant recipients. Surg Gynecol Obstet. 1979;148:871-5. 40. Mader JT. Fluoroquinolones in bone and joint infections. In: Sanders WE Jr., Sanders CC, eds. Fluoroquinolones in the Treatment of Infectious Diseases. Chicago, IL: Physicians Scientists; 1990:71-86. 41. Mader JT, Cantrell JS, Calhoun J. Oral ciprofloxacin compared with standard parenteral antibiotic therapy for chronic osteomyelitis in adults. J Bone Joint Surg Am. 1990;72:104-10. 42. Minami A, Kaneda K, Itoga H. Treatment of infected segmental defect of long bone with vascularized bone transfer. J Reconstr Microsurg. 1992;8:75-82. 43. Henry SL, Seligson D, Mangino P, Popham GJ. Antibiotic-impregnated beads. Part I: Bead implantation versus systemic therapy. Orthop Rev. 1991;20:242-7. 44. Calhoun JH, Mader JT. Antibiotic beads in the management of surgical infections. Am J Surg. 1989;157:443-9. 45. Calhoun JH, Anger DM, Mader J, Ledbetter BR. The Ilizarov technique in the treatment of osteomyelitis. Tex Med. 1991;87:56-9. 46. Green SA. Osteomyelitis. The Ilizarov perspective. Orthop Clin North Am. 1991;22:515-21. 47. May JW Jr., Jupiter JB, Gallico GG 3rd, Rothkopf DM, Zingarelli P. Treatment of chronic traumatic bone wounds. Microvascular free tissue transfer: a 13-year experience in 96 patients. Ann Surg. 1991;214:241-50; discussion 250-2. 48. Anthony JP, Mathes SJ, Alpert BS. The muscle flap in the treatment of chronic lower extremity osteomyelitis: results in patients over 5 years after treatment. Plast Reconstr Surg. 1991;88:311-8. 49. Gayle LB, Lineaweaver WC, Oliva A, Siko PP, Alpert BS, Buncke GM, et al. Treatment of chronic osteomyelitis of the lower extremities with debridement and microvascular muscle transfer. Clin Plast Surg. 1992;19:895-903. 50. Wray JB, Rogers LS. Effect of hyperbaric oxygenation upon fracture healing in the rat. J Surg Res. 1968;8:373-8. 51. Yablon IG, Cruess RL. The effect of hyperbaric oxygen on fracture healing in rats. J Trauma. 1968;8:186-202. 52. Goldhaber P. The effect of hyperoxia on bone resorption in tissue culture. AMA Archives Path. 1958;66:635-41.

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Chapter 34

Superficial Skin Infections (Pyodermas) THOMAS M. FILE, JR, MD, MS DENNIS L. STEVENS, MD, PHD

Key Learning Points 1. Superficial skin infections (Pyodermas) include infections such as folliculitis, furunculosis, carbuncles, erysipelas, cellulitis, impetigo 2. These infections are usually due to S. aureus or β-hemolytic streptococcus, but other organisms may be the cause based on certain underlying conditions (e.g., Pseudomonas folliculitis associated with hot tub usage; mixed infection with hidradenitis suppurativa) 3. Therapy includes local compresses and drainage, topical antimicrobials or oral antimicrobials

B

acterial skin infections range from mild pyodermas to life-threatening necrotizing infections (1-4). The manifestations of bacterial skin infections result from the interaction of bacterial virulence factors with the immune status and underlying conditions of the host. The skin represents an effective physical barrier against invasion by microorganisms. The normal skin of healthy individuals is resistant to invasion by bacteria that can reside on the skin surface. Infection of the skin usually occurs when there is a defect in the integrity of the epidermis, allowing microorganisms that have colonized the skin to invade the underlying tissues and cause clinical effects. Such defects can result from surgery or trauma or can follow relatively innocuous events, such as an insect bite or abrasion. Skin lesions also can result from the hematogenous spread of bacteria or bacterial toxins from distant sites of infections. This chapter reviews the clinical aspects of superficial bacterial skin infections, which are often referred to as primary pyodermas. 629

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New Developments in the Management of Superficial Skin Infections ●

●

The prevalence of skin infections caused by community-associated methicillinresistant Staphylococcus aureus (CA-MRSA) continues to increase. New guidelines for management of skin and soft-tissue infections.

Pathogenesis and Predisposing Factors Most bacteria decrease in number when applied to the surface of the keratinized layers of normal skin. Various physical characteristics of the skin act to reduce bacterial multiplication: ● ●

● ●

The skin environment has relatively low pH (~5.5). Natural antibacterial substances are present in the secretions of the sebaceous glands. Normal skin is relatively dry. Bacterial interference occurs in the suppressive effect of normal flora on the growth of pathogens.

Normal skin is colonized with various microorganisms that are classified as resident flora, including Propionibacterium species, coagulase-negative staphylococci, and Corynebacterium species. For the most part, these organisms are not pathogenic. When a foreign body (e.g., intravenous catheter) is present, such resident organisms can cause localized infection and bacteremia. The skin can be colonized transiently by Staphylococcus aureus and betahemolytic streptococci, which are more likely to cause invasive disease. Additionally, members of the Enterobacteriaceae family, Pseudomonas species, Enterococcus species, and various anaerobes from fecal sources are particularly prone to colonizing the lower extremities. Colonization of normal skin with pathogenic organisms usually precedes clinical infection. Subsequently, minimal trauma can cause an epidermal defect that allows organisms on the skin surface to cross the keratinized layers that normally protect against infection and cause disease. Although the causative pathogens that are associated with many of the pyodermas are fairly predictable (usually S. aureus or betahemolytic Streptococcus species), other organisms (e.g., Pseudomonas in whirlpool-bath folliculitis, anaerobes and Enterobacteriaceae in chronic hidradenitis suppurativa) can be involved. S. aureus often colonizes patients both in and out of the hospital setting. Common sites for colonization include the anterior nares or perineum. Approximately 50% of patients can be found to carry S. aureus transiently at any given time. Individuals who are prone to colonization include health care workers, patients with diabetes, patients who undergo chronic hemodialysis, and users of illicit intravenous drugs. Most patients with staphylococcal folliculitis or furunculosis experience a selflimiting infection. Certain patients, however, are especially prone to recurrent

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infections, including those who have hypogammaglobulinemia, diabetes mellitus, cancer or organ transplants (who are also receiving immunosuppressive drugs), chronic granulomatous disease of childhood, and Job syndrome. Additionally, poor hygiene, obesity, folliculosis, chronic dermatitis, seborrhea, psoriasis, malnutrition, and occupational trauma all can predispose the patient to recurrent S. aureus pyoderma. The pathogenicity of specific microorganisms is measured in part by virulence factors (5). Local invasiveness is an important element in group A streptococcal infection (e.g., Streptococcus pyogenes), which depends on the antiphagocytic M protein of the bacterial cell envelope (6). Several extracellular products associated with S. pyogenes can contribute to the manifestations of skin infection. These include hyaluronidase, proteinase, deoxyribonuclease, and streptokinase, all of which cause liquefaction of pus and enhance the spread of infection throughout tissue planes. Toxins and enzymes seem to play a role in the ability of S. aureus to produce disease. Alpha- and deltatoxins can contribute to disease manifestations by damaging tissue membranes. Exfoliative toxin, which is produced by certain strains of S. aureus, causes separation between the epidermis and the dermis, resulting in the scalded-skin syndrome. Both S. aureus and S. pyogenes can produce pyogenic toxins associated with a toxic shock syndrome. The staphylococcal toxic shock syndrome characterized by hypotension, rash, and multisystem involvement is caused by strains of S. aureus that produce an exotoxin, toxic shock syndrome toxin 1 (7). More recently, serious skin infections caused by S. pyogenes and characterized by necrotizing fasciitis have been described in association with group A streptococcal toxic shock syndrome (see Chapter 31). The pathogenesis of skin infections associated with gram-negative bacilli (e.g., exotoxins produced by Pseudomonas aeruginosa) and anaerobes can be caused by elaboration of various extracellular toxins. In the case of Clostridium perfringens, the elaboration of collagenases, specific toxins, and proteases seems to play an important role in producing the spreading necrotizing infection that can be associated with this organism. Several host factors contribute to the predisposition to skin infections, including a reduced vascular supply, compromised immune system, disruption of lymphatic or venous drainage, the presence of underlying conditions (e.g., dermatitis), and the presence of a foreign body (e.g., intravenous catheter, suture).

Clinical Manifestations and Natural History Primary superficial skin infections, or pyodermas, usually occur on relatively normal skin and are most often caused by beta-hemolytic streptococci (most commonly group A streptococci) or S. aureus (Table 34-1). Such infections are often mild, and most do not require parenteral antibiotic therapy or hospitalization. They often occur in patients who do not exhibit any significant under-

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Table 34-1 Common Microbial Etiology and Antimicrobial Therapy for Superficial Soft-Tissue Infections Infection

Microorganisms

Therapy and Comments*

Impetigo

Streptococcus pyogenes, Staphylococcus aureus (almost all bullous impetigo is S. aureus)

Cellulitis/ Erysipelas

S. aureus; S. pyogenes (Erysipelas usually S. pyogenes and other β-hemolytic streptococci); See Table 34-2 for other causes

Folliculitis, furuncles, carbuncles

S. aureus (MSSA or MRSA)

Topical: mupirocin, bacitracin Oral: antistaphylococcal Pen†, first gen Ceph‡, macrolides§ (some beta-hemolytic streptococci are resistant), clindamycin (300 mg TID); penicillin VK (250-500 mg BID-QID) if only Group A streptococcus documented The following if concern for CA-MRSA: trimethoprim/sulfamethoxazole (1 DS BID, does not cover beta-hemolytic streptococci), minocycline (100 mg BID), doxycycline (100 mg BID) Oral: penicillin VK; if concern for S. aureus: antistaphylococcal Pen, first gen Ceph‡, macrolides§, clindamycin (300 mg TID); levofloxacin (500-750 mg QD), moxifloxacin (400 mg QD) For CA-MRSA-see impetigo IV: antistaphylococcal Pen, first gen Ceph‡, clindamycin (600-900 mg q 8 h); For MRSA: vancomycin (15 mg/kg q12h), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h) Warm saline compresses with or without topical antimicrobials often sufficient for folliculitis Incision and drainage with or without topical antimicrobials often suffices for furuncles Oral: antistaphylococcal Pen, first gen Ceph‡, clindamycin (300 mg q8h), levofloxacin (500-750 mg QD), moxifloxacin (400 mg QD) For CA-MRSA, see impetigo IV: antistaphylococcal Pen, first gen Ceph‡, clindamycin (600-900 mg q8h) For MRSA: vancomycin (15 mg/kg q12h), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h) If nasal culture positive, nasal mupirocin Oral: antistaphylococcal Pen, first gen Ceph‡, clindamycin (300 mg q8h); or therapy for MRSA (see impetigo) plus rifampin (300 mg BID) Self-limiting, treatment not necessary

Recurrent Check for nasal or furunculosis perianal carrier of S. aureus

Whirlpool folliculitis

Pseudomonas aeruginosa

Continued

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Table 34-1 Continued Infection

Hidradenitis suppurativa

Microorganisms

Acute: S. aureus Chronic: S. aureus, Enterobacteriaceae, Pseudomonas spp., anaerobes

Therapy and Comments*

Antistaphylococcal agents for MSSA or MRSA based on susceptibility Empirical: beta-lactam/beta-lactamase inhibitor⎪⎪, cefoxitin (1-2 g q6h), cefotetan (0.5-1 g q12h), carbapenem; clindamycin (600-900 mg TID) plus fluoroquinolone††

* Doses are based on normal renal and hepatic function. Duration of therapy of most superficial skin infections is 7 to 10 days. One recent study of cellulites in immunocompetent hosts found 5 days was effective for uncomplicated infection. † Oral antistaphylococcal penicillins include cloxacillin (250-500 mg q6h) and dicloxacillin (250-500 mg q6h); parenteral antistaphylococcal penicillins include oxacillin (0.5-2 g q4-6h), nafcillin (0.5-2 g q4-6h). ‡ Oral first-generation cephalosporins include cephalexin (250-500 mg q6h) and cefadroxil (250-500 mg q12h); parenteral first-generation cephalosporins include cephalothin (0.5-2 g q4-6h), cefazolin (0.5-1 g q8h). § Erythromycin (250-500 mg q6h), azithromycin (500 mg on day 1 followed by 25 mg QD), clarithromycin (500 mg q12h or 1 g XL QD). ⎪⎪ Oral beta-lactam/beta-lactamase inhibitors include amoxicillin/clavulanate (875/125 mg q12h), parenteral beta-lactam/beta-lactamase inhibitors include ampicillin/sulbactam (1.5-3.0 g q6h), ticarcillin/ clavulanate (3.1 q4-6h), piperacillin/tazobactam (3.375-4.5 q6h). Abbreviations: BID, twice daily; CA-MRSA, community-acquired methicillin-resistant Staphylococcus aureus; Ceph, cephalosporin; DS, dilute strength; gen, general; h, hour; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; Pen, penicillin; q, every; QD, daily; QID, four times daily; TID, three times daily; XL, extended release.

lying condition. The infections include folliculitis, furunculosis, carbunculosis, impetigo, cellulitis, erysipelas, and hidradenitis suppurativa.

Folliculitis Folliculitis originates in the hair follicle and is defined by its anatomical features. Clinically, the lesions present as 2- to 5-mm erythematous papules that surround the hair follicle and often exhibit central pustulation. Systemic manifestations are rare. Sycosis barbae is a distinctive form of deep folliculitis that is often chronic and seen in bearded areas. Folliculitis is most commonly caused by S. aureus; however, in immunocompromised patients the causative agent can be gram-negative bacilli or Candida species. A specific form of Pseudomonas folliculitis has been described in association with whirlpool bathing or use of a hot tub. An outbreak of pustular dermatitis was described among mud-wrestling college students; organisms isolated from the pustules included Enterobacter cloacae and Citrobacter species (8). The pathogenesis of this condition can resemble that of pseudomonal folliculitis, with organisms from mud possibly entering the skin through hair follicles or through breaks in the skin that occurred during the wrestling. Patients with whirlpool-bath folliculitis develop generalized, fine, papular pustules from which P. aeruginosa can be isolated (9). The modified apocrine glands of the external canal of the ear and the areolae of the breasts are structures that are particularly susceptible to this infection. The most common sign

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of this syndrome is a generalized rash accompanied by otitis externa, mastitis, malaise, and fever. The average incubation period is approximately 2 days. Pseudomonas infection can follow immersion in swimming pools, Jacuzzis, or whirlpool baths in which the organism can reside in higher numbers if the chlorination or the pH of the system is not adjusted properly. The disease is usually self-limited. Systemic antibiotic therapy is not indicated for treating whirlpool-bath folliculitis unless cellulitis develops.

Furuncle and Carbuncle Folliculitis that extends beyond the hair follicle and into the subcutaneous tissues can give rise to a furuncle or carbuncle. A furuncle is a deeper inflammatory nodule that often follows folliculitis. Furuncles usually measure less than 5 mm in diameter. A carbuncle is a larger, deeper lesion and often occurs as a confluent infection that comprises many furuncles. S. aureus is the organism most often associated with furunculosis and carbunculosis. Clinically, a furuncle begins as an erythematous, firm, tender, nodular lesion that progresses to a fluctuant mass that can drain pus spontaneously. They occur in skin areas that are subject to friction and perspiration and that contain hair follicles (e.g., the neck, face, axillae, buttocks). Predisposing factors include obesity, corticosteroid use, defects in neutrophil function, and probably diabetes mellitus. Some individuals have repeated attacks of furunculosis; see further discussion in the Prevention section. Carbuncles are larger and frequently comprised of many furuncles that have coalesced and are more serious lesions that often are located at the back of the neck, on the back, or in the region of the thigh. Fever and malaise are frequent accompaniments of a carbuncle, and sepsis can occur. Blood stream infection also can occur with carbuncles (less so with furuncles) and can result in metastatic foci of infection (e.g., endocarditis, osteomyelitis). Furuncles on the upper lip and nose can be associated with the spread of infection by means of emissary veins to the cavernous sinus.

Impetigo Impetigo is a vesicular (initially), crusted (later), superficial, intraepithelial infection of the skin that is associated with S. aureus and beta-hemolytic streptococci (alone or in combination). Mixtures of group A streptococci and S. aureus are isolated from approximately half of patients with nonbullous impetigo. Mixed flora of anaerobic streptococci with Prevotella or Fusobacterium species can be found in infections of the head and neck, whereas enteric gram-negative bacilli (often mixed with Bacteroides fragilis) can be isolated from infections of the buttock (3). A relatively specific form of impetigo (bullous impetigo) has been identified as a primarily staphylococcal disease. Non–group A streptococci (i.e., groups B, C, and G) can be responsible for isolated cases of nonbullous impetigo. Because impetigo is a very superficial infection, vesiculopustules develop just beneath the stratum

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corneum, and it is generally not associated with any systemic manifestations of infection. The disease begins with vesicular lesions that rapidly become pustular and crusted. A honey-colored crust over slightly erythematous areas of inflammation is characteristic (10). Regional lymphadenopathy without systemic symptoms is common. The early vesicular lesions of impetigo can resemble the initial lesions of varicella or herpes simplex; however, the crusts that form in these viral infections are usually harder. Impetigo appears primarily in young children during warm, humid months. Predisposing conditions include minor trauma, insect bites, crowding, poor hygiene, and preexisting skin disease. Spread of the disease within families is common through direct contact with infectious material. Bullous impetigo is more often associated with S. aureus than is the nonbullous form of the disease. As in the nonbullous form, the lesions initially appear as vesicles but progress to flaccid bullous lesions filled with yellow fluid. When these lesions rupture, light brown crusts form. These crusts and the bullous lesions are characteristic of the condition. Regional lymphadenopathy is found less commonly in the bullous form of impetigo. Fever and constitutional symptoms are uncommon in both the bullous and nonbullous forms of the disease. Post-streptococcal glomerulonephritis can follow group A streptococcal impetigo caused by nephrogenic strains such as M-49, although currently in the United States this is a rare occurrence.

Cellulitis Cellulitis is a diffuse, spreading, and nonsuppurative infection of the skin and subcutaneous tissues that presents with localized redness, warmth, swelling, and tenderness of the skin. Both S. aureus and beta-hemolytic streptococci are associated with cellulitis. The lesion in cellulitis is often very red, hot, and swollen, but the borders of the lesion are usually not clearly demarcated. Previous trauma (laceration, abrasion) can precede the development of cellulitis. Within days of the trauma, local tenderness, pain, and erythema develop. Fever, chills, malaise, and regional lymphadenitis commonly accompany the infection. If the condition is untreated, local abscesses can develop, and areas of overlying skin also can become necrotic. Because of this, cellulitis can be mistaken for many other clinical disorders, including deep venous thrombosis, erythema nodosum, allergic reactions, reactions to insect bites, and reactions to chemical irritants. The predominant pathogens are S. pyogenes and S. aureus. The microbiology of cellulitis and its correlation with the site of infection were investigated with more than 200 swab- and 64 needle-aspirate specimens (11). The greatest recovery of anaerobic bacteria (predominantly Peptostreptococcus, B. fragilis, Prevotella, and Clostridium) was from the neck, trunk, groin, external genitalia, and leg area. Aerobes (predominantly S. aureus, group A streptococci, and Escherichia coli) outnumbered anaerobes in the arm and hand areas. Many other pathogens can produce cellulites (Table 34-2). Certain clinical findings correlated with the following pathogens: swelling and tenderness

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Table 34-2 Causes of Cellulitis Based on Specific Predisposing Conditions Condition

Anatomical Location

Likely Pathogen/Antimicrobial Therapy

Body piercing

Ear, nose, umbilicus

Post-mastectomy or CABG Cat/Dog bites

Ipsilateral extremity

Staphylococcus aureus; Streptococcus pyogenes (see Table 34-1) Non-group A streptococcus/penicillin

Hand

Human bites

Hand

Fresh water injury

Extremities mostly

Salt water injury

Extremities mostly

Meat-packer Cat scratch Periorbital in children

Hand mostly Bartonella Periorbital

Pasteurella multocida; Capnocytophaga (in immunocompromised)/ Amoxicillin/clavulanate (doxycycline, fluoroquinolone + clindamycin) Mixed flora/hand-surgery consult; antibiotics as for cat bites Aeromonas/fluoroquinolone, broadspectrum beta-lactam Vibrio vulnificus/fluoroquinolone; ceftazidime Erysipelothrix/Penicillin Azithromycin Haemophilus influenzae/ampicillin/ sulbactam or third-generation cephalosporin

Abbreviation: CABG, coronary artery bypass grafting.

with Clostridium species, S. aureus, and group A streptococci; regional adenopathy with B. fragilis; gangrene and necrosis with anaerobes and Enterobacteriaceae; and a foul odor or gas in tissues containing anaerobes. A frustrating problem for some patients is recurrent cellulitis at sites of previous surgery. This problem has been associated particularly with saphenous venectomy for coronary bypass surgery, stripping of varicose veins, and procedures that affect lymphatic drainage (e.g., neoplasia, radiation therapy, surgery) (12,13). Recurrent cellulitis also has been seen after radical mastectomy. Patients with recurrent cellulitis after surgery can experience acute pain, fever, and erythema of acute onset at the site of the surgical scar. Tinea pedis is often an associated finding; however, Hook and colleagues recently reported an instance of underlying psoriasis (14). Although pathogens are often not isolated from sites of recurrent cellulitis, an underlying skin disorder (e.g., tinea pedis) can predispose to invasion of Streptococcus species. Cellulitis often recurs if the underlying skin disorder is not controlled.

Erysipelas Erysipelas is a distinctive form of cellulitis that involves the superficial epidermis. It differs from cellulitis because the lesion is indurated and red, with a well-demarcated border. Additionally, it is usually painful, and the condition is often complicated by lymphangitis. Erysipelas is more common in children and in older adults. The face and lower extremities are the most frequent sites of involvement. It is almost always caused by beta-hemolytic

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streptococci (usually group A), but similar lesions can be caused by streptococcus serogroups C or G. Rarely group B streptococcus or S. aureus can be involved. Because erysipelas tends to produce lymphatic obstruction, it can recur in an originally affected area of the skin. Occasionally, the infection extends more deeply, producing cellulitis, subcutaneous abscess, and necrosis. Fever and systemic symptoms are found in most cases; bacteremia is found in approximately 5% of patients (4). Patients who have venous or lymphatic insufficiency (e.g., recurrent cellulitis after venectomy or radical mastectomy) have been reported to have a high relapse rate for cellulitis. The lesions of cellulitis should be differentiated from those of erythema nodosum, shingles, erysipeloid, and the skin lesions of Lyme disease.

Hidradenitis Suppurativa Hidradenitis suppurativa is a suppurative disease that affects the apocrine glands in the axillary, genital, or perianal areas. The disease rarely has systemic manifestations. Acute infection usually results from obstruction to drainage of the apocrine gland. The lesion seems to result from plugging of the apocrine gland ducts, causing dilation and eventual rupture of the glands and inflammation of the surrounding tissue. Acute infection is often caused by S. aureus. Chronic hidradenitis suppurativa is characterized by recurrent disease. The initial step in the disease is the formation of nodules that slowly become fluctuant and drain. Eventually, with repeated crops of lesions, sinus tracts form and cause intermittent drainage and cicatricial scarring. In some patients, infection is associated with cellulitis of the scalp (acne conglobata); such patients can experience a distinctive spondyloarthropathy. The lesions in this condition are usually bilateral and vary from a few to many, with widespread involvement. A culture of aspirate from the lesions frequently yields a mixture of aerobic and anaerobic organisms.

Diagnosis The diagnosis of pyodermas usually is made clinically on the basis of the manifestations described in the preceding sections of this chapter. Although the skin is easily accessible for culture, isolation of an infecting organism in cases of pyoderma has not been consistent, usually because of the presence of contaminated normal skin flora. Additionally, because bacterial products or toxins, rather than the bacteria themselves, are the sources of certain skin lesions, the number of bacteria at the site of the pathology can be too small to allow consistent culture of pathogens. Therefore, the etiologic diagnosis and management of bacterial skin infections, especially in the office setting, often is based on the clinical presentation and less commonly on microbiologic techniques. In patients who have skin and soft tissue infections that

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require hospitalization, a more aggressive approach is needed to identify the causative agent because outpatient therapy has failed for some reason (e.g., misdiagnosis, wrong therapy choice, noncompliance). A culture of lesions in folliculitis, furunculosis, carbunculosis, impetigo, and hidradenitis suppurativa usually yields the etiologic agent. Although Staphylococcus is often found, certain special circumstances suggest the presence of other organisms (Table 34-2). An emphasis to obtain a culture from such infections, even if clinically mild, has been increased because of the emergence of community-acquired methicillin-resistant S. aureus (CA-MRSA) infections (see Treatment). Exposure to hot tubs should alert the physician to the possible role of P. aeruginosa; patients who have Candida folliculitis can have systemic Candida infection. Culture in impetigo can be achieved by removing the superficial crust of a lesion with sterile saline and by culturing the surface of the lesion. Blood culture is usually not helpful in cases of pyoderma; however, patients who present with systemic manifestations of disease and who have carbuncles can have bacteremia, for which blood culture is appropriate. The diagnosis of cellulitis is usually made clinically, because generally the condition is a closed-skin infection and is not associated with drainage that can be submitted for culture. Ascertaining a specific bacteriologic cause for cellulitis is difficult. Usually, as with cellulitis, the diagnosis of erysipelas is also made clinically. Leukocytosis is a common occurrence in both conditions. In patients who have erysipelas, culture of the pharynx frequently yields S. pyogenes. Several studies have evaluated the use of intradermal needle aspiration in the bacteriologic diagnosis of cellulitis, but the value of the technique remains controversial (15). Studies have reported rates of isolation of pathogenic organisms that range from 5% to 36% (14,16,17). The most common pathogens isolated in studies of needle aspirates are staphylococci and streptococci. A similar method of needle aspiration was used in most of these studies. Briefly, it involves cleansing the site of aspiration with povidone-iodine solution and, without anesthesia, puncturing the skin over the area with a 22-gauge needle attached to a disposable plastic syringe. The contents of the syringe, consisting of 1 mL of sterile isotonic saline, are injected subcutaneously, and the resulting fluid is then aspirated with the needle kept in the subcutaneous tissue. The aspirated material is promptly taken to the microbiology laboratory and immediately inoculated into culture medium. Generally, needle aspiration is not recommended for the diagnosis of superficial skin infections but can be appropriate in selected circumstances (e.g., treatment failure, immunosuppression).

Treatment When a patient presents with a skin or soft tissue infection, an initial consideration for treatment is whether the clinical illness is severe enough

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to warrant hospital admission. Most superficial pyodermas are without systemic symptoms and can be managed in the outpatient setting with oral antimicrobial agents. Previous classified schemes and algorithms have been proposed to guide clinicians with the decision of hospitalization, but there are no well-documented criteria for choice of a site of care (i.e., outpatient vs. inpatient). (18) Consideration of hospitalization should be based on illness severity (i.e., the extent of abnormality of vital signs and of soft tissue involvement), patient age, presence of comorbid conditions that can be affected by an acute infection (e.g., diabetes, congestive heart failure), and the need for close observation or surgical management. (4) Abnormal laboratory tests (hemogram with differential, creatinine, bicarbonate, creatine phosphokinase, and C-reactive protein levels) can be helpful. In patients with hypotension and/or an elevated creatinine level, low serum bicarbonate and elevated creatine phosphokinase levels (two to three times the upper limit of normal), marked left shift, or a C-reactive protein level greater than 13 mg/L, hospitalization should be considered, and a definitive etiologic diagnosis pursued by means of procedures such as Gram stain and culture of needle aspiration or punch-biopsy specimens, as well as requests for a surgical consultation. Additionally, timely surgical intervention should be considered for deep infections (see Chapter 31). For impetigo or uncomplicated folliculitis and furunculosis, local measures (e.g., warm compresses, topical antimicrobial agents such as Bactroban and bacitracin) are usually sufficient. For other pyodermas, oral agents that have a spectrum of activity against the common infecting organisms (e.g., Staphylococcus, Streptococcus) are preferred for outpatients. For hospitalized patients, empirical antimicrobial therapy is initiated to combat or prevent life-threatening infections. Table 34-1 lists our recommendations for initial therapy for common pyodermas based on the most likely pathogens. In the presence of specific epidemiological conditions, other therapy should be considered (Table 34-2). Of increasing concern is the emergence of antimicrobial resistance among isolates of community-acquired S. aureus that are associated with skin infection In the past MRSA was usually limited to patients who were in the hospital or resided in a long-term care facility. Recently, outbreaks of skin infections caused by CA-MRSA have occurred among prison and jail inmates, injection drug users, gay men, participants in contact sports, and children. However, there are now enough cases in patients without these risk factors that CA-MRSA needs to be considered in all patients with skin infections. This has increased the importance of obtaining cultures of even mild skin infections. CA-MRSA strains are distinct from hospital-acquired strains from an epidemiological, genotypic, and phenotypic perspective (19-21). They tend to be less resistant to non–beta-lactam antimicrobials than hospital-acquired MRSA strains and almost always contain a novel type IV staphylococcus cassette chromosome mec (SCCmec) gene. In addition, many of these strains have been found to contain the gene for Panton-Valentine leukocidin (PVL),

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a toxin that has been associated with clinical features of serious disease. In general CA-MRSA strains are usually susceptible in vitro to trimethoprim/sulfamethoxazole and minocycline or doxycycline, and often susceptible to the fluoroquinolones, although pockets of fluoroquinolone-resistant strains exist. In addition, they are often susceptible to clindamycin, but the emergence of resistance during therapy has been reported—especially in erythromycin-resistant strains; thusly, an erythromycin-induction test (D-test) should be done on such isolates to determine the presence of in-vitro inducible resistance. Persistent pustular skin infections that do not respond to oral betalactam therapy are increasingly likely to be caused by MRSA. Such lesions should be cultured, and antibiotic susceptibilities measured. Fluctuant lesions should be drained. An agent to which the isolate is susceptible should be used. For mild infections, oral agents, such as trimethoprim/sulfamethoxazole, doxycycline, or clindamycin can be considered. One caveat about trimethoprim/sulfamethoxazole, however, is that it does not adequately cover for S. pyogenes; thusly, if S. pyogenes is also likely, an alternative agent or combination with penicillin is recommended. At the present time among patients with infections that are presumed to be caused by S. aureus, the clinician must consider the risk factors for MRSA, the prevalence of MRSA in the community, and the seriousness of the infection in deciding what antibiotics are to be used. For those requiring hospitalization, vancomycin, linezolid, tigecycline, or daptomycin are effective first-line agents for MRSA soft tissue infections. Surgical intervention is usually not required for superficial bacterial infections; however, the role of surgery cannot be overestimated in deeper or necrotizing skin infections (see Chapter 31). However, surgical drainage is indicated for furuncles, carbuncles, and hidradenitis suppurativa with large and fluctuant lesions. Antibiotic treatment of furuncles and carbuncles that are surgically drained is recommended if the lesion is greater than 4.5 cm or if the patient has fever or leukocytosis, and it should be continued until evidence of acute inflammation has subsided. Treatment of hidradenitis suppurativa is difficult, particularly when the disease process is chronic, because of deep-seated abscesses and scar tissue that are inaccessible to antimicrobial agents. Antimicrobial therapy accompanied by the local application of moist heat is often helpful in the initial phases of infection. Surgical drainage is required in the management of abscesses. Radical excision of tissue with subsequent skin grafting is often necessary for severe cases that exhibit extensive scarring. With the exception of hidradenitis suppurativa, the duration of antimicrobial therapy for superficial skin infections is usually 7 to 10 days. However, one recent study found that 5 days of antibiotic treatment was as effective as a 10-day course for uncomplicated cellulitis (22). Duration of therapy for hidradenitis suppurativa will depend on the clinical response.

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Prevention The management of patients with recurrent furunculosis presents a troublesome problem because most patients do not have definable underlying defects. Such patients often have S. aureus present in the anterior nares, or occasionally, elsewhere, such as the perineum. The prevalence of nasal staphylococcal colonization in the general population is 20% to 40%, but why some carriers develop recurrent skin infections and others do not is usually unclear. Higher rates of colonization with S. aureus has been seen in subgroups of patients (e.g., diabetic patients, dialysis patients). Therefore, because even small scratches or blisters can be colonized more rapidly and infected at an early stage, the use of topical antibiotics (e.g., mupirocin, bacitracin, neomycin) is recommended for the early treatment of abrasions in such patients. In one comparative study of the efficacy of topical mupirocin (2%) cream with oral cephalexin in treating secondarily infected traumatic skin lesions (e.g., lacerations), pathogen-eradication rates in the patients who could be evaluated were 100% for both treatment groups (23). Preventive management of recurrent furunculosis involves the following measures: ●

●

Institute a regimen of meticulous skin care with antibacterial soaps (e.g., PHisoDerm) and frequent washing: Because infections (particularly impetigo) can be spread among family members, a separate towel and washcloth (carefully washed in hot water before use) should be reserved for each patient. Chlorhexidine solution or hexachlorophene also can be used to reduce staphylococcal skin colonization. Measures aimed at preventing a carrier state can be considered if infection continues to recur: Nasal application of 2% mupirocin ointment in a soft, white paraffin base for 5 days can eliminate colonization of S. aureus in otherwise healthy patients. This regimen reduces recurrences by approximately 50%. Oral antibiotics (e.g., rifampin with another antimicrobial agent to prevent resistance) can be used in an attempt to eradicate a carrier state. In one very limited study, prophylaxis of oral clindamycin (150 mg four times daily for 3 months), without an accompanying intranasal antimicrobial agent, reduced the frequency of recurrent staphylococcal skin infections (24).

The likelihood of recurrent cellulitis at sites of previous surgery (e.g., after coronary artery bypass surgery or mastectomy) also can be reduced by reducing skin colonization with antibacterial soaps and by controlling tinea pedis in the case of recurrent cellulitis of the lower extremities after coronary artery bypass surgery. Prolonged antimicrobial prophylaxis with erythromycin has been shown to be effective and safe for preventing subsequent recurrent episodes of soft tissue infections in such patients (25). However, it is our

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recommendation that, in the case of recurrent cellulitis of the lower extremities, systemic antibiotic therapy should be reserved only for patients who do not respond to antibacterial soaps and control of tinea pedis. REFERENCES 1. File TM Jr.,Tan JS. Treatment of bacterial skin and soft tissue infections. Surg Gynecol Obstet. 1991;S172:17-24. 2. Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406. 3. Brook I. Cellulitis and fasciitis. Curr Treat Op Infect Dis. 2000;2:127-46. 4. Swartz MN. Cellulitis and subcutaneous tissue infections. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1037-57. 5. Schlüter B, König W. Microbial pathogenicity and host defense mechanisms—crucial parameters of posttraumatic infections. Thorac Cardiovasc Surg. 1990;38:339-47. 6. Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med. 1996;334:240-5. 7. File TM Jr.,Tan JS, DiPersio JR. Group A streptococcal necrotizing fasciitis. Diagnosing and treating the “flesh-eating bacteria syndrome”. Cleve Clin J Med. 1998;65:241-9. 8. Adler AI,Altman J. An outbreak of mud-wrestling-induced pustular dermatitis in college students. Dermatitis palaestrae limosae. JAMA. 1993;269:502-4. 9. Jacobson JA. Pool-associated Pseudomonas aeruginosa dermatitis and other bathing-associated infections. Infect Control Hosp Epidemiol. 1985;6:398-401. 10. Hirshman JV. Impetigo: Etiology and therapy. Curr Clin Top Infect Dis. 2002;22L:42-51. 11. Brook I, Frazier EH. Clinical features and aerobic and anaerobic microbiological characteristics of cellulitis. Arch Surg. 1995;130:786-92. 12. Baddour LM, Bisno AL. Recurrent cellulitis after saphenous venectomy for coronary bypass surgery. Ann Intern Med. 1982;97:493-6. 13. File TM Jr.,Tan JS, Maseelall EA, Snyder RO. Recurrent cellulitis after bypass surgery associated with psoriasis [Letter]. JAMA. 1984;252:1681. 14. Hook EW 3rd, Hooton TM, Horton CA, Coyle MB, Ramsey PG,Turck M. Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med. 1986;146:295-7. 15. Newell PM, Norden CW. Value of needle aspiration in bacteriologic diagnosis of cellulitis in adults. J Clin Microbiol. 1988;26:401-4. 16. Lebre C, Girard-Pipau F, Roujeau JC, Revuz J, Saiag P, Chosidow O. Value of fine-needle aspiration in infectious cellulitis [Letter]. Arch Dermatol. 1996;132:842-3. 17. Sachs MK. The optimum use of needle aspiration in the bacteriologic diagnosis of cellulitis in adults. Arch Intern Med. 1990;150:1907-12. 18. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit Care Med. 2004;32:1535-41. 19. Lina G, Piémont Y, Godail-Gamot F, Bes M, Peter MO, Gauduchon V, et al. Involvement of PantonValentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis. 1999;29:1128-32. 20. Herold BC, Immergluck LC, Maranan MC, Lauderdale DS, Gaskin RE, Boyle-Vavra S, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593-8. 21. Centers for Disease Control and Prevention. Outbreaks of community-associated methicillinresistant Staphylococcus aureus skin infections—Los Angeles County, California, 2002-2003. MMWR Morb Mortal Wkly Rep. 2003;52:88. 22. Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulites. Arch Intern Med. 2004;164:1669-74. 23. Henkel TJ, Bottonfield G, Drehobl M, et al. Comparison of mupirocin calcium cream with oral cephalexin in the treatment of secondarily infected traumatic lesions. 20th International Congress of Chemotherapy. 1997, Sydney, Australia, Abstract No. 5308. 24. Klempner MS, Styrt B. Prevention of recurrent staphylococcal skin infections with low-dose oral clindamycin therapy. JAMA. 1988;260:2682-5. 25. Kremer M, Zuckerman R,Avraham Z, Raz R. Long-term antimicrobial therapy in the prevention of recurrent soft-tissue infections. J Infect. 1991;22:37-40.

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Chapter 35

Necrotizing Soft Tissue Infections THOMAS M. FILE, JR, MD, MS DENNIS L. STEVENS, MD, PHD

Key Learning Points 1. Necrotizing soft tissue infection share a clinical picture which is characterized by necrosis of skin and associated tissues 2. Although these infections can be classified into specific entities (e.g., necrotizing fasciitis, clostridial myonecrosis), the initial clinical manifestations may be similar 3. These infections may be monomicrobial (e.g., group A streptococcal necrotizing fasciitis) or polymicrobial. The latter often follow surgery or in patients with peripheral vascular disease, diabetes, or decubitus ulcers. 4. Management of these infections requires expeditious evaluation and often early surgical intervention 5. A variety of antimicrobials against aerobic gram positive and gram-negative bacteria, as well as anaerobes, may be used in mixed anaerobic infections. For empirical therapy of serious mixed anaerobic infections, a broad spectrum beta-lactam (e.g., piperacillin/tazobactam, ticarcillin/clavulanate, imipenem or meropenem) plus clindamycin is recommended 6. For severe group A streptococcal infection parenteral clindamycin and a penicillin agent is recommended

N

ecrotizing soft tissue infections include infections of the skin and skin structures that share a clinical picture that is characterized by necrosis of the skin and associated tissues (e.g., subcutaneous tissue, fascia, muscle) (1-5). These infections occur less frequently than do pyoderma and differ from the milder, superficial skin infection by clinical presentation, 643

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New Developments in the Management of Necrotizing Soft Tissue Infections ●

●

Community-associated methicillin-resistant Staphylococcus aureus has recently been reported as a cause of necrotizing fasciitis and myositis. New guidelines for management of skin and soft tissue infections, including necrotizing infections, have been recently published.

systemic manifestations, and treatment strategies (2). They often progress rapidly and dramatically and can require urgent, aggressive surgical excision of tissue. Additionally, these infections are often deep and devastating because they can cause major destruction of tissue and can have a fatal outcome. Generally, necrotizing soft tissue infections are classified into specific entities (e.g., necrotizing fasciitis [NF], clostridial myonecrosis, synergistic necrotizing cellulitis) according to selected characteristics (Table 35-1) (1-4). However, the initial clinical manifestations of such infections are not distinct. The classification of these infections into precise categories is often difficult and is not significant to the initial management of the patient (6).

Etiology and Pathophysiology Necrotizing soft tissue infections can be classified etiologically as either polymicrobial (involving mixed aerobes and anaerobes) or monomicrobial infectious processes.

Polymicrobial Infectious Processes Polymicrobial infections are commonly found in the perineal area and lower extremities. In such cases, the fecal flora contribute to other skin pathogens. Gram-positive organisms (e.g., Staphylococcus, Streptococcus, Enterococcus species), gram-negative enteric bacilli, and anaerobes are often isolated from such infections. In combination, these bacteria can induce the formation of abscesses as well as severe necrotizing infections. Clinical medicine has many examples of mixed bacterial infections. The polymicrobial nature of peritonitis and intra-abdominal abscess formation is well known to surgeons. Aspiration of oropharyngeal secretions can lead to necrotizing mixed aerobic/anaerobic pneumonitis, which is often more serious than pneumonia that is caused by a single organism. Polymicrobial causes of skin and soft issue infections can be found in surgical-site infections, bite-wound infections, pressure-ulcer infections, and diabetic foot infections. The evaluating physician must be aware of the possibility of a synergistic polymicrobial infection in such cases so that appropriate early therapy can be initiated.

3-14 d Mixed aerobes, anaerobes

Moderate to severe

Acute Moderate to severe

>3 d Clostridia, others

Minimal

Gradual Minimal

Incubation Etiology

Systemic Toxicity Course Wounds/ Findings Local pain Skin Appearance

Gas Abundant Muscle No Involvement

Variable Variable

Swollen, Erythematous or minimal gangrenous discoloration

Diabetes, prior local lesions, perirectal lesions

Trauma

Synergistic Necrotizing Cellulitis

Predisposing Condition

Anaerobic Gas-Forming Cellulitis

Tense and blanched, yellow-bronze, necrotic with hemorrhagic bullae Usually present Myonecrosis

Acute Severe

Severe

1-4 d Clostridia, especially Clostridium. perfringens

Trauma or surgical wound

Clostridial Myonecrosis (Gas Gangrene)

Table 35-1 Characteristics of Severe, Necrotizing Soft Tissue Infections

Variable Myonecrosis

Erythematous or yellowbronze

Infected Vascular Gangrene

Necrotizing Soft Tissue Infections

Continued

Blanched, Erythematous or erythematous, necrotic necrotic with hemorrhagic bullae Variable Variable No Myonecrosis limited to area of vascular insufficiency

Subacute Variable

Diabetes, trauma, Arterial surgery, perineal insufficiency infection 1-4 d >5 d Type I Mixed aerobes, Polymicrobial anaerobes (aerobic-anaerobic) Type II Streptococcus pyogenes Moderate to severe Minimal

Necrotizing Fasciitis

Minimal until late in course Subacute Acute to subacute Late only Minimal to moderate

3-4 d Anaerobic streptococci

Trauma, surgery

Streptococcal Myonecrosis

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Thin, dark, Dark pus or dishwater, sweetish or putrid foul odor PMNs, gram- PMNs, mixed flora positive bacilli Débridement Wide filleting incisions

Synergistic Necrotizing Cellulitis

Extensive excision, amputation

PMNs, gramPMNs, mixed flora; positive bacilli gram-positive cocci Excision of Wide filleting necrotic incisions muscle

Sparse PMNs, grampositive bacilli

Seropurulent or dishwater, putrid

Necrotizing Fasciitis

Seropurulent

Streptococcal Myonecrosis

Serosanguineous, sweet or foul odor

Clostridial Myonecrosis (Gas Gangrene)

Amputation

PMNs, mixed flora

Minimal

Infected Vascular Gangrene

Data from File TM Jr. Necrotizing soft tissue infections. Clin Infect Dis Rep. 2003;5:407-15; Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406; Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part I: Necrotizing fasciitis. Infect Dis Clin Pract. 1996;5:406-11; Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part II: Myositis, Meleney’s gangrene, pyomyositis, necrotizing cellulitis, nonclostridial cellulitis, and Fournier’s gangrene. Infect Dis Clin Pract. 1996;5:463-72. Abbreviations: PMN, polymorphonuclear leukocyte.

Surgical Therapy

Gram Stain

Discharge

Anaerobic Gas-Forming Cellulitis

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Table 35-1 Continued

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The pathogenic role of mixed aerobic/anaerobic infections has been well demonstrated in many anatomical models of infection (7). Weinstein and coworkers first published results of a rat model of peritonitis/intra-abdominal abscess that demonstrated a biphasic process of infection (8). The first phase manifested itself by peritonitis that was caused by facultative aerobes, whereas anaerobes were predominant in the second phase. Using an animal model that more closely resembles skin and soft tissue infections, Brook evaluated the effect of subcutaneously inoculating various combinations of aerobes and anaerobes into mice (9). The mice were then challenged with either a single organism or a mixture of Bacteroides species and facultative aerobic organisms. The bacterial strains tested included Bacteroides fragilis, Escherichia coli, B. melaninogenicus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecalis, all of which are organisms commonly found in the mixed aerobic/anaerobic skin and soft tissue infections of humans. Infection caused by individual isolates was relatively innocuous, but combinations of facultative organisms and aerobes showed a synergistic effect, as manifested by the formation of abscesses and by a significant animal death rate. This synergistic effect was demonstrated for Bacteroides species in conjunction with all of the facultative aerobic organisms tested. The effect also was seen among most Peptostreptococcus, P. aeruginosa, and S. aureus. Brook electively treated inoculated animals with various antibiotics that were chosen specifically to cover aerobes, anaerobes, or both of these components of mixed infections (9). Antimicrobial agents that were directed at one component of a mixed infection did not eliminate the infection or the untreated organisms completely; therefore, the abscesses persisted. Treatment aimed at both components was required to achieve significant reductions in the numbers of both contributing agents. Using another model of soft tissue infection, Kelly demonstrated synergy between E. coli and B. fragilis when these organisms were injected subcutaneously into guinea pigs (10). A certain threshold count or number of organisms was required for this synergistic effect to occur. When the size of the E. coli or B. fragilis inoculum was below a critical threshold (104B. fragilis or 103E. coli), there was no abscess or necrosis, whereas when bacterial numbers were above the threshold, significant bacterial growth, abscess formation, and necrosis were present. These animal studies and others tend to confirm the observation that mixed aerobic/anaerobic infections are often more virulent than monomicrobial infections caused by the same organisms. Mackowiak proposed the following four principles by which microorganisms can interact to produce a synergistic infection (11): 1. There is an effect on host defenses (most commonly inhibition of phagocytosis). 2. Vital nutrients are supplemented.

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3. Environmental conditions are provided that are favorable for growth. 4. The infecting organisms exhibit increased virulence.

Monomicrobial Infectious Processes Several individual pathogens can cause necrotizing soft tissue infections. The most clinically significant of these infections are caused by Clostridium species and S. pyogenes. Clostridia can play a role in various infections of skin, subcutaneous tissue, and muscle that include crepitant cellulitis, pyomyositis, and clostridial myonecrosis (gas gangrene). Clostridium perfringens is the major causative species of such infections and accounts for approximately 80% of cases. Other species that cause such infections include C. septicum, C. novyi, C. sordellii, C. histolyticum, and C. bifermentans. Clostridial species that have been implicated in necrotizing soft tissue infections produce various exotoxins that contribute to the pathophysiology of such infections. Clostridia are anaerobic and therefore require an anaerobic environment for multiplication and production of these necrotizing toxins. The clostridial organisms that cause necrotizing soft tissue infections can be of either endogenous or exogenous origin, in that they can be present in the patient’s normal gastrointestinal flora or can come from soil contamination in wounds caused by, for example, motorcycle or lawn-mower accidents. The past decades have seen an increasing number of reports of NF caused by the group A streptococcus (GAS) S. pyogenes (12,13). Such infections can appear suddenly, sometimes in previously healthy patients with no history of a wound or injury, and can progress within hours to necrosis of an entire limb, often culminating in amputation or death. The lay media quickly named this disease the flesh-eating bacteria syndrome. GAS produce many surface components and extracellular products that are believed to play important roles in the pathogenesis of necrotizing soft tissue infections. Such components include M proteins, hyaluronic acid capsules, and pyrogenic exotoxins (streptococcal pyrogenic exotoxins A, B, and C). Streptococcal pyrogenic exotoxins belong to a group of proteins called super antigens, which in some individuals can activate a much larger proportion of T cells than do conventional peptide antigens and can cause various cytokines to be produced. These cytokines, in turn, are thought to be responsible for the manifestations of streptococcal toxic shock syndrome (TSS) and NF (14). Norrby-Teglund and colleagues studied the host-pathogen interactions of patents with severe invasive group A streptococcus soft-tissue infections and compared findings from biopsy samples from such patients to those without inflamed tissue (15). There was increased expression of interleukin-1 and tumor necrosis factor (TNF) in samples from the infected tissue. The cytokine profile at the local site mimicked that of a typical superantigen cytokine response. These findings support the role of super-

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antigens as crucial players in the pathogenesis of NF associated with group A streptococcus. Other single pathogens associated with necrotizing soft tissue infections include group B streptococci, Staphylococcus species, Vibrio vulnificus (in cases of salt-water injury), Aeromonas hydrophila (in cases of fresh-water injury), Enterobacteriaceae, P. aeruginosa, and Yersinia enterocolitica (1).

Predisposing Conditions Necrotizing soft tissue infections frequently occur in association with previous trauma, surgery, or other forms of tissue damage. The portal of entry is varied, and the entrance of bacteria can occur from any break in the skin including preexisting skin conditions, such as psoriasis, pressure ulcers, or dermatitis. Immunosuppression caused by various conditions, such as diabetes, AIDS, or complement deficiency can be a predisposing condition although the degree to which it contributes is not well defined (16). Soft tissue infections associated with preexisting ulcers (i.e., diabetic foot ulcer or decubitus ulcers) can progress to necrotizing infections. Various underlying conditions or medications have been described as predisposing factors for necrotizing infections. These infections have been increasingly reported as a complication of illicit drug injection (17). In addition, although group A streptococcus is a well-recognized complication of varicella in children, NF caused by S. pyogenes or S. aureus has also recently been described in adults with herpes zoster infection (18). Infliximab, an inhibitor of tumor necrosis factor-alpha (TNFα), which has been linked with many infections caused by its effects on lymphocytes and cytokines, has been associated with necrotizing fascitis (19). Several reports have implicated nonsteroidal anti-inflammatory drugs (NSAIDs) with severe presentations of invasive group A streptococcus soft-tissue infections (20-22). NSAIDs are known to have several actions which can lessen the immunological response to bacterial infection: impairment of granulocyte function (adherence, phagocytosis, and cidal activity); augmentation of inflammatory cytokine release; and inhibition of renal prostaglandin synthesis. In addition, NSAIDs can confound the progression of disease by suppressing fever and pain, thus attenuating some of the cardinal manifestations of inflammation in patients with serious streptococcal infection. However, experimental data in at least one animal model refutes this, suggesting that the administration of diclofenac after infection protected rabbits from NF caused by group A streptococcus instead of potentiating tissue damage (23).

Clinical Manifestations Clinical features that suggest necrotizing soft tissue infections include the following (2):

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● ● ● ●

● ● ●

The patient experiences severe, constant pain. There are bullous lesions. There is skin necrosis or ecchymosis that precedes skin necrosis. Gas in soft tissues is detected by palpation, radiography, or scanning; the gas is produced by metabolic activity of the infecting aerobic and/or anaerobic bacteria; when anaerobes are present, there is often a distinctive putrid odor. Edema extends beyond the margin of erythema. Systemic toxicity manifests by fever and occasionally by delirium. There is a tendency toward the rapid spread of infection centrally along fascial planes.

The inflammatory reaction in tissues with necrotizing soft tissue infections is often much different from that seen in pyodermas caused by staphylococci because there is often an associated serous, putrid, dish-watery discharge in the former compared with the purulent discharge associated with abscess formation in the latter. Infections associated with preexisting ulcers (e.g., foot ulcers, decubitus ulcers) can progress to necrotizing infections. Tissue necrosis is characteristic and can occur by any of the following means: pressure necrosis in infected areas of the fascia or skin; vascular thrombosis caused by anaerobic organisms by means of heparinase production or by direct acceleration of coagulation; and extracellular toxins produced by bacteria (e.g., the necrotoxins of C. perfringens). The clinical characteristics of the more common necrotizing soft tissue infections are given in Table 35-1. Many of these conditions are differentiated from one another on the basis of anatomic extent of disease, which often can be measured only at the time of surgical intervention. The following paragraphs discuss further salient clinical features of necrotizing soft tissue syndromes:

Necrotizing Fasciitis NF is the most common of the severe necrotizing soft tissue infections and refers to deep tissue infection involving the fascial cleft between the subcutaneous tissue and underlying muscle. NF can be classified into two types: Type I associated with polymicrobial (mixed aerobic and anaerobic) infection and type II with Streptococci pyogenes (or other single pathogens) as the microbial cause (24). Examples of polymicrobial infection (Type I) include: diabetic foot infections, decubitus ulcer infection, postoperative infection, and infection associated with trauma and bite wounds. The initial presentation of NF is often that of cellulitis, which can advance rapidly. As it progresses, there is systemic toxicity with fever. The local site shows the following features: cellulitis (90% of cases), edema (80%), and skin discoloration or gangrene (70%) (2). A distinguishing clinical feature of NF is the wooden-hard feel of the subcutaneous tissues. In

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cellulitis the subcutaneous tissues are softer, but in fasciitis, the underlying tissues are firm, and the fascial planes cannot be discerned by palpation. If there is an open wound, probing the edges with a blunt instrument permits ready dissection of the superficial fascial planes well beyond the wound margins (2). Childers and coworkers reviewed 163 consecutive patients with NF treated at a university teaching hospital or a large general hospital from 1984 through 1997 (25). The most commonly involved areas were the lower extremities (32%), upper extremities (24%), perineum (16%), trunk (16%), and head and neck (10%). Most patients (83%) had a preceding injury; 24% and 14% were associated with intravenous injection or operative site respectively. Other injuries included insect bites, skin ulcers, tooth abscesses, abrasions, gunshot wounds, and blunt trauma. Of the 145 patients with positive wound cultures 29% had only one bacterial species. The remaining 71% had polymicrobial flora with up to six organisms and infection. Beta-hemolytic streptococcus and S. aureus were found in 32% and 23% of cases respectively. The death rate was 28%. Predictors of death included: age younger than 1 year or older than 60 years; comorbid conditions (cancer, renal insufficiency, CHF); and prolonged time to diagnosis and treatment (although the authors do not indicate specific times evaluated).

Fournier Gangrene Fournier gangrene is a form of NF that involves the fascial planes of the perineum and abdominal wall along with the scrotum and penis in men and the vulva in women. Various pathogens (usually polymicrobial, mixed aerobic/anaerobic flora) have been isolated from infected tissue. Treatment usually includes wide surgical excision of devitalized tissue with the administration of broad-spectrum antibiotics. In a recent review of Fournier gangrene from a single center, Kilic and colleagues reviewed the clinical characteristics of 23 patients (all but one were men) who were treated between 1990 and 1999 (26). Seventy-four percent of patients had a preceding infection (colorectal in 39% and genitourinary tract in 35%). The most commonly isolated pathogens were E. coli (57%), S. aureus (25%), and anaerobic Streptococcus species (13%). Wide scrotal, penile, perineal, and inguinal debridement was done in 10 patients. The remaining 13 patients had limited debridement. Nineteen patients (82.6%) survived.

Group A Streptococcal Necrotizing Fasciitis NF caused by GAS usually follows a rapid course: Diffuse erythema and swelling, exquisite tenderness, and pain are the usual first signs of symptoms; lymphangitis and lymphadenitis are infrequently seen initially. Bullae filled with clear liquid follow next (commonly these bullous lesions rapidly

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become maroon or violaceous). Frank cutaneous gangrene then often evolves rapidly and extends along fascial planes. In some patients necrosis proceeds less quickly; For example, Kaul and coworkers described a subset of patients with diabetes or peripheral vascular disease or both, in whom ischemia and necrosis progressed less rapidly (27). Overlying skin anesthesia provides a clue that a soft-tissue infection is NF and not simple cellulitis. As tissue necrosis progresses, the pain can disappear as thrombosis of small blood vessels leads to destruction of the superficial nerves located in the underlying subcutaneous tissues. TSS is linked to NF in approximately 50% of cases. In the largest population surveillance study of GAS-NF (a prospective, population-based study conducted in Ontario, Canada, from 1992 through 1996), the incidence increased from 0.08 cases per 100,000 population in 1992 to 0.49 cases per 100,000 in 1995 (28). The authors defined patients with either NF or other “soft tissue infection.” Factors which were significantly associated with NF included the presence of diabetes, hypotension at presentation, and the use of NSAIDs after onset of symptoms. Of interest was that patients with cancer and soft-tissue infections were less likely to develop NF. The authors offered possible explanations of this observation: It is possible that the natural progression of NF depends on a certain level of immune status that can be altered with malignancy or its treatment; many of these infections were nosocomial and because the patients were hospitalized they can have had earlier treatment, which can have reduced the risk for NF. The present study did observe that taking NSAIDs after the onset of illness was a risk factor for developing NF. However, because the NSAIDs were used for pain and fever management, it was not possible to determine whether NSAIDs caused more severe infection or were taken for more severe symptoms. In addition, in the multivariate analysis the use of NSAIDs is no longer held as an independent risk factor of NF. Sixty percent of all patients had bacteremia and 78% of NF cases had infection caused by one of six serotypes: M1, M12, M3, M28, M6, and M4. Risk factors for death for all patients with invasive GAS soft-tissue infection included age older than 65 years, hypotension at presentation, any underlying condition and the presence of NF (29). Dahl and colleagues reported the experience of seven patients with GAS-NF seen at the Mayo Clinic or Mayo Clinic Jacksonville between 1992 and 1995 (29). The average age of the patients was 47 years. NF occurred on an extremity (four upper extremities) in all cases. Five patients had associated TSS, and all died. The first symptom in all patients was severe pain in the affected area that was disproportionate to objective findings. In four patients, the pain developed simultaneously with ill-defined violaceous, edematous areas of the skin. GAS NF tends to be sporadic in occurrence. Secondary cases are rare but have been reported among family members and with intimate contact and also among medical personnel caring for patients (30,31).

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Necrotizing Fasciitis Caused by Community-Acquired Methicillin-Resistant Staphylococcus Aureus In the past S. aureus has been an uncommon cause of NF. However, recent reports of NF and necrotizing myositis have been published. Miller and coworkers identified 14 cases of necrotizing infection caused by methicillinresistant S. aureus (MRSA) from January 2003 through April 2004 (32). The median age was 46 years with 71% of patients being men. Coexisting conditions included injection-drug use, diabetes, chronic hepatic C, cancer, and HIV infections. All patients received combined medical and surgical therapy; although none died, they had serious complications, including the need for reconstructive surgery and prolonged intensive care unit (ICU) stays. All the MRSA-isolated recovered belonged to the same USA300 type (USA300 carries the type IV staphylococcus cassette chromosome methicillin-resistance gene [SCCmec IV]) and carried the Panton-Valentine leukocidin.

Necrotizing Fasciitis Associated with Other Monomicrobial Etiology Other single pathogens associated with necrotizing soft tissue infections include: Group B Streptococcus, Staphylococcus species, V. vulnificus (salt water injury), A. hydrophilia (fresh water injury), Enterobacteriaceae, P. aeruginosa, and Y. enterocolitica (1). There are several recent reports of NF caused by S. pneumoniae (1). Most of the patients described in these reports were immunocompromised because of various conditions including drug abuse, diabetes chronic renal failure, and systemic lupus erythematosus (SLE). In several cases, NF seemed to be associated with the use of NSAIDS or steroids.

Other Necrotizing Soft-Tissue Syndromes Synergistic necrotizing cellulitis is similar to Type I NF as both are caused by a mixed aerobic-anaerobic infection; however with necrotizing cellulitis there is often extension beneath the fascia involving muscle. Just as in clostridial myonecrosis, amputation is required when there is muscle involvement of an extremity (1-5). Progressive bacterial synergistic gangrene (often referred to as Meleney gangrene) is an indolent process characterized by poor healing often after a previous surgical operation. The presentation can be one of a slowly progressive (often over several weeks) expanding necrosis. Local pain and tenderness are nearly always present, however fever and systemic toxicity are not as associated as with the other syndromes. Pyomyositis is a discreet abscess within individual muscle groups caused primarily by S. aureus but occasionally by other gram-positive organisms or gram-negative enteric rods. Because of its geographic distribution, this

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condition is often referred to as tropical pyomyositis, but cases are increasingly recognized in temperate climates, especially in patients with human immunodeficiency virus or diabetes. Presenting findings are localized pain in a single muscular group, muscle spasm, and fever. The disease most often occurs in an extremity, but any muscle group can be involved. Additionally it may not be possible to palpate a discreet abscess because the infection is localized deep within the muscle, but the area has a firm, woody feel on palpation, along with pain and tenderness. A recent review of pyomyositis from an urban hospital in the United States was recently reported by Hossain and colleagues (33). The authors reviewed hospital records for the diagnosis of “pyomyositis” from 1988 through 1998 and identified eight patients who fulfilled the criteria for primary pyomyositis. S. aureus was isolated from four cases and betahemolytic streptococcus from three cases (one case had no identified pathogen isolated). The authors found that magnetic resonance imaging (MRI) or computed tomography (CT) seemed to be the most useful tests in identifying pyomyositis. Half of the patients had drainage of the infected muscle; the remaining were treated with antimicrobial agents alone. All the patients recovered.

Clostridial Necrotizing Infections The clinical picture of clostridial myonecrosis, or classic gas gangrene, is well described (1-5). Clostridial myonecrosis can occur within hours of an initiating insult or surgery, and is often associated with sudden pain that increases in severity and extends beyond the wound. Systemic toxicity indicated by tachycardia and mental confusion is common. A thin watery discharge is often noted early in the process; large hemorrhagic bullae can appear in the vicinity of the wound. Microscopic examination of the discharge often reveals gram-positive rods and a paucity of polymorphonuclear leukocytes (PMNs). The lack of PMNs is, in part, attributable to clostridial toxins that cause lysis of cell membranes and cause subsequent cell death. The characteristic finding of clostridial myonecrosis is the appearance of necrotic infected muscle. As the disease progresses, the muscle loses viability and becomes black. Early diagnosis is essential so that complete resection (amputation) of the devitalized tissue can be accomplished. It should be stressed that although classic gangrene implies infection by Clostridium species, the isolation of Clostridium species (i.e., C. perfringens) does not necessarily indicate clinical disease. This is because Clostridium species (including C. perfringens) not uncommonly colonizes or contaminates wounds (either postsurgical or posttraumatic) without causing tissue invasion. In addition, C. perfringens can cause only cellulitis (anaerobic cellulitis) without deep tissue involvement. In such cases there can be an abundance of gas formation, but severe pain and systemic toxicity are absent.

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Diagnosis Although the diagnosis of NF and other necrotizing soft tissue infections can be clear-cut at the later stage of disease (extensive necrosis), it is often difficult to differentiate from primary cellulitis early in presentation. Because cellulitis can be treated with antimicrobial agents without surgical management, whereas deep necrotizing soft tissue infections require timely surgical debridement and excision of tissue in addition to the use of antimicrobial agents, their distinction is important. In cellulitis or erysipelas, the subcutaneous tissues can be palpated and are usually yielding. But in fasciitis, the underlying tissues tend to be firm, and the fascial planes and muscle groups cannot be discernible by palpation. It is often possible to observe a broader erythematous track of the skin along the route of the fascial plane as the infection advances. If there is an open wound, probing the edges with a blunt instrument permits ready dissection of the superficial fascial planes well beyond the wound margins. Remarkably little pain can be associated with this procedure because of anesthesia which occurs secondary to necrosis of nerve endings. Infection of the fascial cleft can spread rapidly; however, on occasion it can be indolent. In more indolent cases, biopsy has been useful. Majeski and coworkers reported a series of cases in which an early, accurate diagnosis of NF was established by a frozensection tissue biopsy obtained at the bedside (34). Of 43 patients evaluated, 12 were found to have NF. These patients were then treated with immediate surgical debridement of all necrotic tissue, broad spectrum antibiotics, and adequate nutritional support. All patients survived. One pitfall from this approach is sampling error. When in doubt, it is better for a surgeon to visualize the tissue to obtain tissue. A blind percutaneous sampling can provide false-negative results. Bullae are often seen with necrotizing soft tissue infections but can also be seen in cellulitis without fasciitis or deep involvement. Bullae can also be associated with toxins (e.g., brown recluse spider bites), and primarily dermatologic conditions (such as pyoderma gangrenosum). Fever with unexplained severe musculoskeletal pain is an important clue to the possibility of necrotizing infection. Other conditions that can mimic the early manifestations of necrotizing soft tissue infections include trauma with hematoma (although fever and leukocytosis is usually absent), phlebitis, bursitis, and arthritis. Leukocytosis is usually present in most deep necrotizing soft tissue infections. Wall and colleagues compared clinical characteristics on hospital admission of 21 cases of NF (most of whom were injection-drug users) with matched non-necrotizing soft tissue infection controls (35). A leukocyte count of more than 15.4 × 106 cells/mL and/or a serum sodium level of less than 135 had a sensitivity of 90% and specificity of 76% for NF. An elevated serum creatine phosphokinase level is often a clue to the presence of NF or myositis. Simonat and coworkers compared data from 17 patients with GAS-NF with data from 145 patients hospitalized for cellulitis (36).

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Admission variables for C-reactive protein and creatine phosphokinase were significantly higher ( p < .001) for patients with NF. The most definitive diagnostic test is therapeutic surgical exploration to define the extent of infection in the involved tissues (i.e., subcutaneous, fascia, muscle). Whenever necrotizing skin infection is considered in the differential diagnosis, an immediate surgical evaluation is imperative. Diagnostic studies before surgical incision and drainage can include radiography, which can demonstrate soft tissue swelling or the presence of gas, and a CT scan or ultrasound to detect fluid or abscesses, for which needle aspiration or biopsy can be directed. Different radiologic methods have been evaluated for the detection of NF. A CT scan can detect subcutaneous and fascial edema, gas formation, and abscesses. However, magnetic resonance (MR) has the highest sensitivity for detecting NF and is better for differentiating between NF and cellulitis. Schmid and colleagues compared MR imaging to surgical findings in 17 patients with severe softtissue infection caused by either NF (11 cases) or cellulites (6 cases) (37). MR was able to identify all 11 cases of NF; however, one false-positive case of cellulites was over interpreted and was thought to be NF. The authors concluded that MR has high sensitivity in the diagnosis of NF, with its characteristic findings of thickening and fluid collections along deep fascial sheaths; but can be associated with false-positive results. Radiologic studies should not delay surgical evaluation if necrotizing soft tissue infection is highly suspected. Rather they should serve to expedite and direct surgical intervention.

Therapy The approach to management of necrotizing soft tissue infections requires expeditious evaluation, with prompt surgical intervention (1-5,38). Kaul and coworkers reported that the death rate of patients with NF approached 100% if appropriate surgical intervention was not done (27). McHenry and colleagues reported that survival of NF correlated with timing of surgery (39). Thus regardless of the antimicrobial cause, the primary therapy is urgent surgery and accompanied with antibiotics active against the most likely pathogens (these include Streptococci, Staphylococci, Clostridium species, and mixed aerobic and anaerobic flora).

Surgical Therapy In patients with signs of NF, expeditious and extensive surgical débridement has been the standard recommended therapeutic strategy. The goals of surgery are threefold: to remove all necrotic tissue by radical débridement, to preserve as much viable skin as possible, and to maintain hemostasis. Amputation can be necessary to remove all nonviable tissues (this is particularly important for myonecrosis). A second-look procedure can be and is often

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necessary within 12 to 24 hours to reculture and further remove all necrotic and infected materials that were missed. Multiple débridements are often necessary: McHenry and coworkers recorded a case series of 65 patients with NF, each of whom needed an average of three operative débridements and several of whom needed amputations to control the infection (40). The general principles in the care of NF that apply to many other necrotizing soft tissue infections as listed by Stevens include the following: (41) ●

●

●

●

●

Patients with NF or myonecrosis who do not undergo exploration and débridement will surely die. Devitalized tissue, including muscle, fascia, and skin must be removed. Appropriate surgical débridement in certain locations of the body (e.g., head, neck, thorax, abdomen) can be virtually impossible. Multiple débridements over the course of several weeks are usually necessary. Extensive reconstructive surgery is generally necessary.

Although early aggressive surgery has been the conventional approach, a recent report suggests that surgical débridement can be limited or delayed until the patient is stabilized by the use of high-dose intravenous immunoglobulin (IVIG). This can allow a more conservative approach. Muller described six patients with severe group A streptococcal diseases and soft tissue involvement who were managed conservatively with treatment of clindamycin, a beta-lactam, and high-dose IVIG (40). Only one patient had a limited exploratory surgery without débridement. All patients survived. Such an approach can present an effective alternative to aggressive surgery that in many cases is mutilating (42). However, more experience is needed before such an approach can be generally recommended.

Empiric Antimicrobial Therapy It is difficult to determine the antimicrobial cause on the basis of the clinical presentation; therefore, empiric antibiotic therapy should be started as soon as these serious infections are suspected (Table 35-2). Unless there is specific evidence of the pathogens, antimicrobial agents chosen should have activity against streptococci, staphylococci, clostridium, and mixed aerobic and anaerobic organisms particularly if polymicrobial flora is possible (1-5). If GAS is considered likely, the combination of a beta-lactam plus clindamycin is recommended. Although streptococcus remains very susceptible to the beta-lactam antibiotics, studies in experimental animals have shown that penicillin is not always effective in the presence of a large inoculum of bacteria because the growth of the streptococci is not in a rapidly growing phase (38). In a mouse model of GAS, Stevens and colleagues demonstrated a better outcome with clindamycin than with penicillin (43). The efficacy of clindamycin is not affected by inoculum size or stage of growth. In addition

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Table 35-2 Antimicrobial Treatment of Necrotizing Soft Tissue Infections First-Line Agent(s)

Adult Dosage

Alternative Therapy/Comment

Mixed Infection* Ampicillin-sulbactam† or Piperacillin-tazobactam or Clindamycin plus ciprofloxacin or levofloxacin or Imipenem/Cilastatin or Meropenem or Ertapenem* or Cefotaxime* plus metronidazole or clindamycin Streptococcal infection Penicillin plus clindamycin

1.5-3.0 g q6-8h

Clindamycin (600-900 mg q8h) or metronidazole (500 mg q6h) with an aminoglycoside (gentamicin or tobramycin 7 mg/kg QD, amikacin 20 mg/kg QD or fluoroquinolone (ciprofloxacin 400 mg q8-12h‡; levofloxacin 750 mg 2 24 h)

Staphylococcus aureus infection Nafcillin or Oxacillin or Cefazolin If MRSA, vancomycin If CA-MRSA consider clindamycin

3.375-4.5 g q6h 600-900 mg q8h 400 mg q12h‡ 750 mg q24h 0.5-1 g q6-8h 1 g q8h 1 g q24h 2 g q6h 500 mg q6h 600-900 mg q8h 2-4 MU q4-6h

1-2 g q4h 1-2 g q4h 1 g q8h

Cephalosporin (cefotaxime 2 g q6h; ceftriaxone 1-2 g q24h) plus clindamycin (600-900 mg q8h); vancomycin (30 mg/kg/d in two divided doses), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h) Vancomycin (30 mg/kg/d in two divided doses), linezolid (600 mg q12h), daptomycin (4 mg/kg q24h)

30 mg/kg/d in Linezolid (600 mg q12h), two divided doses daptomycin (4 mg/kg q24h) 600-900 mg q8h Potential of cross-resistance and emergence of resistance in erythromycin-resistant strains; inducible resistance in MRSA

Modified with permission from Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406. * For empirical therapy the addition of clindamycin to a beta-lactam agent is recommended—see text for explanation. † Does not cover Pseudomonas aeruginosa. ‡ The dose of ciprofloxacin should be q8h if P. aeruginosa is a concern. Abbreviations: CA-MRSA, community-acquired methicillin-resistant S. aureus; h, hour; MRSA, methicillinresistant S. aureus; q, every; QD, daily.

clindamycin suppresses bacterial toxin synthesis, facilitates the phagocytosis of S. pyogenes by inhibiting M-protein synthesis, has a longer postantibiotic effect than beta-lactams, and suppresses LPS-induced monocyte synthesis of TNF-alpha. Thus, the efficacy of clindamycin can be related to the combination of its antimicrobial effect and its capacity to modulate the immune response. In a recent retrospective analysis of streptococcal TSS cases,

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Zimbelman and coworkers found improved survival in patients who received clindamycin compared to those treated with beta-lactams (44). The combination of a broad spectrum beta-lactam (i.e., betalactam/beta-lactam inhibitor combination, a carbapenem, or extended cephalosporin) and clindamycin is an appropriate consideration for empirical therapy. For patients who cannot tolerate a beta-lactam, the combination of clindamycin and fluoroquinolone effective for Enterobacteriaceae and Pseudomonas species (or an aminoglycoside) is an appropriate alternative. Once the results of appropriate cultures are available, antimicrobial therapy should be specified for the pathogens isolated. The duration of therapy will vary based on the extent of infection, the course of the infection, and whether or not metastatic infection is present; however, a minimum of 2 weeks is usually required.

Other Therapies Hyperbaric oxygen is debated as a therapy for these diseases (1-5). It has long been recommended for the treatment of clostridial myonecrosis and more recently has been applied to other necrotizing infections. However, the role of hyperbaric oxygen is at best adjunctive. The benefits are far clearer in clostridial myonecrosis than in other necrotizing infections because hyperbaric oxygen is bacteriocidal for C. perfringens, and it can reduce generation of exotoxin in clostridial myonecrosis (but it will not neutralize toxin already present). Hyperbaric oxygen should be limited to specialized centers where complications can be kept to a minimum, and it should never take precedent over surgical debridement. IVIG has been shown to have some beneficial effect in TSS associated with GAS-NF (45-47). This effect can be caused by its ability to neutralize superantigen. Kaul and colleagues saw a beneficial effect of IVIG for patients with GAS TSS in 21 consecutive patients who were treated with IVIG (single dose of 2 gm/kg with a repeated dose at 48 hours if the patent remained unstable) (46). The proportion of cases with 30-day survival was higher in patients treated with IVIG compared to a control group (67% vs. 34%; p = .02). The findings of this study must be tempered on the basis that the control group was a historical one and that IVIG treated patients were more likely to have had surgery and were more likely to have received clindamycin. It is unlikely that a randomly assigned, controlled trial to test the use of this therapy can be done. At the present time it seems reasonable to consider IVIG for patients with severe GAS NF.

Prevention Because necrotizing soft tissue infections often occur as complications of less serious cutaneous infections (i.e., diabetic lower extremity ulcers),

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attention should be focused on preventing pressure ulcers and wounds in patients with identifiable risk factors. Patients with conditions such as diabetes need to be educated about their predisposition to infections and alerted to the early signs of infection. Hopefully early treatment of superficial infections in such patients can ward off the serious complication of necrotizing, deep infections. The occurrence of outbreaks of GAS necrotizing infections (especially clusters of TSS and NF) has raised the concern about the transmissibility of these invasive strains and the need for prophylaxis. Although this strategy is supported by some, it has not been verified by clinical data. Based on several observations of familial and health care provider transmission, some have recommended two possible strategies: to administer preventive treatment to those in contact with secretions, or to culture specimens from close contacts and treat those for whom cultures are positive (31). Chemoprophylaxis (i.e., a 10-day course by a beta-lactam) can be considered in contacts of invasive GAS (i.e., household contacts, or persons cases who have had direct mucous membrane contact with oral or nasal secretions of a case within 76 days before case patient illness) presenting with TSS, NF, or death within 7 days of diagnosis. There are no controlled studies to support such recommendations; but based on the present state of knowledge, this seems a reasonable approach.

Summary Necrotizing soft tissue infections are much less common than usual pyogenic soft tissue infections (i.e., cellulitis, carbunculosis, etc.). However, they are associated with a much greater illness and death rate. Early recognition and expeditious surgical therapy are required in most patients for optimal outcomes. Initial antimicrobial therapy often needs to be directed against various pathogens, which include Streptococcus and Staphylococcus species, gram-negative bacilli, and anaerobes. Recent advances in the care of patients with NF caused by GAS include the use of IVIG, which can neutralize some of the detrimental effects of superantigens.

REFERENCES 1. File TM. Necrotizing Soft Tissue Infections. Curr Infect Dis Rep. 2003;5:407-415. 2. Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41:1373-406. 3. Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part I: Necrotizing fasciitis. Infect Dis Clin Pract. 1996;5:406-11. 4. Gorbach SL. IDCP Guidelines: Necrotizing skin and soft tissue infections. Part II: Myositis, Meleney’s gangrene, pyomyositis, necrotizing cellulitis, nonclostridial cellulitis, and Fournier’s gangrene. Infect Dis Clin Pract. 1996;5:463-72. 5. Majeski JA, John JF Jr. Necrotizing soft tissue infections: a guide to early diagnosis and initial therapy. South Med J. 2003;96:900-5.

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6. Dellinger EP. Severe necrotizing soft-tissue infections. Multiple disease entities requiring a common approach. JAMA. 1981;246:1717-21. 7. File TM Jr., Tan JS. The triple threat of gram-positive cocci, gram-negative bacilli, and anaerobes. In: Nord CE, ed. The Role of Piperacillin/Tazobactam in the Treatment of Skin and Soft Tissue Infections. Montreal: PharmaLibri; 1994. 8. Weinstein WM, Onderdonk AB, Bartlett JG, Gorbach SL. Experimental intra-abdominal abscesses in rats: development of an experimental model. Infect Immun. 1974;10: 1250-5. 9. Brook I. Synergistic aerobic and anaerobic infections. Clin Ther. 1987;20(suppl A):19-35. 10. Kelly MJ. The quantitative and histological demonstration of pathogenic synergy between Escherichia coli and Bacteroides fragilis in guinea pig wounds. J Med Microbiol. 1978;11:511-22. 11. Mackowiak PA. Microbial synergism in human infections (second of two parts). N Engl J Med. 1978;298:83-7. 12. Stevens DL. Invasive group A streptococcus infections. Clin Infect Dis. 1992;14:2-11. 13. File TM Jr.,Tan JS. Group A streptococcus necrotizing fasciitis. Compr Ther. 2000;26:73-81. 14. Stevens DL, Bryant AE, Hackett SP, Chang A, Peer G, Kosanke S, et al. Group A streptococcal bacteremia: the role of tumor necrosis factor in shock and organ failure. J Infect Dis. 1996;173:619-26. 15. Norrby-Teglund A,Thulin P, Gan BS, Kotb M, McGeer A, Andersson J, et al. Evidence for superantigen involvement in severe group A streptococcal tissue infections. J Infect Dis. 2001;184:853-60. 16. Trent JT, Kirsner RS. Necrotizing fasciitis. Wounds. 2002;14(8):284-92. 17. Chen JL, Fullerton KE, Flynn NM. Necrotizing fasciitis associated with injection drug use. Clin Infect Dis. 2001;33:6-15. 18. Jarrett P, Ha T, Oliver F. Necrotizing fasciitis complicating disseminated cutaneous herpes zoster. Clin Exp Dermatol. 1998;23:87-8. 19. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J. 2002;78:47-8. 20. Smith RJ, Berk SL. Necrotizing fasciitis and nonsteroidal anti-inflammatory drugs. South Med J. 1991;84:785-7. 21. Barnham M, Anderson AW. Non-steroidal anti-inflammatory drugs (NSAIDs). A predisposing factor for streptococcal bacteraemia? Adv Exp Med Biol. 1997;418:145-7. 22. Stevens DL. Could nonsteroidal antiinflammatory drugs (NSAIDs) enhance the progression of bacterial infections to toxic shock syndrome? Clin Infect Dis. 1995;21:977-80. 23. Guibal F, Muffat-Joly M, Terris B, Garry L, Morel P, Carbon C. Effects of diclofenac on experimental streptococcal necrotizing fasciitis (NF) in rabbit. Arch Dermatol Res. 1998;290:628-33. 24. Giuliano A, Lewis F Jr., Hadley K, Blaisdell FW. Bacteriology of necrotizing fasciitis. Am J Surg. 1977;134:52-7. 25. Childers BJ, Potyondy LD, Nachreiner R, Rogers FR, Childers ER, Oberg KC, et al. Necrotizing fasciitis: a fourteen-year retrospective study of 163 consecutive patients. Am Surg. 2002;68:109-16. 26. Kiliç A,Aksoy Y, Kiliç A. Fournier’s gangrene: Etiology, treatment, and complications. Ann Plast Surg 2001;47:523-527. 27. Kaul R, McGeer A, Low DE, Green K, Schwartz B. Population-based surveillance for group A streptococcal necrotizing fasciitis: Clinical features, prognostic indicators, and microbiologic analysis of seventy-seven cases. Ontario Group A Streptococcal Study. Am J Med. 1997;103:18-24. 28. Ontario Group A Streptococcal Study Group. Severe group A streptococcal soft-tissue infections in Ontario: 1992-1996. Clin Infect Dis. 2002;34:454-60. 29. Dahl PR, Perniciaro C, Holmkvist KA, O’Connor MI, Gibson LE. Fulminant group A streptococcal necrotizing fasciitis: clinical and pathologic findings in 7 patients. J Am Acad Dermatol. 2002;47:489-92. 30. DiPersio JR, File TM Jr., Stevens DL, Gardner WG, Petropoulos G, Dinsa K. Spread of serious disease-producing M3 clones of group A streptococcus among family members and health care workers. Clin Infect Dis. 1996;22:490-5. 31. Gamba MA, Martinelli M, Schaad HJ, Streuli RA, DiPersio J, Matter L, et al. Familial transmission of a serious disease—producing group A streptococcus clone: case reports and review. Clin Infect Dis. 1997;24:1118-21. 32. Miller LG, Perdreau-Reminington R, Rieg G, et al. Necrotizing fasciitis caused by communityassociated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005;352-53.

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33. Hossain A, Reis ED, Soundararajan K, Kerstein MD, Hollier LH. Nontropical pyomyositis: analysis of eight patients in an urban center. Am Surg. 2000;66:1064-6. 34. Majeski J, Majeski E. Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J. 1997;90:1065-8. 35. Wall DB, de Virgilio C, Black S, Klein SR. Objective criteria may assist in distinguishing necrotizing fasciitis from nonnecrotizing soft tissue infection. Am J Surg. 2000;179:17-21. 36. Simonart T, Simonart JM, Derdelinckx I, et al. Value of standard laboratory tests for the early recognition of group A beta-hemolytic streptococcal necrotizing fasciitis. Clin Infect Dis. 2001;32(1):E9-12. 37. Schmid MR, Kossmann T, Duewell S. Differentiation of necrotizing fasciitis and cellulitis using MR imaging. AJR Am J Roentgenol. 1998;170:615-20. 38. Norrby-Teglund A, Norrby SR, Low DE. The Treatment of Severe Group A Streptococcal Infections. Curr Infect Dis Rep. 2003;5:28-37. 39. McHenry CR, Piotrowski JJ, Petrinic D, et al. Determinants of mortality for necrotizing soft tissue infections. Ann Surg. 1995;221:556-63. 40. Muller MP, McGeer A, Low DE, Ontario Group A Streptococcal Study Group. Successful outcomes in six patients treated conservatively for suspected necrotizing fasciitis (NF) due to group A streptococcus (GAS). Poster Presented 41st ICAAC Abstracts, Chicago, Illinois, September 22-25, 2001. 41. Stevens DL. Necrotizing fasciitis: Don’t wait to make a diagnosis. Infect Med. 1997; 14:684-88. 42. Low DE. New concepts in the therapy of severe streptococcal infections. Poster Presented 42nd ICAAC Abstracts, San Diego, California, September 27-30, 2002. 43. Stevens DL, Gibbons AE, Bergstrom R, Winn V. The Eagle effect revisited: efficacy of clindamycin, erythromycin, and penicillin in the treatment of streptococcal myositis. J Infect Dis. 1988;158:23-8. 44. Zimbelman J, Palmer A,Todd J. Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive Streptococcus pyogenes infection. Pediatr Infect Dis J. 1999;18:1096-100. 45. Norrby-Teglund A, Kaul R, Low DE, McGeer A, Newton DW, Andersson J, et al. Plasma from patients with severe invasive group A streptococcal infections treated with normal polyspecific IgG inhibits streptococcal superantigen-induced T cell proliferation and cytokine production. J Immunol. 1996;156:3057-64. 46. Kaul R, McGeer A, Norrby-Teglund A, Kotb M, Schwartz B, O’Rourke K, et al. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome—a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis. 1999;28:800-7. 47. Basma H, Norrby-Teglund A, Guedez Y, McGeer A, Low DE, El-Ahmedy O, et al. Risk factors in the pathogenesis of invasive group A streptococcal infections: role of protective humoral immunity. Infect Immun. 1999;67:1871-7.

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Chapter 36

Foot Infections in Patients with Diabetes Mellitus WARREN S. JOSEPH, DPM JAMES S. TAN, MD

Key Learning Points 1. For all but the most severe or chronic infection the majority of these infections are caused by aerobic gram positive cocci. Therefore, empiric therapy directed against those pathogens is frequently sufficient 2. Aggressive surgical intervention is often necessary to control diabetic foot infections 3. Superficial swab cultures of either infected or non-infected diabetic foot ulcerations is unnecessary and often leads to the isolation of non pathogenic organisms 4. Methicillin-resistant Staphylococcus aureus is becoming a more frequent isolate from these infections 5. Empiric antibiotic therapy for moderate to severe infections includes drugs such as ertapenem or pipercillin/tazobactam

F

oot infections in diabetic patients are responsible for 50% to 70% of all non–trauma-related amputations done in hospitals throughout the United States. The American Diabetes Association estimates that there are roughly 90,000 lower extremity amputations each year as a result of diabetic foot infections. Of limbs that are amputated, 85% had a diabetic foot ulceration as a predisposing factor. The 5-year survival rate of a unilateral diabetic amputee averages 50% (1). The average hospital stay for the diabetic patient with foot infection has been reported to range from 22 to 36 days, and in some areas more than 40% of patients remain hospitalized for 3 months (2,3). Considering that 6% to 12% of the population of the United States has diabetes (either diagnosed or undiagnosed) (4), it is easy to recognize that the 663

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New Developments in the Management of Foot Infections Associated with Diabetes Mellitus ●

●

●

●

Two organizations, including the International Working Group on the Diabetic Foot and the Infectious Diseases Society of America, have published evidence based treatment guidelines for diabetic foot infections. Methicillin-resistant Staphylococcus aureus (MRSA) has become a pathogen of concern. New antibiotics effective against severe MRSA skin and skin structure infections have been approved including linezolid, daptomycin, and tigecycline. More studies have been conducted on antibiotic therapy for diabetic foot infections leading to drugs with specific FDA approved package insert indications for their use against these infections. Specifically, both ertapenem and linezolid have been studied and received the indication.

incidence of diabetic foot infections reaches massive proportions. Therefore, the prevention and optimal management of this disease is of paramount importance in decreasing the illness, death, and financial burden it incurs.

Pathophysiology The diabetic patient’s susceptibility to foot infection is caused by 3 metabolic abnormalities associated with the disease: neuropathy, vasculopathy, and immunopathy. These abnormalities are highly prevalent in diabetic patients. Neuropathy is manifested by autonomic nerve dysfunction, peripheral mononeuropathy, and polyneuropathy, all of which affect the lower extremities to a greater extent than the upper extremities. Autonomic nerve dysfunction reduces sweating and impairs vasomotor responses, resulting in dryness, fissuring, and cracking of the skin and in the formation of calluses at points of increased stress on the skin. Insensitivity to pain may result in physical trauma, thermal or chemical injury, or ischemic damage from unperceived shoe tightness or chronic pressure. The patient may walk on parts of the foot that are injured or poorly adapted for weight bearing, leading to microfractures, ligament tears, and progressive articular damage (Charcot osteoarthropathy). Neuropathy also may result in uneven weakening of the extrinsic muscles of the foot, leading to toe deformity, prominent metatarsal heads on the plantar side, loss of the plantar arch, or foot drop. Vasculopathy may result in both macro- and microangiopathy. The vascular disease process, in conjunction with autonomic vasomotor impairment, may cause local hypoxia, atrophy, and necrosis. The combination of neuropathy and vasculopathy may accelerate the process of soft tissue breakdown. Deficient circulation may retard wound healing, and open wounds invite infection.

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Immunopathy manifests in several ways. Metabolic abnormalities have been implicated in defects in polymorphonuclear leukocyte function (adherence, chemotaxis, phagocytosis, and microbial killing) (5-7). Poor wound healing, defective granuloma formation, and prolonged persistence of abscesses have been described in animals rendered experimentally diabetic (8,9).

Clinical Manifestations and Classification Foot infections in diabetes can vary in both severity and clinical presentation (10). Most infections arise from some type of trauma, whether from improperly fitting footwear or from puncture or other mechanical injury of the foot. Infections of the diabetic foot can range in severity from the relatively mild (e.g., early infection of a ruptured blister, infected abrasion, corn, or callus; an early web-space infection; paronychia; infected superficial ulcer; mild cellulitis) to the more severe (e.g., crepitant anaerobic cellulitis, abscess of the plantar space, infected gangrene, osteomyelitis, necrotizing fasciitis, nonclostridial myonecrosis). Approximately 15% of all diabetic patients develop foot ulcers during the course of their illness (11). Spread of infection from the ulcer may result in deep-space infection and may be responsible for three fourths of all foot amputations among diabetic patients (12). Neuropathic ulcers are commonly found on the soles of the feet at the sites of bony prominences, such as metatarsal heads, and are often surrounded by a halo of hyperkeratinization but generally have a good blood supply (mal perforans). Ulcers that are caused by vascular insufficiency are usually seen at the tips of the toes or on the heel. Recently, 2 fairly similar evidence based systems classifying diabetic foot infections have been published. In 2003 The International Working Group on the Diabetic Foot published its International Consensus Guidelines on Diagnosing and Treating Diabetic Foot Infections (13). This system used a 4-grade classification and introduced the acronym PEDIS standing for perfusion, extent/size, depth/tissue loss, infection and sensation. Many members of that committee along with the authors of this chapter participated in a Diabetic Foot Guidelines Committee of the Infectious Diseases Society of America (IDSA). These guidelines, published in 2004, mirror the international system in many ways and are the focus of this discussion (14). The IDSA guidelines classify diabetic foot infections based on the clinical severity of the presentation. Wounds are looked at as being uninfected or presenting with a mild, moderate or severe infection (Table 36-1). An uninfected wound lacks purulence or any manifestations of inflammation. This is an important point, because it is clear that the diagnosis of infection in these ulcerations should be made on a clinical basis. Microbiological testing of such lesions will lead to a false-positive result

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Table 36-1 Clinical Classification of a Diabetic Foot Infection Clinical Manifestations of Infection

Wound lacking purulence or any manifestations of inflammation Presence of ≥2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration), but any cellulitis/erythema extends ≤2 cm around the ulcer, and infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness Infection (as previously mentioned) in a patient who is systemically well and metabolically stable but has ≥1 of the following characteristics: cellulitis extending >2 cm, lymphangitic streaking, spread beneath the superficial fascia, deep-tissue abscess, gangrene, and involvement of muscle, tendon, joint or bone Infection in a patient with systemic toxicity or metabolic instability (e.g., fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia)

Infection Severity

PEDIS Grade*

Uninfected

1

Mild

2

Moderate

3

Severe

4

* Printed with permission from: Lipsky BA, et al. International consensus on the diabetic foot. Clin Infect Dis. 2004;39:885-910. Note: Foot ischemia may increase the severity of any infection, and the presence of critical ischemia often makes the infection severe. Abbreviation: PEDIS = perfusion, extent/size, depth/tissue loss, infection and sensation.

because many colonizing bacteria will invariably grow from a swab culture. This may lead to the mistaken conclusion that these are infected lesions that need antibiotic treatment. Work by Chantelau demonstrated that using antibiotics in clinically uninfected wounds adds no benefit over standard therapy without antibiotics (15). Theoretically, in addition to other adverse drug effects, using inappropriate antibiotics in clinically uninfected wounds could lead to resistance. The first reported case in the United States of vancomycinresistant S. aureus occurred in such a case. Clinically uninfected wounds should be managed with local wound care including débridement, dressings, and off-loading (Fig. 36-1a). A wound with a mild infection presents with purulence or at least 2 manifestations of inflammation including erythema, pain, tenderness, warmth, or induration. The cellulitis must be localized, extending no more than 2 cm around the ulcer. These are superficial infections with no systemic complications. A moderate infection is one in which the patient is both systemically well and metabolically stable, but the patient has at least 1 of the following characteristics: cellulitis spreading beyond 2 cm around the ulcer, streaking, a deep tissue abscess, gangrene, or deep tissue spread. Finally, a severe infection presents with all the clinical findings in the moderate category but in a patient who is metabolically unstable, systemically unwell, or with significant peripheral arterial disease.

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Diabetic patient with a foot wound

Cleanse, debride, and probe wound Determine the depth and tissues involved Assess for neuropathy (protective sensation) and food deformity Assess for ischemia (pedal pulses)+ Assess for evidence of inflammation

Is the wound clinically infected?

No

Ensure appropriate wound care Off-load local foot pressure Ensure proper footwear Optimize glycemic control Consult (podiatrist, vascular surgeon, etc.) as needed No antimicrobial therapy

Yes

See Figure 36-1b

Is the wound healing?

Yes

Monitor until healed Reinforce preventive foot care

No Re-evaluate wound management Check patient's woundcare compliance Re-evaluate for infection Re-evaluate vascular status Consider foot radiographs

Figure 36-1a Algorithm for the assessment and management of a foot wound in patients with diabetes mellitus. (Republished with permission from Lipsky BA et al. International concensus on the diabetic foot. Clin Infect Dis. 2004;39:885-910.)

Microbiology Traditional thinking has diabetic foot infections being polymicrobial and caused by a vast array of organisms including gram-positives, gram-negatives, and anaerobes. One of the most salient points emphasized in both newer classification systems is the primary role of the aerobic gram-positive cocci, primarily S. aureus and group B Streptococcus, as the causative pathogen of most diabetic foot infections. This is particularly true of the mild and moderate classes of infection. Occasionally, gram-negative aerobic bacilli (e.g., Klebsiella, Proteus mirabilis, Pseudomonas aeruginosa) may be recovered

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from culture specimens; however, anaerobes are isolated infrequently from these types of lesions. Despite care in methodology to avoid isolating skincolonizing bacteria in cases of chronic, nonhealing ulcers (i.e., by débriding the base of the ulcer with a dermal curette or scalpel to avoid such contamination before specimen collection), it may be impossible to exclude completely such contamination in these types of lesions. However, it must be kept in mind that these organisms play little to no pathogenic role in the infection. Only in the more severe or longstanding infections are the other organisms thought to become more important. These more severe infections of the diabetic foot, especially when associated with necrotic tissue and/or gangrene, are generally polymicrobial (16-20). Sapico and coworkers (17) investigated quantitative deep tissue cultures of feet that were amputated from patients with moderately severe to severe diabetic foot infections, while meticulously avoiding potentially colonized open ulcers during the collection of specimens for culture. An average of 5 species per specimen were isolated, with anaerobes and aerobes almost equally represented. Of the 32 specimens studied, 25 yielded both aerobes and anaerobes, six yielded only aerobes, and one yielded only anaerobes. Anaerobes, when present, produced growth of a heavier density in culture than did aerobes. Table 36-2 shows the most common isolated representative species in the order of approximate frequency. Table 36-3 shows the pathogens associated with various clinical foot-infection syndromes. However, a special situation exists with osteomyelitis associated with puncture wounds, particularly when it occurs during the wearing of rubber sneakers. In these cases, P. aeruginosa has been isolated with remarkable frequency (20).

Table 36-2 Bacterial Species Isolated from Deep Tissue Cultures of Moderate to Severe Diabetic Foot Infections* Aerobes

Gram-negative bacilli ● Proteus mirabilis ● Escherichia coli ● Pseudomonas aeruginosa ● Enterobacter aerogenes ● Other organisms Gram-positive cocci Enterococcus species ● Staphylococcus aureus ● Streptococcus group B ● Other organisms ●

Anaerobes

Gram-negative bacilli Bacteroides fragilis ● Bacteroides ovatus ● Bacteroides ureolyticus ● Other Bacteroides species ●

Gram-positive cocci Peptostreptococcus magnus ● P. anaerobius ● Other Peptostreptococcus species ●

Gram positive bacilli Clostridium bifermentans ● Other Clostridium species ●

Republished with permission from: Sapico FL, Witte JL, Canawati HN, et al. The infected foot of the diabetic patient: Quantitative microbiology and analysis of clinical features. Rev Infect Dis. 1984;6(suppl 1): 171-6. * Listed in descending order of frequency.

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Table 36-3 Pathogens Associated with Various Clinical Foot-Infection Syndromes Foot-Infection Syndrome

Pathogens

Cellulitis without an open skin wound

Beta-hemolytic streptococcus* and Staphylococcus aureus S. aureus and beta-hemolytic streptococcus* S. aureus, beta-hemolytic streptococcus, and Enterobacteriaceae

Infected ulcer and antibiotic naive† Infected ulcer that is chronic or was previously treated with antibiotic therapy‡ Ulcer that is macerated because of soaking‡ Long duration nonhealing wounds with prolonged, broad-spectrum antibiotic therapy‡§

Fetid foot: extensive necrosis or gangrene, malodorous‡

Pseudomonas aeruginosa (often in combination with other organisms) Aerobic gram-positive cocci (S. aureus, coagulase-negative staphylococci, and enterococci), diphtheroids, Enterobacteriaceae, Pseudomonas species, nonfermentative gram-negative rods, and, possibly, fungi Mixed aerobic gram-positive cocci, including enterococci, Enterobacteriaceae, nonfermen-tative gram-negative rods, and obligate anaerobes

* Groups A, B, C, and G. † Often monomicrobial. ‡ Usually polymicrobial. § Antibiotic-resistant species (e.g., methicillin-resistant S. aureus, vancomycin-resistant enterococci, or extended-spectrum beta-lactamase producing gram-negative rods) are common.

When confronted with a diabetic foot infection of any severity grade, the role of MRSA must be considered. As in many types of infection both community associated MRSA (CA-MRSA) and hospital associated (HA-MRSA) strains have become much more prevalent in the past few years. A 1996 study by Goldstein showed that MRSA was isolated in 20% of his diabetic foot infection cases (21). This has increased to greater than 40%. In their paper “Methicillin Resistant Staphylococcus Aureus in the Diabetic Foot Clinic: A Worsening Problem” Dang and colleagues noted that the number of diabetic foot patients in which MRSA was isolated doubled between 1999 and 2003 (22). Fortunately, they also comment that in most cases the MRSA was eradicated with topical antibiotics, débridement, and isolation without the use of specific anti-MRSA therapy. Empiric therapy for CA-MRSA should be considered in cases where the patient is at an increased risk for presenting with an MRSA infection. This occurs in patients who have had a previous infection with MRSA, those exposed to many courses of antibiotics in the past year, and those with hospital or nursing home admissions in their recent past. Appropriate material must be submitted for culture if the results are to be accurate. In the case of infected ulcers, the necrotic tissue that overlies the base of the ulcer must be removed surgically, and culture specimens must be taken from the underlying tissue. Swab cultures are unreliable and lead to spuriously positive results. Specimens taken with a dermal curette or tissue removed with a scalpel are the preferred specimens. Abscesses need to be drained

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completely by incision and drainage or aspiration, and the pus must be sent for culture. Specimens for culture also may be obtained at the time of surgery, and anaerobic transport media must be used for the culture of anaerobes.

Diagnosis Diabetic patients with foot infections require a thorough examination that includes evaluation of the patient’s vascular and neurological status. The patient should be asked about foot symptoms (e.g., burning, tingling, numbness, pain, coldness), nocturnal pain (or pain while at rest, especially if relieved by dependency of the foot), and intermittent claudication. The evaluation for vascular compromise may be done initially by noninvasive means. Doppler ultrasonography with waveform analysis is a timehonored procedure that has shown good reliability in evaluating blood flow. However, always remember that noncompliant sclerotic arteries can produce ratios of lower- to upper-extremity flow that exceed 1.0, despite significant circulatory impairment in the legs and feet. Alternative studies include transcutaneous oximetry and magnetic resonance angiography. Contrast arteriograms are invasive and generally are reserved for patients who need vascular reconstruction. Computed tomography (CT) may be valuable in assessing the extent of soft tissue involvement in diabetic foot infections in which edema and gas accumulation may be seen along the fascial planes, such as in necrotizing fasciitis. However, early osteomyelitis may not be detected readily with CT. Triple-phase bone scans are very sensitive but lack specificity in the diagnosis of osteomyelitis. Gallium-67 (67Ga) scans and Indium-111–labeled leukocyte scans are sometimes insufficiently sensitive, especially when the bone infection is chronic. Sequential bone and 67Ga scans show better specificity than do bone scans alone, but the results do not seem to be as good as those with magnetic resonance imaging (MRI), which has a sensitivity of approximately 98% and a specificity of approximately 80% (23-25). Although false-positive MRI results may occur in cases of neuropathic osteoarthropathy, especially if it is of relatively acute onset, this may still be the best single technique available for the evaluation of osteomyelitis.

Treatment In managing infections in diabetic patients, the existing disordered metabolic state should be controlled promptly and aggressively. The effects of sepsis (e.g., hypotension) must be controlled with intravenous hydration and, if necessary, with vasopressor drugs (Figure 36-1b). The extent of tissue involvement, including the extent of cellulitis, tissue necrosis, and gangrene, must be assessed. The adequacy of the patient’s vascularity,

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Assess severity of infection: depth and tissue involved, evidence of systemic infection, presence of metabolic instability, and critical limb ischemia Plain radiographs of the foot Review patient's comorbid conditions Assess psychosocial status

Is hospitalization required?

No

671

Debride and probe the wound Obtain appropriate wound specimen(s) for culture Prescribe wound-care regimen Initiate an empirical (usually oral) antimicrobial regimen Re-evaluate in 3–5 days (or sooner if worsening) Set up any necessary consultations

Yes Medically stablize patient (fluid, electrolytes, insulin, etc ) Surgical (e.g., orthopedic, vascular, podiatric) consultation for wound debridement, revascularization. pr amputation Obtain appropriate specimens (wound and blood) for cultures Consider additional imaging (CT, MRI, and radionuclide scans) Intitiate empirical (usually parenteral) antimicrobial therapy Re-evaluate the patient at least daily

Infection improving?

Yes

Infection improving?

No Yes

No

Figure 36-1c

Reassess antimicrobial regimen; consider narrower-spectrum, less-expensive, and more-convenient agent(s), if possible Review wound- care regimen Prepare patient for discharge (if hospitalized) Set up return appointments in 1–2 weeks

Figure 36-1b Approach to treating a diabetic patient with a foot infection. (Republished with permission from LIPSKY BA et al.)

severity of neuropathy, and presence and extent of underlying osteomyelitis must be measured (Figure 36-2). If the patient exhibits inadequate metabolic control of diabetes despite taking oral antidiabetic agents, the treatment should be replaced by insulin. Surgical intervention is often necessary to control diabetic foot infections. A decision may have to be made about the need for ablative surgery. Infected ulcers may have to be débrided thoroughly. Early incision and drainage decrease the inoculum size of infecting microorganisms and may accelerate local healing. Before definitive surgery, a trial of appropriate antimicrobial therapy may be indicated to maximize control of cellulitis and minimize the extent of infection at the intended surgical site. As much of

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Poor response to treatment

Was appropriate tissue specimen obtained for culture?

No

Obtain appropriate culture specimens by aspiration, curettage, or biopsy

No

Change regimen to cover all isolated organisms likely to be pathogens

No

Reconsult appropriate surgical specialist for further procedures

No

Correct any metabolic disorders Reassess wound-care regimen and offloading compliance Reduce any limb odoma Consider adjunctive treatments (e.g., hyperbaric oxygen and hematopoietic factors)

No

Reconsult vascular surgeon Consider further diagnostic evaluation (e.g., angiography and TcPO2 measurement) Consider lower extremity revascuarization

Yes Are all pathogens covered by current antibiotic regimen? Yes Was surgical debridement, drainage, or resection adequate? Yes Has metabolic status and wound care been obtimized? Yes

Is limb perfusion adequate?

Yes Continue antibiotic therapy Consider amputation at appropriate level

Figure 36-1c Approach to assessing a diabetic patient with a foot infection who is not responding well to treatment. (Republished with permission from LIPSKY et al.) Abbreviation: TCPO2, transcutaneous partial pressure of O2.

the limb as is necessary must be preserved for future rehabilitation and ambulation, but not so much that it compromises control of the infectious state. Localized osteomyelitis often requires limited surgical ablation, such as toe amputation, ray resection, transmetatarsal amputation, or throughthe-ankle (Syme) amputation. Removal of the infected bone decreases the duration of need for antimicrobial therapy, hastens recovery, and decreases the incidence of relapse. Recent studies have shown that early and limited surgical intervention with aggressive antimicrobial therapy may reduce the number of days of hospitalization, the incidence of relapse, and the need for above-ankle amputation in cases of diabetic foot infection (26,27).

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Initial empirical antimicrobial therapy for diabetic foot infections must be directed at the organisms most likely to be involved (Figure 36-3). Generally, severe infections call for broader-spectrum antimicrobial coverage. More severe infections are associated with extensive cellulitis, tissue necrosis, gas formation, gangrene, and/or bone involvement. Once a patient has begun antimicrobial therapy, it may be adjusted according to the results of culture and susceptibility testing. However, the clinician should be cautioned that isolation of anaerobic bacteria depends heavily on proper specimen collection, the use of anaerobic transport media, and the use of good anaerobic microbiology technique on the part of the clinical laboratory. If any criteria have not have been met and if the infectious

Longstanding or deep ulcer? Elevated levels of inflamatory markers? Yes No Is bone visible or palpable by probe?

No

Plain foot radiograph findings compatible with1 osteomyelitis?

No

Yes

Yes

Yes

No

High clinical suspicion of osteomyelitis?

Severe peripheral neuropathy?

Yes

Consider additional diagnostic imaging (e.g., MRI or radionuclide scan) No

Presumptive osteomylitis Consider bone biopsy for definitive diagnosis or susceptibility testing on causative organism

Scan suggestive of osteomyelitis?

Yes

No Biopsy2 shows osteomyelitis

Treat for soft-tissue infection Repeat plain radiography in 2 weeks

No

Yes Treat for osteomyelitis

Infection improving?

No

Surgical resection (if not previously done), or Amputation

Yes Continue therapy as planned Monitor for at least 1 year

Figure 36-2 Algorithm for the management approach to the patient with diabetes mellitus with longstanding or deep ulcers of the feet. (Republished with permission from LIPSKY et al.)

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process is likely to involve anaerobes (e.g., there is an associated foul smell, necrotic tissue is present, gangrene is evident), coverage of anaerobes is strongly recommended despite the failure to isolate these organisms by culture (see Chapter 35, Necrotizing Soft Tissue Infections). Generally, mild-grade infections can be managed on an outpatient basis with antimicrobial therapy directed specifically at the aerobic grampositive cocci. For outpatient antimicrobial therapy, an oral agent (e.g., cephalexin, clindamycin, amoxicillin–clavulanate) may be used empirically. Subsequent culture and susceptibility-testing results may dictate changes in the treatment regimen, especially if there is no clinical response to the originally chosen drug. If hospitalization is required for other reasons (e.g., for control of the patient’s metabolic state), parenteral therapy may be given with a first- or second-generation cephalosporin (e.g., cefazolin, cefuroxime). Moderate to severe infections of the diabetic foot, may require coverage of a broader-spectrum of potential pathogens. Recently, emphasis has been given to the use of cost-effective, single-drug regimens that provide broad-spectrum coverage. Antimicrobial agents for these regimens include ertapenem, ampicillin-sulbactam, ticarcillin-clavulanate, and piperacillin-tazobactam (2830). Another possible option, especially in a beta-lactam–allergic patient is moxifloxacin, which has a very broad spectrum of antimicrobial coverage (including anaerobes) and can be given on an oral once-daily basis. Although no studies have specifically addressed the efficacy of moxifloxacin in the treatment of the infected diabetic foot, the drug is indicated for complicated skin and skin structure infections, and there are in vitro and clinical trials that suggest that it should be an effective antibiotic (31-32). All these drugs have a broad spectrum of activity that includes not only the aerobic gram-positive cocci but also many gram-negative rods and anaerobic pathogens. As of this writing, ertapenem and piperacillin-tazobactam are the only drugs to carry specific FDA indications for use in diabetic foot infections. Lipsky and colleagues (28) specifically studied ertapenem versus piperacillin-tazobactam in 445 infected diabetic feet. This was the largest study to date in moderate to severe diabetic foot infections and demonstrated that ertapenem doses of 1 g once daily is at least as effective as piperacillin-tazobactam 3.375 g every 6 hours for the first 5 days, after which patients were given oral amoxicillin/clavulanate 875/125 mg every 12 hours. Based on this study the FDA granted ertapenem a specific indication for diabetic foot infections without osteomyelitis. Linezolid, daptomycin, tigecycline or vancomycin may need to be added or begun empirically, especially in institutions where MRSA is a frequent clinical isolate, in patients with positive MRSA cultures, or in patients at high risk for MRSA infection including those with previous MRSA infection, those who have been hospitalized or living in nursing homes, or those who have received many courses of different antibiotics over the previous 24 months. For less severe infections caused by MRSA, oral antibiotics such as trimethoprim-sulfamethoxazole, doxycycline, or minocycline may be

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Table 36-4 Suggested Route, Setting, and Durations of Antibiotic Therapy, by Clinical Syndrome Site, by Severity or Extent, of Infection

Route of Administration

Setting for Therapy

Mild

Topical or oral

Outpatient

Moderate

Oral (or initial Outpatient/ parenteral) inpatient Initial parenteral, Inpatient, switch to oral then when possible outpatient

Duration of Therapy

Soft-Tissue Only

Severe

1-2 wk; may extend up to 4 wk if slow to resolve 2-4 wk 2-4 wk

Bone or Joint

No residual Parenteral or oral Inpatient, infected tissue then (e.g., postamputation) outpatient Residual infected soft Parenteral or oral Inpatient, tissue (but not bone) then outpatient Residual infected Initial parenteral, Inpatient, (but viable) bone then consider then oral switch outpatient No surgery, or Initial parenteral, Inpatient, residual dead bone then consider then postoperatively oral switch outpatient

2-5 d

2-4 wk

4-6 wk

>3 mo

Abbreviations: d = day; wk = week.

useful. Of these anti-MRSA antibiotics, only linezolid has been specifically studied in the diabetic foot infection and carries an FDA indication for diabetic foot (33). Milder soft tissue infections of the diabetic foot may require no more than 10 to 14 days of antimicrobial therapy (Table 36-4). More severe infections require longer therapy, especially if bone involvement is present. Limited ablative surgery to remove localized bone infection may decrease the duration of therapy and incidence of relapse. If bone infection is not ablated completely, prolonged therapy (involving a minimum of 4 weeks of intravenous or 10 weeks of combined intravenous and oral therapy) may be required (34,35). Management in the event of poor response to treatment is outlined in Figure 36-1c.

Prevention The prevention of infection is the cornerstone of diabetic foot care (33). The basic principles of such prevention include good control of the diabetic

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Foot infection established Appropriate specimen for culture collected Pathogens not known initially Initiate empirical antimicrobial therapy on the basis of available clinical and laboratory data Reassess after 24–72 hours Causative organisms isolated?

No

Infection improving?

No

Reconsider need for surgical procedure Perform cultures again (with optimal specimen collection)

Continue empirical regimen Re-evaluate after 1–2 weeks

No

Broaden antimicrobial spectrum to include gram-negative rods and anaerobes Consider adding coverage for MRSA and resistant gram-negative rods

No

Yes Infection improving?

Yes

Yes Select the safest, narrowest-spectrum, most-convenient regimen.

Continued improvement?

Yes

Yes

No

Causative organism isolated?

Re-evaluate wound care Re-evaluate spectrum of antimicrobial coverage Re-evaluate need for surgery (revascularization, amputation, etc.)

No

Consider changing to safer, narrowerspectrum, cheaper, or more-convenient regimen, based on results of susceptibility testing, if available Complete course of therapy

improving?

Yes

Figure 36-3 Algorithm for the treatment of foot infections in patients with diabetes mellitus. (Republished with permission from LIPSKY et al.)

state, weight reduction, smoking avoidance, and a diet low in fat and cholesterol. Appropriate footwear is of paramount importance, and special shoes and/or orthotic devices may have to be made for diabetic patients, especially if they have foot deformities. Patients should take the primary responsibility for their own foot care, inspecting their feet at least once daily. Hand mirrors may be used for this, and the help of family members or friends should be solicited if the patient’s vision is too poor for adequate self-examination. The feet should be washed daily with nonmedicated soap and tepid water, temperature first tested with the fingers (but only if significant sensory neuropathy does not

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exist in the upper extremities as well). The feet, including the interdigital areas, should be dried thoroughly after washing, and then a light coat of lubricating lotion or talcum powder may be applied. Woolen socks should be used when the feet feel cold; hot water bottles or heating pads should never be used to warm the feet. To prevent ingrown toenails, the toenails should be cut straight across with nail clippers, without rounding at the corners. Ingrown toenails should be discussed with the patient’s primary care physician and/or podiatrist. Diabetic patients should avoid walking barefoot, indoors and outdoors. They also should refrain from removing corns or calluses without professional help and from using caustic chemicals on the feet. Open-toed footwear should be avoided. Primary care physicians should be familiar with their responsibilities to the diabetic patient. Physical examination for vascular and neurological status should be done at least twice yearly or more often if problems exist. Specialized examinations, such as Doppler studies, should be done when indicated. Studies of shoe fitting and foot-loading patterns may occur when necessary. Referral for a podiatric examination should be considered in all diabetic patients, especially those at higher risk for ulceration because of neuropathy, foot deformity or a history of previous ulceration.

Summary Total care of the diabetic patient requires the coordination of specialists in various fields of health care, including the primary care physician, podiatrist, orthopedist, shoe specialist, orthoses specialist, vascular surgeon, physical therapist, diabetologist and/or endocrinologist, dietician, neurologist, and infectious disease specialist. Despite the knowledge gained and progress made in diabetic foot care over the past several decades, considerable illness is still associated with diabetic foot infections. More effort should be given to preventing such infections, and education about the preventive aspects of diabetic foot care should be directed not only to the patient but also to the patient’s primary care physician. REFERENCES 1. American College of Foot and Ankle Surgeons. Diabetic foot disorders: a clinical practice guideline. American College of Foot and Ankle Surgeons. J Foot Ankle Surg. 2000;39:S1-60. 2. Lipsky BA, Pecoraro RE,Wheat L J. The diabetic foot. Soft tissue and bone infection. Infect Dis Clin North Am. 1990;4:409-32. 3. Bridges RM Jr., Deitch EA. Diabetic foot infections. Pathophysiology and treatment. Surg Clin North Am. 1994;74:537-55. 4. Minow M. The role of families in medical decisions. Utah Law Rev. 1991;1991:1-24. 5. Bagdade JD, Root RK, Bulger R J. Impaired leukocyte function in patients with poorly controlled diabetes. Diabetes. 1974;23:9-15. 6. Repine JE, Clawson CC, Goetz FC. Bactericidal function of neutrophils from patients with acute bacterial infections and from diabetics. J Infect Dis. 1980;142:869-75.

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7. Tan JS,Anderson JL,Watanakunakorn C, Phair JP. Neutrophil dysfunction in diabetes mellitus. J Lab Clin Med. 1975;85:26-33. 8. Bessman AN, Sapico FL,Tabatabai M, Montgomerie JZ. Persistence of polymicrobial abscesses in the poorly controlled diabetic host. Diabetes. 1986;35:448-53. 9. Mahmoud AA, Rodman HM, Mandel MA, Warren KS. Induced and spontaneous diabetes mellitus and suppression of cell-mediated immunologic responses. Granuloma formation, delayed dermal reactivity and allograft rejection. J Clin Invest. 1976;57:362-7. 10. Sapico FL, Bessman AN. Diabetic foot infections. In Frykberg RG, ed. The High Risk Foot in Diabetes Mellitus. New York, NY: Churchill Livingstone; 1991:197-211. 11. Todd WF,Armstrong DG, Liswood P J. Evaluation and treatment of the infected foot in a community teaching hospital. J Am Podiatr Med Assoc. 1996;86:421-6. 12. Edmonds ME, Blundell MP, Morris HE, et al. The diabetic foot: Impact of a foot clinic. Q J Med. 1986;232:763-71. 13. International Working Group on the Diabetic Foot. International consensus on the diabetic foot (CD-ROM). Brussels, Germany: International Diabetes Foundation, May 2003. 14. Infectious Diseases Society of America. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2004;39:885-910. 15. Chantelau E,Tanudjaja T, Altenhöfer F, Ersanli Z, Lacigova S, Metzger C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med. 1996;13:156-9. 16. Louie T J, Bartlett JG,Tally FP, Gorbach SL. Aerobic and anaerobic bacteria in diabetic foot ulcers. Ann Intern Med. 1976;85:461-3. 17. Sapico FL, Witte JL, Canawati HN, et al. The infected foot of the diabetic patient: Quantitative microbiology and analysis of clinical features. Rev Infect Dis. 1984;6(suppl 1):171-6. 18. Scher KS, Steele F J. The septic foot in patients with diabetes. Surgery. 1988;104:661-6. 19. Hughes CE, Johnson CC, Bamberger DM, Reinhardt JF, Peterson LR, Mulligan ME, et al. Treatment and long-term follow-up of foot infections in patients with diabetes or ischemia: a randomized, prospective, double-blind comparison of cefoxitin and ceftizoxime. Clin Ther. 1987;10 Suppl A:36-49. 20. Glober GA,Wilkerson JA. Biliary cirrhosis following the administration of methyltestosterone. JAMA. 1968;204:170-3. 21. Goldstein E J, Citron DM, Nesbit CA. Diabetic foot infections. Bacteriology and activity of 10 oral antimicrobial agents against bacteria isolated from consecutive cases. Diabetes Care. 1996;19:638-41. 22. Dang CN, Prasad YD, Boulton A J, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med. 2003;20:159-61. 23. Wang A,Weinstein D, Greenfield L, Chiu L, Chambers R, Stewart C, et al. MRI and diabetic foot infections. Magn Reson Imaging. 1990;8:805-9. 24. Yul W, Carson J, Baraimewski H. Osteomyelitis of the foot in diabetic patients: Evaluation with plain film 99Te-MDP bone scintigraphy and MR imaging. Am J Roentgenol. 1989;152:795-800. 25. Beltran J, Campanini DS, Knight C, McCalla M. The diabetic foot: magnetic resonance imaging evaluation. Skeletal Radiol. 1990;19:37-41. 26. Tan JS, Friedman NM, Hazelton-Miller C, Flanagan JP,File TM Jr. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis. 1996;23:286-91. 27. Eckman MH, Greenfield S, Mackey WC,Wong JB, Kaplan S, Sullivan L, et al. Foot infections in diabetic patients. Decision and cost-effectiveness analyses. JAMA. 1995;273:712-20. 28. Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet. 2005;366:1695-703. 29. Grayson ML, Gibbons GW, Habershaw GM, Freeman DV, Pomposelli FB, Rosenblum BI, et al. Use of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients. Clin Infect Dis. 1994;18:683-93. 30. Tan JS, Wishnow RM,Talan DA, Duncanson FP, Norden CW. Treatment of hospitalized patients with complicated skin and skin structure infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The Piperacillin/Tazobactam Skin and Skin Structure Study Group. Antimicrob Agents Chemother. 1993;37:1580-6. 31. Giordano P, Song J, Pertel P, Herrington J, Kowalsky S. Sequential intravenous/oral moxifloxacin versus intravenous piperacillin-tazobactam followed by oral amoxicillin-clavulanate for the treatment of complicated skin and skin structure infection. Int J Antimicrob Agents. 2005;26:357-65.

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32. Edmiston CE, Krepel C J, Seabrook GR, Somberg LR, Nakeeb A, Cambria RA, et al. In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intraabdominal and diabetic foot infections. Antimicrob Agents Chemother. 2004;48:1012-6. 33. Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: A randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clinical Infect Dis. 2004;38:17-24. 34. Bamberger DM, Daus GP, Gerding DN. Osteomyelitis in the feet of diabetic patients. Long-term results, prognostic factors, and the role of antimicrobial and surgical therapy. Am J Med. 1987;83:653-60. 35. Sapico FL. Foot infections in patients with diabetes mellitus. J Am Podiatr Med Assoc. 1989;79:482-5.

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Chapter 37

Bite-Wound Infections JOSEPH P. MYERS, MD

Key Learning Points 1. Initial and appropriate wound irrigation and débridement are the most important initial steps in the treatment of bite wounds. The most common error made in the treatment of bite wounds is failure to adequately perform such irrigation and débridement. 2. Prophylactic antibiotic therapy is really presumptive treatment of microbially contaminated tissue. Such antibiotic therapy should be used in high-risk clinical circumstances such as in moderate to severe injury less than eight (8) hours old especially with crush injury, in clinical situations where there is high suspicion for bone or joint penetration/inoculation, in any hand bite wound, in any foot bite wound, in any bite wound in a compromised patient, in any bite wound adjacent to a prosthetic joint and in any bite wound to the genital area. Every patient should be assessed for risk of tetanus and for the possibility of rabies virus, human immunodeficiency virus, hepatitis B virus and hepatitis C virus exposure depending upon the clinical situations encountered during the patient evaluation.

A

nimal and human bite wounds are common injuries to adults and children and account for an estimated 1% of U.S. emergency room visits. It has been estimated that more than 1 million domestic animal bites are inflicted per year in the United States. The true estimate can be significantly higher given the nonreporting of many of the more trivial of these injuries (1-5). Many of these bites are innocuous, but some can be serious in nature. Ten to twenty fatal animal bites are reported per year in 680

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New Developments in the Management of Bite-Wound Infections ●

●

●

Some of the newer antimicrobial agents should allow cost effective and/or microbially effective treatment of patients with complicated bite-wound infections and coexistent antibiotic allergies. Agents in this category include daptomycin, ertapenem, tigecycline, and linezolid. Rabies immunization in wild animal populations can be induced by bait drops in which wild animals are immunized by exposure to oral rabies animal vaccine encased in bait packets dropped by air into high-risk areas for wild animal rabies transmission/spread. Ongoing education about the need for aggressive irrigation and débridement of bite wounds of all types is not truly new, but it is of the greatest necessity because the lack of this aggressive approach is the single most important reason for initial failure of treatment of bite-wound infections.

the United States (6). Significant bite-wound illness can result from direct traumatic injury or infectious complications such as osteomyelitis, septic arthritis, tenosynovitis, cellulitis, and septicemia (7). The true incidence of human-bite wounds is uncertain because many of these injuries, especially those of the clenched-fist variety, are concealed by the victim because of embarrassment or fear of legal ramifications (1,3,8). Wild-animal bites follow dog, cat, and human bites in frequency of occurrence and can have infectious and noninfectious complications (1). This chapter reviews the infectious complications of dog, cat, and human-bite wounds with occasional references to other types of bite wounds. Several excellent publications review the zoonotic diseases transmitted by domestic and wild animals. Please refer to these articles for detailed information (6,9-12).

Epidemiology Dog-Bite Wounds Although fatalities from dog bites are rare (4,5), dog-bite wounds are common (1,13,14) and account for up to 1% of all emergency room visits in the United States (1,4,13,14). Most dog-bite injuries are inflicted by family or neighborhood dogs and not by stray dogs (7,8). Dog-bite victims are commonly men with a 2:1 predominance and usually younger than 16 years of age (4,6,7). It has been estimated that up to 20% of all children in the United States will be bitten by a dog at some time in their lives (7). Children are more likely than adults to be bitten by dogs because children are less intimidating to animals, more likely to be engaged in inadvertently provocative behavior and less likely to recognize and thereby avoid threatening behavior in animals (7). It is estimated that dog-bite wounds account for 70% to

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93% of the mammalian bites seen in emergency rooms throughout the United States (4,11).

Cat-Bite Wounds Almost half a million people are bitten by a cat each year in the United States (1,6). Cat bites are twice as common in women as in men and occur primarily on the upper extremities (7). In one prospective study of cat bites presenting in the emergency room, 45% of all cat bites occurred to the hand; 22% were sustained on the arm above the hand; 13% occurred on the lower extremity; and the remainder of the bites (20%) occurred on the head, neck, or trunk (15). It has been estimated that cat bites account for 3% to 15% of all patients with bite wounds admitted to emergency rooms in the United States (4). The incidence of cat bites is highest in people aged 21 to 35 years, with women accounting for most of cat-bite victims (4). In the prospective study of cat bites previously referenced (15), the cat inflicting the bite wound was a pet or an acquaintance of the owner in 55% of the bite wounds and was a stray or wild cat in 42% of cases. Only 3% of cat-bite wounds were inflicted by cats of unknown origin (15).

Human-Bite Wounds Human-bite wounds generally are classified into three types: self-inflicted paronychia, occlusional bite wounds, and clenched-fist injuries. Self-inflicted paronychia can be the result of nail biting, thumb sucking, or similar activities. Occlusional bite wounds usually are intentionally inflicted injuries that occur during a physical confrontation. Clenched-fist injuries are unintentionally induced injuries occurring to the hand of an offensive-minded pugilist (1,3,8,16). Human-bite wounds are the third most common type of bite wound encountered in emergency rooms (1). Human-bite wounds also can be sustained during passionate sexual activity (3). Common locations for human-bite wounds in children are the scalp and face, whereas the distal portion of the index or middle finger is the most common site for occlusional bite wounds (1,3). The ear, nose, forearm, breast, penis, scrotum, and vulva can be affected in adult bite wounds resulting from passionate or pugilistic activity (3). The clenched-fist injury usually produces a wound over the third, fourth, or fifth metacarpal head of the dominant hand (1). Any injury at this site should be presumed to be caused by an inadvertent human-bite wound until proven otherwise (1,17). Patients with clenched-fist injuries often provide the physician with false information about the exact circumstances of the injury because of embarrassment or fear of legal ramifications (1,3). Approximately 60% to 70% of all human-bite wounds are sustained to the hand and upper extremities, 15% to 20% to the head or neck, 10% to 20% to the trunk, and 5% to the lower extremities, with other sites accounting for the remaining 5% to 10% of human-bite wounds (18).

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Pathophysiology Animal-bite wounds can cause severe tissue injury and severe infection. Large animal bites can generate up to 450 lb per square inch of pressure, more than sufficient force to perforate even light sheet metal. This pressure can produce a severe crush injury to human tissue (7,19). Edema and necrosis of crushed tissue in the area surrounding a bite wound predisposes the tissue to infection. Normal human cutaneous microflora and normal animal oral microflora can thrive in this necrotic, edematous tissue, causing further predisposition to infection (7).

Etiology and Microbiology In the evaluation and management of patients with mammalian bites, the species of the biting animal can help the physician assess the most likely type of injury and the potentially associated microbiologic pathogens (1,13,14,20). Cat-bite wounds are more likely than other bite wounds to become infected, which is probably related to the aforementioned puncture-type wounds normally inflicted by the sharp, piercing feline teeth. A significant percentage of human-bite wounds subsequently develop active infectious complications (3,7). Dog-bite wounds are the least likely to become infected because the usual avulsion-type injury produced in canine bites allows for open drainage at the wound site (7). Wound factors that predispose to infection include bite wounds older than 12 hours, bite wounds on the hand or foot, bite wounds caused by clenched-fist injury, and bite wounds that are pure puncture wounds (7). Victim factors that predispose to infection include a victim older than 50 years of age, chronic alcohol abuse, diabetes mellitus, malignancy, or other immunocompromised state caused by radiotherapy, chemotherapy, immunosuppressive medication, or asplenism (7). These factors should be explored carefully in the historic evaluation of patients with documented or potential bite-wound injuries. The presence of any of these factors suggests the need for initiation of prophylactic antimicrobial therapy in patients with bite-wound injuries evaluated within 8 hours of infliction and in which there is no definitive sign of clinical infection. Meticulous wound care is more effective than antimicrobial prophylaxis in preventing bite-wound infection (7). Débridement of devitalized tissue at the initial time of bite-wound management has been shown to reduce infection rates from 62% to 2% in one study (7). Other studies have shown a significant increase in the infection rate when débridement is omitted from the management regimen (21). Irrigation of the wound decreases the infection rate by 6 to 10 times (7). Puncture wounds are infection-prone, at least partially because they are extremely difficult to débride and irrigate (7).

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Most infections complicating mammalian and human-bite wounds are polymicrobial with mixed aerobic and anaerobic microflora usually isolated in culture (3,4). Sources of infecting organisms include the oral and gingival microflora of the biting animal species, the skin of the bitten person, and the environmental microflora (e.g., water, soil) pertinent to the clinical situation in which the bite wound occurred (13,14). Common aerobic isolates from bite-wound infections include alpha-hemolytic streptococci, Staphylococcus aureus, Streptococcus pyogenes, Staphylococcus intermedius, coagulase-negative staphylococci, Capnocytophaga canimorsus, Pasteurella multocida, Centers for Disease Control and Prevention (CDC) alphanumerically designated bacteria such as EF-4 and M-5, and many anaerobic microflora (1). A prospective study showed Pasteurella species, streptococci, staphylococci, Neisseria species, Corynebacterium species, and Moraxella species as the most common aerobic isolates from dog and cat-bite wounds (22).

Dog-Bite Wounds The oral microflora of dogs includes up to 64 species of bacteria that can be potential human pathogens. Staphylococci, streptococci, P. multocida, other Pasteurella species, Pseudomonas species, other gram-negative aerobes, and many anaerobic species are most commonly isolated from infected bite wounds (7,16,22). Staphylococcus intermedius is a coagulasepositive Staphylococcus species that is a normal component of the canine oral microflora. It can be mistaken for S. aureus and has been reported as a cause of dog-bite wound infection (16,23). S. intermedius displays sensitivity and resistance patterns similar to methicillin-sensitive S. aureus. Therefore, confusion in the identification of this organism should not affect therapy. Pasteurella multocida is isolated less frequently from infected dog bites than from infected cat-bite wounds (1,7,22). Capnocytophaga canimorsus, formerly CDC alphanumeric designation DF-2 can be a normal component of the canine oral microflora. It can cause a devastating infectious illness in patients who are immunocompromised and asplenic (4,13,14).

Cat-Bite Wounds Most cat-bite wound infections are caused by P. multocida, a facultative anaerobic gram-negative organism that is a normal component of the oral flora of most feline species (7,15). Polymicrobial infections are common; staphylococci, streptococci, and aerobic enteric gram-negative bacilli are isolated often from cat-bite wound infections (7,13,14). Bartonella henselae, the cat scratch bacillus, is an unusual cause for infection complicating cat bites or scratches but must be considered in certain clinical situations (1).

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Human-Bite Wounds Under healthy circumstances, the human mouth can harbor more than 40 species of bacteria. Almost 200 species of potentially pathogenic bacterial species have been described in the presence of gingivitis and periodontal disease (7). More than 50% of human-bite wound infections contain mixed gramnegative and gram-positive bacteria (7,13,14). Anaerobes are found in more than 60% of human-bite wounds, and it has been estimated that if sophisticated anaerobic culture techniques are used, up to 100% of human-bite wounds can include anaerobic species. The most common bacterial isolates from human-bite wounds are alpha-hemolytic streptococci (40% to 50%), staphylococci (25% to 50%), and Eikenella corrodens (10% to 35%) (7,9,16).

Wild-Animal Bite Wounds The medical literature is replete with isolated cases of bite-wound infections caused by exotic and/or wild animals. Infections caused by specific microorganisms have been associated with the bites of certain animals (4). Consult the appropriate reference resources for specific animal-microorganism associations (1,4,7,13,14,24).

Other Infections Risk factors for tetanus and the patient’s previous immunization status against Clostridium tetani must be evaluated in the treatment of every bitewound injury. Standard CDC guidelines and protocols should be used to evaluate the adequacy of previous tetanus immunization (Table 37-1) (25). All cat, dog, and wild-animal bite wounds should be evaluated for the potential transmission of rabies virus infection. The likelihood of the biting

Table 37-1 Tetanus Prophylaxis in Wound Management History of absorbed tetanus toxoid (doses)

Unknown or < three ≥ Three (§)

Clean, minor wounds 1

‡

2

All other wounds (*)

Td ( )

TIG

Td (‡)

TIG

Yes No (¶)

No No

Yes No (**)

Yes No

* Such as, but not limited to, wounds contaminated with dirt, feces, soil, and saliva; puncture wounds; avulsions; and wounds resulting from missiles, crushing, burns and frostbite. ‡ For children < 7 years old; DTP3 (DT4, if pertussis vaccine is contraindicated) is preferred to tetanus toxoid alone. For persons > 7 years of age, Td is preferred to tetanus toxoid alone. § If only three doses of fluid toxoid have been received, then a fourth dose of toxoid, preferably an absorbed toxoid, should be given. ¶ Yes, if > 10 years since last dose. ** Yes, if > 5 years since last dose. More frequent boosters are not needed and can accentuate side effects. 1 Td: Tetanus and Diptheria Toxoids Adsorbed for Adult use 2 TIG: Tetanus Immune Globulin 3 DTP: Diptheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed for Pediatric use 4 DT: Diptheria and Tetanus Toxoids Adsorbed for Pediatric use

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animal carrying the rabies virus should be evaluated on an individual basis depending on the genus and species of the biting animal and on local epidemiologic information about the potential transmission of the rabies virus. Standard CDC guidelines and protocols should be consulted to evaluate the need for rabies immunization based on the type of animal exposure (26). Table 37-2 contains detailed information about the rabies virus postexposure prophylaxis protocol (26). Because monkeys are kept as pets, used in medical research, cared for in zoos, and encountered in the wild, their bites can be encountered more frequently in the medical care setting than would be anticipated. A review of simian-bite wound infection by Goldstein and colleagues (24) suggests a microbiologic picture similar to human-bite wound infection, and antimi-

Table 37-2 Rabies Postexposure Prophylaxis Schedule Vaccination Status

Treatment

Regimen*

Not previously vaccinated

Local wound cleansing

All postexposure treatment should begin with immediate cleansing of all wounds with soap and water. If available, a virucidal agent such as a povidone-iodine solution should be used to irrigate the wounds. 20 IU/kg body weight. If anatomically feasible, the full dose should be infiltrated around the wounds and any remaining volume should be administered IM at an anatomical site distant from vaccine administration. Also, RIG should not be administered in the same syringe as vaccine. Because RIG can partially suppress active production of antibody, no more than the recommended dose should be given. HDCV, RVA, or PCEC 1.0 mL, IM into deltoid area†, one each on days 0, 3, 7, 14, and 28. All postexposure treatment should begin with immediate thorough cleaning of all wounds with soap and water. If available, a virucidal agent such as a povidone-iodine solution should be used to irrigate the wounds. RIG should not be administered. HDCV, RVA, or PCEC 1.0 mL, IM into deltoid area†, one each on days 0 and 3.

RIG

Vaccine Previously vaccinated‡

Local wound cleansing

RIG Vaccine

* These regimens are applicable for all age groups, including children. † The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh can be used. Vaccine should never be administered in the gluteal area ‡ Any person with a history of preexposure vaccination with HDCV, RVA, or PCEC; prior postexposure prophylaxis with HDCV, RVA, or PCEC; or previous vaccination with any other type of rabies vaccine and a documented history of a response to the prior vaccination. Abbreviations: HDCV, human diploid cell vaccine; IM, intramuscularly; PCEC, purified chick embryo cell vaccine; RVA, rabies vaccine adsorbed; RIG, rabies immune globulin.

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crobial therapy should include agents effective against Eikenella corrodens. This study documents that infection after a simian bite is common, and complications such as osteomyelitis and flexion contractures of the hand are frequent. Of added significance is the transmission of herpesvirus simiae (B-virus) by Old World (Macaca) monkeys. Therefore, information about the type of monkey implicated in a simian-bite wound is critical in evaluating the need for prophylactic acyclovir treatment of such bite wounds (27). Many other infectious diseases can be transmitted by animal bites. Brucellosis (Brucella species), blastomycosis (Blastomyces dermatitidis), tularemia (Francisella tularensis), cat scratch disease (Bartonella henselae), rat bite fever (Streptobacillus moniliformis and Spirillum minor), bubonic plague (Yersinia pestis), leptospirosis (Leptospira species), Erysipelothrix (Erysipelothrix rhusiopathiae), and seal finger (possible Mycoplasma species) are some of the other infections that can be transmitted by various domestic and wild animals (1,6-8,27,28). Human-bite wounds should be evaluated on an individual basis for the potential transmission of infectious agents other than the usual bacterial pathogens that cause bite-wound infection. Hepatitis B virus, hepatitis C virus, human immunodeficiency virus, Treponema pallidum, and Mycobacterium tuberculosis, can be transmitted by bite wounds (1,29-31). The treating physician should ask the patient about the health and disease status of the assailant biter if such information is available.

Classification Bite wounds are classified as tears (avulsions), punctures, or scratches (1,13,14,20). Tear wounds can have an associated component of crush injury (1). Tear injuries or avulsions are more commonly seen with dog-bite wounds (9). Puncture wounds most commonly occur when the bite wound is inflicted by a cat (9). Such puncture wounds are the result of the sharp, piercing feline teeth that usually puncture the skin and inoculate oral microflora into the subcutaneous tissue including tendons, joint spaces, and bones. Human-bite wounds are classified as self-inflicted, occlusional, or clenched-fist (1,3,8,16). Self-inflicted bites tend to be relatively superficial although complicated paronychial infections can occur. Violent, occlusional bite wounds frequently cause full-thickness injury resulting in deep soft tissue infection, osteomyelitis or even traumatic amputation of the digit (1). Clenched-fist injuries usually occur during pugilistic activity and can present a challenging diagnostic and therapeutic scenario to the physician. The true diagnosis is often obscured by a cover-up story, and the injury often causes serious infectious complications because of the retraction of polymicrobial mouth flora deep into the soft tissues of the hand with extension of the fingers after the clenched-fist injury (3,32).

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Clinical Manifestations Two distinct groups of patients eventually seek medical care for animal and human-bite wounds. Members of the first group are seen within 8 hours of the original injury. These patients usually seek immediate wound care and fear rabies or tetanus related to the bite wound. The second group of patients seeks treatment more than 8 hours after the injury (or often much later) and almost always after infection has been established. In this second group, a gray malodorous discharge can exude from the bite wound with concomitant localized pain, tenderness, and erythema. Patients from the first group can seek treatment without evidence of clinical infection and must be fully evaluated for risk factors for infection. Patients in the second group usually have active infection, and a treatment strategy must be established immediately (1,13,14,20).

Complications Infectious complications of bite wounds include cellulitis, wound infection, septic arthritis, osteomyelitis, tenosynovitis, lymphangitis, bacteremia, meningitis, brain abscess, sepsis, and disseminated intravascular coagulation (3,6,16). Noninfectious complications include: peripheral neuropathy, direct or indirect; osseous crush injury and skeletal fracture; soft tissue crush injury; and cosmetic damage to skin and soft tissue (3,8). Potential delayed infectious complications include tetanus, rabies virus infection, Herpes simiae (Bvirus) infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, cat scratch disease, and others (1,7,25-27,29-31).

Diagnosis History Detailed information about the biting animal or person should be obtained. Animal-related information should include the type of animal; the immunization status, health, and behavior of the animal; whether or not the bite was provoked; the situation and/or environment in which the bite occurred; the exact time of the biting incident; and whether the source animal was captured and isolated for rabies observation (1,4). If the injury is a human bite, the physician should determine who bit the patient, whether the biting human has hepatitis B, hepatitis C, syphilis, herpes simplex infection, or HIV infection and the date, time, and exact circumstances of the human-bite injury. Important patient-related information should include antibiotic allergies, current medications, especially immunosuppressive therapy, a history of previous splenectomy, mastectomy, or

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chronic liver disease, and any self-administered treatment that occurred before the patient sought medical care.

Physical Examination The number, type, anatomic site, and depth of all wounds should be recorded in exquisite detail. Detailed diagrams should be made part of the medical record, and photographic documentation should be procured, if available. Other factors that should be recorded include range of motion of joints adjacent to the injury, examination for the possibility of joint penetration, the presence of edema or crush injury, nerve and tendon function, clinical extent of infection (e.g., erythema), purulent drainage, and the presence of necrotic tissue. The odor of any exudate should be recorded. Pertinent findings during physical examination should be noted and recorded. These should include: number, depth, and type of wounds; tissue edema and erythema; purulent drainage; presence of crush injury; nerve damage; tendon damage; presence of necrotic tissue; malodorous exudates; range of motion of involved joints; an evaluation of joint penetration; detailed wound diagrams; and photographs or videotapes of the involved areas of injury (1,4,7,15,25).

Cultures If possible, aerobic and anaerobic cultures should be obtained from all bite wounds. Some deep puncture wounds do not have drainage that is accessible to culture. Viral, mycobacterial, and fungal cultures should be obtained when clinical, environmental, or epidemiologic data dictate.

Radiographs If fracture or bone or joint penetration is a consideration, radiographic examination of the involved area should be obtained. These radiographs can be compared to subsequent radiographic studies in the event that osteomyelitis of the affected area is eventually suspected. More detailed radiographic testing with computerized axial tomographic scanning or magnetic resonance imaging can be indicated in complicated infections (7,13,14).

Treatment Irrigation All bite wounds should be irrigated with copious amounts (≥ 200 mL) of normal saline. If possible, puncture wounds should be irrigated with a highpressure jet using a 20-mL syringe and an 18-gauge needle or catheter tip to

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access the wound. However, some puncture wounds are tiny and relatively inaccessible to irrigation (7,13,14). Appropriate wound irrigation can produce a 6- to 10-fold reduction in bite-wound infection rates compared to bite wounds not receiving irrigation (7).

Débridement The most common error made in the treatment of bite wounds is failure to adequately débride and irrigate the wounds (7). Devitalized or necrotic tissue should be cautiously débrided and foreign bodies and all other debris should be removed fastidiously from the wound. Appropriate and adequate anesthesia should be provided to make the procedure tolerable for the patient (1,4,7,13,14). Appropriate débridement decreased bite-wound infection rates from 62% to 2% in one study (33) and by 2.5 times in another study (21).

Wound Closure Primary wound closure can be indicated for some uninfected wounds, especially facial wounds. However, closure of other types of bite wounds is not usually indicated. Wound edges should be approximated with adhesive strips in certain cases, and healing by secondary intention or by delayed closure can be indicated when infectious complications have been addressed (13,14).

Antimicrobial Therapy If a bite wound shows signs of active infection such as cellulitis, purulent drainage, or evidence of deep tissue infection, appropriate antimicrobial therapy should be administered immediately. Antibiotics should be directed against the usual intra-oral pathogens of the biting animal, the usual human cutaneous pathogens of humans, and the pertinent environmental pathogens. Antibiotic therapy should be directed against S. aureus, S. pyogenes, and the mouth microflora of dogs, cats, or humans (including alphahemolytic streptococci and many anaerobic species). Ampicillin/sulbactam can be administered intravenously for patients who are hospitalized. Other beta-lactam/beta-lactamase inhibitor compounds such as ticarcillin/clavulanic acid and piperacillin/tazobactam, or carbapenems such as imipenem, meropenem, or ertapenem (34), provide excellent broad-spectrum antimicrobial coverage of the microorganisms commonly isolated from patients with severe bite-wound infections. Amoxicillin/clavulanic acid is an excellent selection for oral therapy (14,18,35). Patients who are allergic to penicillin or other beta-lactam antibiotics can be treated with a combination of clindamycin plus a fluoroquinolone such as ciprofloxacin or levofloxacin, or with clindamycin plus trimethoprim/sulfamethoxazole. Cefoxitin can be

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administered intravenously for the treatment of bite-wound infections in patients with non–life-threatening reactions to penicillin. Moxifloxacin (36) has excellent activity against most nonfusobacterial bite-wound pathogens and seems to be an excellent single-agent treatment of most bite-wound infections. When culture results are available, antimicrobial therapy should be tailored to the most cost-effective regimen for the isolated microorganisms. Table 37-3 contains detailed information about the antimicrobial susceptibility patterns of microorganisms commonly implicated as pathogens in patients with bite-wound infection (1,6,13,14,34,36-37). The duration of antibiotic therapy depends on the severity of the infectious process. Osteomyelitis and septic arthritis generally require longer courses of antibiotic therapy than cellulitis and soft tissue infection require and can require concomitant surgical intervention. A difficult decision for the treating physician is whether to use prophylactic antibiotics for a bite wound that is not yet clinically infected. Few prospective studies evaluate this issue. Prophylactic antibiotic therapy is presumptive treatment of microbially contaminated tissue at the site of the bite wound. Prophylactic antibiotic therapy should be administered when clinical circumstances predict a high likelihood of subsequent infection after bite-wound injury. These high-risk clinical circumstances include moderate to severe injury less than 8 hours old especially if edema or crush injury are present, documentation of or high suspicion for bone or joint penetration and inoculation, any hand bite wound, any foot bite wound, any bite wound in an immunocompromised patient, any bite wound adjacent to a prosthetic joint, and any bite wound to the genital area. Amoxicillin/clavulanic acid, clindamycin plus a fluoroquinolone, clindamycin plus a tetracycline, or clindamycin plus trimethoprim/sulfamethoxazole would be reasonable oral treatment regimens in the clinical setting of a presumptively infected bite wound (1,4,7,13,14). Table 37-3 contains detailed information about antimicrobial susceptibility patterns of pathogenic microorganisms commonly encountered in infected bite wounds (13,14,34,36-37). Table 37-4 contains specific antibiotic recommendations for prophylaxis within 12 hours of the bite injury or for presumptive treatment of clinically established infection.

Immunizations A thorough history of the bite victim’s immunization status should be obtained when the patient seeks treatment. Standard tetanus immunization guidelines should be followed in all circumstances and appropriate vaccine or tetanus immune globulin should be administered as required (25). Bite wounds from domestic animals, wild animals, and humans are at risk for the development of tetanus. If information about the bite victim’s primary tetanus immunization series is inadequate, the primary immunization series should be initiated immediately, and tetanus immune globulin (TIG) should be administered concomitantly. See Table 37-1 for more information (25).

+ ± + ± − + ± − − − + + + + +

+ + + ND ND + + + ND + + + + + ±

+

± + − − − ± + ± − ± + ± ± −

+

Eikenella corrodens

+

Capnocytophaga canimorsus

+

Anaerobes

+ ± + − + + − − − + + − − +

+

+

Haemophilus species

+ + + − + ± − − − + + + + +

+

+

Pasteurella multocida

Abbreviations: ND, no data available; +, good antimicrobial activity; ±, variable antimicrobial activity; −, poor antimicrobial activity. * Does not refer to methicillin-resistant S. aureus (MRSA); for MRSA, (See Chapter 34).

Amoxicillin/ Clavulanic acid Ampicillin/ Sulbactam Azithromycin Cefoxitin Cefuroxime Cephalexin Ciprofloxacin Clarithromycin Clindamycin Dicloxacillin Erythromycin Levofloxacin Moxifloxacin Penicillin Tetracycline Trimethoprim/ Sulfamethoxazole

Antimicrobial Agents

+ + + + + + + + + + + − + +

+

+

Staphylococcus aureus*

ND ND ND + + ND + + + + + ± ND ND

+

+

Staphylococcus intermedius

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Table 37-3 Antimicrobial Agent Activity Versus Selected Bite-Wound Pathogens

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Table 37-4 Antimicrobial Therapy of Infected Bite Wounds Type of Bite

Route of Administration

Dog and Cat

Intravenous

Oral

Antibiotic Regimen

Ampicillin/Sulbactam 1. Cefoxitin 2. Ticarcillin/clavulanate 3. Piperacillin/tazobactam 4. Imipenem/cilastatin 5. Meropenem 6. Ertapenem 7. Clindamycin PLUS 8. Levofloxacin 9. Clindamycin PLUS 9. Ciprofloxacin 10. Clindamycin PLUS 10. Trimethoprim/ Sulfamethoxazole 11. Moxifloxacin 11. 1. Amoxicillin/ 1. Clavulanate 2. Clindamycin PLUS 2. Ciprofloxacin 3. Clindamycin PLUS Levofloxacin

Human

Intravenous

Oral

Dosages of Antibiotics

1. 2. 3. 4. 5. 6. 7. 8.

3.

4. Clindamycin PLUS 4. Trimethoprim/ Sulfamethoxazole 5. Clindamycin PLUS 5. Doxycycline 6. Cefuroxime axetil PLUS 6. Metronidazole 7. Moxifloxacin 7. 1. Ampicillin/Sulbactam 1. 2. Cefoxitin 2. 3. Ticarcillin/clavulanate 3. 4. Piperacillin/tazobactam 4. 5. Imipenem/cilastatin 5. 6. Meropenem 6. 7. Ertapenem 7. 8. Clindamycin PLUS 8. Ciprofloxacin 9. Clindamycin PLUS 9. Levofloxacin 10. Clindamycin PLUS 10. Trimethoprim/ Sulfamethoxazole 11. Moxifloxacin 11. 1. Amoxicillin/ 1. Clavulanate

1.5 - 3.0 g IV q6h 2.0 g IV q6h 3.1 g IV q6h 3.375 g IV q6h 500 mg IV q6h 1.0 g IV q8h 1.0 g IV q24h 600-900 mg IV q8h 500-750 mg IV q24h 600-900 mg IV q8h 400 mg IV q12h 600-900 mg IV q8h 160/800-320/1600 mg IV q8h 400 mg IV q24h 500/125 mg PO TID to 875/125 mg PO BID 300 mg PO TID or QID 500-750 mg PO BID 300 mg PO TID or QID 500-750 mg PO QD 300 mg PO TID or QID 160/800 mg PO BID or TID 300 mg PO TID or QID 100 mg PO BID 500 mg PO BID 500 mg PO TID 400 mg PO QD 1.5-3.0 g IV q6h 2.0 g IV q6h 3.1 g IV q6h 3.375 g IV q6h 500 mg IV q6h 1.0 g IV q8h 1.0 g IV q24h 600-900 mg IV q8h 400 mg IV q12h 600-900 mg IV q8h 500-750 mg IV q24h 600-900 mg IV q8h 160/800 mg IV BID or TID 400 mg IV QD 500/125 mg PO TID to 875/125 mg PO BID Continued

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Table 37-4 Continued Type of Bite

Route of Administration

Antibiotic Regimen

2. Clindamycin PLUS Ciprofloxacin 3. Clindamycin PLUS Levofloxacin 4. Clindamycin PLUS Trimethoprim/ Sulfamethoxazole 5. Moxifloxacin

Dosages of Antibiotics

2. 300 mg PO TID or QID 500-750 mg PO BID 3. 300 mg PO TID or QID 500-750 mg PO QD 4. 300 mg PO TID or QID 160/800 mg PO BID or TID 5. 400 mg PO QD

Abbreviations: BID, twice daily; h, hour; IV, intravenously; PO, orally; q, every; QD, daily; QID, 4 times daily; TID, 3 times daily.

Domestic and wild-animal bites should be investigated for the risk of rabies virus infection (25). Standard protocols and local knowledge about the presence of the rabies virus in the animal population, domestic and wild, should be used to evaluate the risk factors for rabies virus infection (25). Patients at significant risk for rabies virus exposure through the bite wound should receive human diploid cell rabies vaccine and rabies immune globulin per standard protocol (26). The recommendations of the Advisory Committee on Immunization Practices (26) and Table 37-2 contain detailed information about prevention of rabies virus infection.

Hospitalization Patients with bite wounds should be hospitalized if any of the following criteria are present: fever greater than 38.1ºC (100.5ºF); evidence of clinical sepsis; progressive cellulitis; septic arthritis; osteomyelitis; failure of previous outpatient management; immunocompromised status of the patient; infection that has spread across a joint; hand or foot infection; severe crush injury; tendon or nerve injury; tenosynovitis; and patient noncompliance with therapy (1,7,13,14).

Consultation Appropriate consultation to general surgery, orthopedic surgery, hand surgery, plastic surgery, infectious disease medicine, rehabilitative medicine, and other appropriate services in the care of patients with bite wounds should be initiated as dictated by the severity and nature of the bite-wound injuries (7,20).

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Elevation and Immobilization Elevation of the involved extremity alleviates edema and prevents the spread of infection in the immediate proximity to the bite-wound site (13,14,20). Failure of the patient to appropriately elevate the involved extremity is a common cause of treatment failure in patients with bite wounds. Bite wounds to the hand should be immobilized with a splint that allows the patient’s hand to remain in the functional position (13,14,17).

Reporting Local government regulations can require reporting bite wounds to the health department. In the absence of local reporting requirements, appropriate consultation with the local health department can be necessary to ascertain the likelihood of rabies virus transmission by domestic and wild animal species in the area (7,13,14).

Follow-Up The appropriate management of bite wounds on an outpatient basis requires follow-up 24 and possibly 48 hours after initial evaluation. During the follow-up visit, the patient should be fully evaluated for infectious and noninfectious complications of the original injury and for side effects of antibiotics or other medications prescribed during the initial visit (3,16).

Surgical Management Surgical intervention often is required during the management of patients with bite-wound infection. Irrigation and débridement of the bite wound should be part of the standard management protocol when the patient initially seeks medical care. Further surgical treatment can be required for therapeutic evacuation of purulent drainage, for therapeutic relief of tissue tension, for decompression to abort peripheral nerve injury and neuropathy, and for the diagnostic recovery of microorganisms from the site of a closed-space infection such as septic arthritis, osteomyelitis, or tenosynovitis. Other indications for surgery include repair of vascular, muscular, or neurologic tissue and cosmetic repair of disfiguring skin and soft tissue injuries (4,13,14,19).

Common Perils and Pitfalls of Bite-Wound Management The most common error in the management of bite wounds is the failure to adequately irrigate and débride the wound. Other common mistakes include failure to dress the wound with bulky dressings, failure to elevate the extremity for 24 to 48 hours, failure to recognize a clenched-fist injury as a human-bite wound, failure to recognize wounds to the genitalia as

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human-bite wounds, failure to obtain appropriate cultures during the initial evaluation of the patient, and failure to recognize wounds that are unresponsive to oral antimicrobial therapy (7). Other causes of therapeutic failure in the treatment of animal and human-bite wounds include incorrect selection of antimicrobial agents, insufficient duration of antimicrobial therapy, inappropriately low antimicrobial dosage, antibiotic-resistant microbial isolates, and failure to recognize the presence of abscess, osteomyelitis or pyarthrosis (13,14,20).

Medical-Legal Considerations Many states require that animal bites be reported to public health authorities (13,14). Because animal bites often result in civil litigation against the owner of the biting animal, it is prudent to thoroughly document all injuries and all diagnostic and therapeutic regimens. Although detailed diagrams and drawings are certainly appropriate, photographs or videotapes are extremely useful adjuncts to the initial evaluation of and follow-up documentation of bite-wound injuries (2-4,7,13,14,20). Photographs and videotapes provide graphic documentation of the exact nature of the injuries and can help clarify issues about the extent and severity of injury should litigation eventually ensue. The medical-legal ramifications of disease transmission by a human bite are extremely complex and only sparsely addressed in the legal literature (7).

Summary Bite-wound injuries and infections are common. Dog, cat, and human bites are the bite wounds most frequently encountered in clinical practice. Bitewound injuries are underreported and some, especially human bites (7), are actively concealed. The cornerstones of bite-wound management include scrupulous irrigation and débridement with surgical care appropriate to the individual case. Antimicrobial therapy should be administered in cases of active infection. In cases in which there is no evidence of clinical infection, broad-spectrum empiric antimicrobial therapy is frequently appropriate as prophylactic treatment when the likelihood of infection is high. Immunization for tetanus and rabies virus should be provided as required by standard CDC protocols (25,26). Special circumstances, such as monkey bites, and human bites from individuals known to be infected with HIV, can dictate the initiation of specialized evaluation and treatment protocols (27,38). There must be a detailed assessment of bite-wound complications in all patients who have sustained a bite injury. Judicious and expedient follow-up is essential for optimal clinical outcome after bite injury.

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REFERENCES 1. Goldstein E J,Talan DA. Bite wounds. In: Hoeprich PD, Jordan MC, eds. Infectious Diseases, A Treatise of Infectious Processes. Philadelphia: JB Lippincott; 1994; 1420-3. 2. McDonough J J, Stern P J,Alexander J W. Management of animal and human bites and resulting human infections. Curr Clin Top Infect Dis. 1987;8:11-36. 3. Wahl RP, Eggleston J, Edlich R. Puncture wounds and animal bites. 4th ed. In: Tintinalli JE, Krome RL, eds. Emergency Medicine. A Comprehensive Study Guide. New York: McGraw-Hill; 1996:317-22. 4. Weber D J, Hansen AR. Infections resulting from animal bites. Infect Dis Clin North Am. 1991;5:663-80. 5. Weiss HB, Friedman DI, Coben JH. Incidence of dog bite injuries treated in emergency departments. JAMA. 1998;279:51-3. 6. Bowman M JA. Animal bites in infants and children: An approach to diagnosis and treatment. Pediatr Emerg Med Rep. 1999;4:53-62. 7. Newton E. Mammalian bites. In: Schwartz GR, Roth PB, Cohen JS, eds. Principles and Practice of Emergency Medicine. Philadelphia: Lea & Febiger; 1992:2750-61. 8. Goldstein EJ, Richwald GA. Human and animal bite wounds. Am Fam Physician. 1987;36:101-9. 9. Chretien JH, Garagusi VF. Infections associated with pets. Am Fam Physician. 1990;41:831-45. 10. Plaut M, Zimmerman EM, Goldstein RA. Health hazards to humans associated with domestic pets. Ann Rev Public Health. 1996;17:221-45. 11. Tan JS. Human zoonotic infections transmitted by dogs and cats. Arch Intern Med. 1997;157:1933-43. 12. Weber DJ, Weinberg AN. Animal-associated human infections. Infect Dis Clin North Am. 1991;5:1-181. 13. Goldstein E J. Bites. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. New York: Churchill Livingstone; 1995:2765-9. 14. Goldstein E J, Bites. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone; 2000:3202-6. 15. Dire DJ. Cat bite wounds: Risk factors for infection. Ann Emerg Med. 1991;20:973-9. 16. Moran G J,Talan DA. Hand infections. Emerg Med Clin Norh Am. 1993;11:601-19. 17. McGrath MH. Infections of the hand. In: May MJG, Littler JW, eds. Plastic Surgery. Philadelphia: WB Saunders: 1990;5529-56. 18. Brook I. Human and animal bite infections. J Fam Pract. 1989;28:713-8. 19. Chambers GH, Payne JF. Treatment of dog bite wounds. Minn Med. 1969;52:427-30. 20. Goldstein E J. Human and animal bites. In: Schlossberg D, ed. Current Therapy of Infectious Disease. St. Louis: Mosby; 1996:66-8. 21. Callaham ML. Treatment of common dog bites: Infection risk factors. JACEP. 1978;7:83-7. 22. Talan DA, et al. Bacteriologic analysis of infected dog and cat bites. N Engl Med J. 1999;340(2):85-92. 23. Talan DA. Staphylococcus intermedius: Clinical presentation of a new human dog bite pathogen. Ann Emerg Med. 1989;18:427-30. 24. Goldstein E J. Simian bites and bacterial infection. Clin Infect Dis. 1995;20:1551-2. 25. Immunization Practices Advisory Committee (ACIP). Diphtheria, tetanus, and pertussis: Recommendations for vaccine use and other preventive measures: Recommendations of the Immunization Practices Advisory Committee. MMWR Recomm Rep. 1991;40(RR-10):1-28. 26. Immunization Practices Advisory Committee (ACIP). Human rabies prevention—United States 1999. MMWR Recomm Rep. 1999;48(RR-1):1-21. 27. Holmes GP, Chapman LE, Stewart JA. Guidelines for prevention and treatment of B-virus infections in exposed persons. Clin Infect Dis. 1995;20:421-39. 28. Baker AS, Ruoff KL, Madoff S. Isolation of Mycoplasma species from a patient with seal finger. Clin Infect Dis. 1998;27:1168-70. 29. HIV transmission by a human bite. Infect Control Hosp Epidemiol. 1996;17:707. 30. Andreo SM, Barra LA, Costa L J, Sucupira MC, Souza IE, Diaz RS. HIV type 1 transmission by human bite. AIDS Res Hum Retroviruses. 2004;20:349-50. 31. Vidmar L, Poljak M,Tomazic J, Seme K, Klavs I. Transmission of HIV-1 by human bite [Letter]. Lancet. 1996;347:1762. 32. Edlich RF, Spengler MD, Rodeheaver GT. Mammalian bites. Compr Ther. 1983;9:41-7. 33. Callaham M. Prophylactic antibiotics in common dog bite wounds: a controlled study. Ann Emerg Med. 1980;9:410-4.

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34. Goldstein E J, Citron DM, Merriam CV, Warren YA,Tyrrell K, Fernandez H. Comparative in vitro activity of ertapenem and 11 other antimicrobial agents against aerobic and anaerobic pathogens isolated from skin and soft tissue animal and human bite wound infections. J Antimicrob Chemother. 2001;48:641-51. 35. Goldstein E J, Reinhardt JR, Murray PM. Animal and human bite wounds, a comparative study: Augmentin vs. a penicillin + dicloxacillin. Postgrad Med J. 1984;60(suppl):105-10. 36. Goldstein E J, Citron DM, Hudspeth M, Hunt Gerardo S, Merriam CV. In vitro activity of Bay 128039, a new 8-methoxyquinolone, compared to the activities of 11 other oral antimicrobial agents against 390 aerobic and anaerobic bacteria isolated from human and animal bite wound skin and soft tissue infections in humans. Antimicrob Agents Chemother. 1997;41:1552-7. 37. Goldstein E J. Animal bite infections. In: Stevens DL, ed. Skin, Soft Tissue, Bone, Joint Infections. Philadelphia: Churchill Livingstone; 1995:4.1-16. 38. Centers for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV in the United States: Recommendations from the US Department of Health and Human Services. MMWR Recomm Rep. 2005;54(RR-2):1-20.

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Chapter 38

Viral Exanthems BLAISE L. CONGENI, MD

Key Learning Points 1. The diagnosis of a specific viral exanthem can usually be made by carefully considering the epidemiology as well as the characteristics of the rash. 2. Establishing the diagnosis may be crucial in order that complications might be recognized and appropriately treated as in the case of rubeola, mononucleosis or varicella. 3. Certain of these exanthems can be prevented following exposure with appropriate use of active or passive immunization as in the case of rubeola, varicella and possibly rubella. 4. Infection with these viruses may be particularly hazardous for the pregnant woman, as in the case of rubella, erythema infectiousum, varicella or enterovirus.

A

combination vaccine has recently been released that combines the antigens of measles-mumps-rubella (MMR) with Varivax, the antigen of varicella zoster virus (VZV). This vaccine enables the physician to immunize for these 4 diseases with a single injection. Coverage rates for MMR has consistently been greater than 90% in the United States. All states in the United States currently have a school-entry requirement for measles immunization. It is hoped that the new combination vaccine will improve coverage for the varicella component. High coverage rates for immunization against measles, mumps, and rubella have been achieved in the United States. This has led to complete eradication of both rubella and congenital rubella syndrome in the United States. Health officials can now turn their efforts to achieving eradication on a 699

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New Developments in the Management of Viral Exanthems ●

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A combination vaccine has recently been released which combines the antigens of MMR-V, measles, mumps and rubella, with Varivax, the antigen of varicella zoster virus. This vaccine will enable the physician to immunize for these four diseases with a single injection. Coverage rates for MMR has consistently been greater than 90% in the U.S. All states in the U.S. currently have a school-entry requirement for measles immunization. It is hoped that the new combination vaccine will improve coverage for the varicella component. High coverage rates for immunization against measles, mumps and rubella have been achieved in the U.S. This has led to complete eradication of both rubella and congenital rubella syndrome in the U.S. Health officials can now turn their efforts to achieving eradication on a global basis. Immunization of children from households with pregnant women does not pose a risk. Rubella vaccine or MMR should not be administered to women who are pregnant or become pregnant within 28 days. Arthralgia and transient arthritis are more common in post-pubertal susceptible recipients of the vaccine than pre-pubertal recipients. It is important to note that joint manifestations are more common following natural disease than active immunization. Pregnancy is also a contraindication for active immunization with the varicella vaccine or the combination ProQuad vaccine, MMR-V. While most primary infections with HHV-7 are mild or asymptomatic, some may present as roseola. This then could result in a second or recurrent case of roseola. Increasingly, outbreaks of varicella have been reported. Some of the patients reported in these outbreaks are vaccinated children. Breakthrough disease also occurs as a significant proportion of all cases currently seen in the U.S. given the sharp decline in wild type disease. Breakthrough disease is generally milder, shorter in duration, with 2-5 days of fever, and these children have fewer lesions, less than 50, which are more often described as papular. Administration of a second dose of Varivax is apparently more efficacious in preventing disease and providing durable immunity. A recommendation for universal use of a second dose of varicella vaccine has recently been made by the Advisory Committee on Immunization Practice of the CDC. This second dose is to be administered at age 4-6 years. Zoster (shingles) remains a common and debilitating problem especially seen in the elderly. The varicella vaccine has been reformulated into a zoster vaccine, Zostavax®. This vaccine containes substantially more plaque-forming units of virus than the vaccine used to immunize. VZIG will no longer be produced. For patients needing passive protection following exposure to varicella, Immune Serum Globulin (ISG) is now recommended.

global basis. Immunization of children from households with pregnant women does not pose a risk. Neither rubella vaccine nor MMR should be administered to women who are pregnant or may become pregnant within 28 days. Arthralgia and transient arthritis are more common in postpubertal susceptible recipients of the vaccine than prepubertal recipients. It is important to note that joint manifestations are more common after natural disease than active immunization. Pregnancy is also a contraindication for active immunization with the varicella vaccine or the combination ProQuad vaccine, MMR-V.

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Although most primary infections with HHV-7 are mild or asymptomatic, some may present as roseola. This then could result in a second or recurrent case of roseola. Increasing numbers of varicella outbreaks have been reported. Some patients reported in these outbreaks are vaccinated children. Breakthrough disease also occurs as a significant proportion of all cases currently seen in the United States given the sharp decline in wild type disease. Breakthrough disease is generally milder, shorter in duration, and with 2 to 5 days of fever; these children have fewer lesions, less than 50, which are more often described as papular. Administration of a second dose of Varivax is apparently more efficacious in preventing disease and providing durable immunity. A recommendation for universal use of a second dose of varicella vaccine has recently been made by the Advisory Committee on Immunization Practice of the Centers for Disease Control and Prevention. This second dose is to be administered at age 4 to 6 years. Zoster (shingles) remains a common and debilitating problem especially seen in the elderly. The varicella vaccine has been reformulated into a zoster vaccine, Zostavax. This vaccine contains substantially more plaque-forming units of virus than the vaccine used to immunize. Varicella-zoster immune globulin (VZIG) will no longer be produced. For patients needing passive protection after exposure to varicella, Immune Serum Globulin (ISG) is now recommended. Because the skin is the largest of the body’s organs, it is not surprising that skin involvement is seen in the course of various infectious diseases. This is especially the case for viral infections. An exanthem, eruption, or rash may be the only manifestation of an infection and the only reason that a patient may seek medical care. Furthermore, frequently the physician is able to arrive at a diagnosis from the dermatologic manifestation of an infection purely on clinical grounds. By paying careful attention to the characteristics of the exanthem, the physician can at least develop a differential diagnosis (before laboratory results are available). Common viral exanthems are listed in Table 38-1.

Table 38-1 Viral Exanthems Disease

Common Name

Etiologic Agent

Rubeola Rubella Mononucleosis Exanthem subitum Erythema infectiosum Varicella Boston exanthem

Measles German measles Mononucleosis Roseola Fifth disease Chicken pox Roseola Petechiae

Morbillivirus Rubella virus EBV, CMV HHV-6, HHV-7 Parvovirus B-19 Varicella–zoster virus Echovirus 16, 25 Coxsackie; A49; B2-4; echovirus 4,7,9 Coxsackie, echovirus, enterovirus

Hand–foot–mouth disease

CMV = cytomegalovirus; EBV = Epstein–Barr virus; HHV = human herpesvirus.

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Measles (Rubeola) Measles was one of the earliest viral exanthems to be recognized. An accurate diagnosis of this disease can be made on the basis of the rash and associated symptomatology alone. Traditionally, measles has been distinguished from another childhood disease called rubella, or German measles. Both derive their name from the Latin ruber, meaning red or reddish. Generally, immunization for both diseases is given simultaneously; however, the significance of both infections is quite different. Measles causes significant illness and even occasional death through its complications; in the prevaccine era, measles killed more people than did polio. In the prevaccine era, virtually all children became infected with the measles virus. After widespread immunization became available in 1963, the incidence of measles steadily declined until 1983 (1). The number of reported cases then steadily increased, and many outbreaks occurred in school children and college students (2). Approximately one half of these cases occurred in unvaccinated preschool children and the other half in previously vaccinated students between the ages of 5 and 24 years (3). For this reason, a two-dose vaccination strategy was adopted in the early 1990s, and subsequently the incidence of measles has been very low (4).

Etiology Measles virus (Morbillivirus) is a member of the Paramyxovirus family. Other members of this family include respiratory syncytial virus, parainfluenza virus, influenza virus, and mumps virus. The measles virus contains a single-stranded ribonucleic acid (RNA) genome with a lipid envelope. The hemagglutinin of the virus is a surface protein that facilitates its attachment to cells. In contrast with the influenza virus, the measles virion lacks a neuraminidase. Only one antigenic type of the virus exists, and, because humans are the only hosts, measles seems to be an excellent candidate for worldwide eradication after universal immunization.

Clinical Manifestations Measles is a highly contagious infection, with approximately 90% of susceptible exposed individuals becoming infected. In contrast to most viral infections, subclinical disease seems to occur infrequently in measles virus infection. After an incubation period of 8 to 12 days, the individual exposed to the measles virus develops symptoms of a common cold. This prodrome lasts 2 to 4 days, with fever, cough, conjunctivitis, photophobia, and coryza being prominent. A faint scarlatinal rash that quickly fades may then be seen. Then Koplik spots, which are pathognomonic for measles and look like small grains of sand on an erythematous base, appear on the buccal

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mucosa. The Koplik spots disappear within 12 to 18 hours, and the characteristic exanthem of measles appears within 1 to 2 days thereafter. This rash is first noted on the face, neck, and behind the ears, later spreading down the body. It may start as a macular rash, becoming maculopapular and then finally coalescing, especially on the trunk. Within 2 to 3 days the rash begins to fade and takes on a darker color, which is when desquamation may occur. Additionally, the rash can have a hemorrhagic appearance. Complications of measles (e.g., otitis media, pneumonia) are primarily secondary to bacterial infection. However, pneumonia may be caused by the measles virus itself. Encephalitis is the most feared complication of measles, occurring in 1 to 2 cases per 1000, with a death rate as high as 10% and a substantial number of survivors suffering sequelae.

Atypical Measles Children who received the killed measles vaccine between 1963 and 1968 and who later either received live vaccine or were exposed naturally to measles virus frequently developed atypical measles (5). The clinical disease seen in these children was more severe than what is usually seen, and approximately three fourths of them required hospitalization. Koplik spots were notably absent, and the rash developed after a fever of abrupt onset. Prodromal symptoms were less conspicuous than the typical manifestation. The exanthem was noted to include papules and vesicles and was seen to start distally, in contrast with typical measles. Additionally, peripheral edema, cough, and pulmonary complications were noted more commonly.

Diagnosis The diagnosis of measles is usually made on clinical grounds alone. A history of exposure, presence of prodromal symptoms (e.g., cough, conjunctivitis, coryza, Koplik spots), and typical rash are sufficient to make the diagnosis. Symptoms in previously vaccinated patients may be mild. Cultivating the measles virus from nasopharyngeal secretions, conjunctiva, blood, or urine is seldom done. Serology is used more often to confirm the diagnosis in suspected cases. The presence of immunoglobulin M (IgM) antibody or a 4-fold increase in acute and convalescent antibody titers also confirms the diagnosis. The serologic tests generally used for measles are complement fixation, hemagglutination inhibition, or enzyme immunoassay. Neutralization assays are less likely to be available and are more difficult to do.

Treatment The treatment of measles is primarily supportive. Appropriate antibiotic therapy is indicated for any of the bacterial complications that may occur,

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such as otitis media or pneumonia. Low serum concentrations of vitamin A have been associated with severe measles. Consequently, vitamin A therapy should be considered for children diagnosed as having measles under the following circumstances: ● ● ●

Children from countries associated with vitamin A deficiency Children 6 to 12 months of age hospitalized with measles Children older than 12 months of age with the risk factors of immunodeficiency, ophthalmologic evidence of vitamin A deficiency, incomplete intestinal absorption of vitamin A, moderate to severe malnutrition, or recent immigration from countries known to have high measles-related death rates

Measles is susceptible to ribavirin in vitro. Controlled studies that have documented a clinical benefit of ribavirin in immunosuppressed or other patients are unavailable.

Prevention Since the mid-1960s, the prevention of measles has been accomplished with a live measles virus vaccine. Several significant changes have occurred since 1963 about the recommendations for the initiation of measles immunization. Currently, it is recommended that all children receive measles vaccine after their first birthday unless there are contraindications. Usually, the first dose is given as a part of the standard MMR at the age of 12 to 15 months (6). A second dose of measles vaccine is given on entry into school at an age of 4 to 6 years, but this dose can be given as early as 1 month after the initial dose. All children should have their immunization records reviewed at 11 to 12 years of age.

Rubella The rash and clinical features of rubella were initially described early in the 19th century. The importance of diagnosing rubella was thought to derive primarily from the ability to distinguish it from rubeola (measles) and scarlet fever, 2 illnesses known to be associated with significant illness. The notion that rubella was a trivial disease continued until 1941, when Australian ophthalmologist Norman Gregg noticed congenital cataracts in 58 infants in association with maternal rubella early in pregnancy (7). Congenital heart disease and failure to thrive also were seen in many of these infants. Within a few years, it became apparent that microcephaly, deafness, and mental retardation were a part of the congenital rubella syndrome as well. Throughout the first half of the 20th century, rubella was noted to occur in epidemics in 7- to 10-year cycles. The last major epidemic in the United

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States occurred in 1964 and resulted in 20,000 infants born with congenital defects and perhaps as many fetal deaths (8,9). The first of many live vaccines for rubella was introduced in 1969, and its widespread use was achieved within a year (10). Since then, the number of cases of congenital rubella syndrome has declined steadily.

Etiology The rubella virus is a member of the togavirus family and is the only member of the Rubivirus genus. It is an enveloped, spherical virion that measures 60 nm in diameter and has a single-stranded RNA genome. There is only one serotype. Humans are usually the only natural hosts of the virus, but other species have been infected, including monkeys and ferrets.

Clinical Manifestations In most patients with rubella, clinical disease is mild or unapparent. Patients with clinically recognizable disease are noted to have a mild prodrome of malaise and low-grade fever after an incubation period of 14 to 21 days. Swelling of lymph nodes in the suboccipital and postauricular region is then noted, which may be followed by mild, transient conjunctivitis. The lymph nodes remain swollen. Within a few days, a rash—most often described as a fine, discrete, maculopapular eruption starting on the face and trunk—is noted. By the second day, the rash spreads to involve the arms and trunk and then may become confluent. In another day, the rash begins to fade. Within 3 to 4 days of its onset, the rash is gone. As in children, adults with rubella often have clinically unapparent disease. At times, however, the disease in adults may be more severe and prolonged, especially in women in whom rubella may be associated with polyarthralgia or even arthritis. Complications are rare but include encephalitis or thrombocytopenia.

Diagnosis As with measles, the diagnosis of rubella is almost always based on clinical grounds alone. Although rubella virus can be cultured from the throat, blood, urine, cerebrospinal fluid, and cataracts, most clinicians rely on serology to confirm the diagnosis when confirmation is necessary (11). Growing the virus in tissue cultures is time consuming and not done routinely, but it is generally available by special request. Rubella virus grows well in various primary and continuous cell lines, including monkey kidney cells. This has no cytopathic effect, but after several days the culture is challenged with a picornavirus and inhibition of growth is seen.

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Traditionally, the hemagglutination inhibition antibody test has been used for serologic testing for rubella; however, more recently, various other assays have replaced this test in most clinical laboratories. These newer tests include passive hemagglutination, latex agglutination, fluorescent immunoassay, and enzyme immunoassay. A 4-fold increase in titer or a positive rubella-specific IgM-antibody test is needed to confirm the diagnosis.

Treatment and Prevention Treatment of rubella is supportive, and specific antiviral chemotherapy is unavailable. Rubella immunization is now accomplished with a live vaccine in a 2 dose regimen. The vaccine is given as a part of the standard measles, mumps, and rubella vaccine. Generally, the first dose is administered at 12 to 15 months of age and the second dose at 4 to 6 years of age. Primary vaccine failures have not been a significant problem with the rubella vaccine, but the addition of a second dose has added a measure of safety. Because the primary target population for immunization against rubella consists of women of childbearing age, the immunization of susceptible postpubertal individuals (e.g., college students, military recruits, health care workers) remains a priority. Contraindications to immunization with the live rubella virus vaccine include pregnancy, immunodeficiency, and having received intravenous gammaglobulin or blood products within the previous 3 to 4 months, depending on the dose of gammaglobulin. The care of an individual with rubella, especially a pregnant woman, primarily involves confirming the diagnosis. If serologic testing indicates that the exposed individual is susceptible to rubella, a second serum specimen should be examined in 3 to 4 weeks to check for seroconversion. Vaccination after exposure to rubella has not clearly been demonstrated to prevent infection, and the administration of immune serum globulin after exposure generally is not recommended. However, administration of vaccine within 3 days of exposure could theoretically prevent infection and therefore immunization of nonpregnant susceptible individuals should be considered. Studies have suggested that immune serum globulin may modify or attenuate the course of disease but that it does not necessarily prevent viremia or fetal infection.

Infectious Mononucleosis Infectious mononucleosis (IM) is an illness characterized by fever, pharyngitis, and adenopathy. The 20th century saw the gradual emergence of the association of IM with atypical lymphocytes, heterophilic antibodies, and the Epstein-Barr virus (EBV).

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Infections with EBV occur commonly during childhood; however, primary infection in children is usually either mild or asymptomatic (12,13). Consequently, 50% of college freshmen in the United States already have antibodies to EBV. Approximately 10% to 20% of the susceptible population are expected to seroconvert every year during college. Most of these infections, however, tend to be asymptomatic (14).

Etiology Epstein-Barr virus is the responsible agent in approximately 90% of patients who present with typical IM. Cytomegalovirus (CMV) infection is responsible for most of the remaining patients. Both closely related viruses are members of the herpes family. The virion of EBV is 110 nm in diameter and has a genome of double-stranded deoxyribonucleic acid (DNA). EBV infects cells of the lymphoreticular system exclusively.

Clinical Manifestations The onset of IM is often heralded by constitutional reports, including headache, chills, myalgia, and cough, followed within a week by sore throat and dysphagia. Sweats associated with fever are common. These symptoms frequently last 7 to 10 days and are followed by malaise, fatigue, and anorexia that persist from several days to weeks (Table 38-2). Between 83% and 100% of IM patients have abnormal liver function studies, but the serum bilirubin level is invariably below 5 mg/dL. Thirty percent of these patients have an associated positive throat culture for group A streptococci. Skin manifestations occur in approximately 3% to 10% of IM cases (15,16). In most patients a macular or maculopapular or morbilliform rash is seen, which generally involves the trunk but also may involve the extremities and palms and soles. Occasionally, this rash has been described as petechial, erythema multiforme, or even papulovesicular or urticarial (17,18).

Table 38-2 Clinical Features of Infectious Mononucleosis Symptoms

Frequency

Adenopathy Malaise and fatigue Sweats Anorexia Nausea Chills Fever Pharyngitis Splenomegaly

100% 90%–100% 80%–95% 50%–80% 50%–70% 40%–60% 80%–95% 65%–85% 50%–60%

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Because IM patients often have a sore throat and a positive throat culture for group A streptococci, antibiotics are commonly prescribed. Patients who are treated with antibiotics are much more likely to develop a rash, and 69% to 100% of patients who receive ampicillin and 14% of those treated with either penicillin or tetracycline have been noted to develop a rash (15). One fourth of patients also have an enanthem, which is most often described as palatal petechiae. Various complications can be seen with IM (Table 38-3); other clinical manifestations of IM may not be obvious, and patients may lack heterophilic antibodies (19). Generally, patients with IM caused by CMV who are negative for heterophilic antibodies are slightly older than those with IM caused by EBV. Additionally, pharyngitis and adenopathy are often not as striking, and a rash also may be a part of this syndrome. Often, primary infection with perinatally acquired CMV also is associated with an erythematous and maculopapular rash. However, the rash of congenital CMV acquired in utero is most often petechial and a consequence of thrombocytopenia.

Diagnosis Physicians frequently arrive at a tentative diagnosis of IM on the basis of fever, marked adenopathy, pharyngitis, and splenomegaly. Confirming a diagnosis of IM rests primarily on serologic methods. EBV culture is technically difficult and not generally available. The presence of atypical lymphocytosis often can be helpful, especially in children younger than 5 years of age, who often lack heterophilic antibodies (18). The presence of heterophilic antibodies is documented with the Paul-Bunnell test or the slide agglutination (monospot) test. Although these tests are not very sensitive in children younger than 5 years of age, their sensitivity approaches 90% in older children and adults (20). Various specific serologic tests are available to document EBV infection. Tests for both IgG and IgM antibody to the viral capsid antigen are readily available. The presence of IgM antibody suggests an acute, recent infection. Antibody to early antigen also suggests an acute or recent infection and

Table 38-3 Complications of Infectious Mononucleosis Neurological Guillain–Barré seizures Meningoencephalitis Peripheral neuritis Bell’s palsy Hematologic Hemolytic anemia Thrombocytopenia Aplastic anemia

Liver Necrosis Cirrhosis Cardiac Myocarditis Pericarditis Spleen Splenic rupture

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may be helpful in the diagnosis. Occasionally, antibody to EBV nuclear antigen can be identified in a patient whose other antibody test results are confusing relative to the time of infection occurrence. Because antibody to EBV nuclear antigen develops at a late stage and is not present during an acute infection, its absence is consistent with other serologic findings that indicate acute infection. This specific EBV test should be done only when the monospot test is negative. Patients who present with IM in the absence of serologic evidence for EBV infection may be infected with CMV. CMV can be cultured readily from the throat and from urine. Serologic methods are used less often to confirm infection with CMV than they are with EBV.

Treatment and Prevention The treatment of IM is primarily supportive. Antiviral chemotherapy for EBV is ineffective. Steroids are probably used more often than indicated. In severe IM caused by EBV, the use of steroids shortens the duration of fever (21). Additional indications for steroid use include impending airway obstruction, hemolytic anemia, and thrombocytopenia. Possible indications for steroids include neurological complications of IM, pericarditis, and myocarditis. Neither active nor passive immunization is currently available to prevent EBV-associated IM.

Roseola (Exanthem Subitum) Roseola is a common pediatric exanthematous illness that occurs in children between the ages of 3 months and 3 years. It has often been overdiagnosed by physicians who care for children, many of whom typically assign this diagnosis to any child with an acute febrile illness who develops a rash after defervescence. Subsequent to the identification of the causative agent-human herpesvirus 6 (HHV-6), a better understanding of the clinical disease has emerged (22). Primary infection has been reported occasionally in adults who presented either with hepatitis or mononucleosis syndrome. Infection also has been reported in immunocompromised patients (e.g., transplant recipients, HIV-infected individuals, patients with malignancy). The role of HHV-6 in the manifestations of the diseases seen in these patients is often unclear. Few children escape infection with HHV-6 during the first 2 years of life (23,24). Acquisition of antibody to the virus occurs at an age earlier than with either CMV or EBV. Within the first 6 months of life, the titer of maternal antibody to HHV-6 decreases, and the illness caused by the virus becomes common. By the age of 2 years, few children have had recognizable disease, yet virtually all of them have acquired antibody to HHV-6.

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Etiology As with other members of the herpesvirus family, HHV-6 is enveloped, has a double-stranded DNA genome, and demonstrates tropism to T lymphocytes, especially activated CD4 cells. Two serogroups of the virus (A and B) have been identified.

Clinical Manifestations Primary infection with HHV-6 is a major cause of undifferentiated febrile illness in children younger than 2 years of age. In a recent study, 14% of acutely ill febrile children younger than 2 years of age who presented to an emergency room had documented HHV-6 infection (23). Although a wide variety of clinical manifestations were seen, rash was present in only 18% of the patients. Fever in excess of 40ºC, malaise, irritability, inflamed tympanic membranes, and nasal congestion were seen in most patients. However, febrile seizures occurred in only 1 of 34 (3%) patients. The average leukocyte count was lower in HHV-6-infected patients than in control individuals. An exanthem was noted in only 18% of the patients in the study described previously; it most often involved the face and trunk and was defined as macular or maculopapular (23). In slightly more than half of patients with the rash it was noted to have appeared after fever had abated. Therefore, it seems that the characteristic rash of roseola occurs infrequently in HHV-6–infected patients and even less often after the fever has disappeared. Infection with HHV-7, a closely related virus, is also universal but generally occurs slightly later than does infection with HHV-6. Primary infection with HHV-7 is believed to result in an acute, undifferentiated, febrile illness that occasionally is accompanied by a rash similar to that seen with HHV-6.

Diagnosis Confirmation of roseola is not readily available. A reduction in the total leucocyte count, especially the presence of lymphocytosis in a child who presents with a typical clinical picture, is helpful in suggesting the diagnosis. Growth in tissue culture of HHV-6 remains investigational. Various serologic assays are available for identifying HHV-6 infection, including an indirect immunofluorescent antibody assay and enzyme immunoassay. The presence of maternal antibody, viral reactivation, and cross-reacting antibody occasionally may make serologic results difficult to interpret.

Treatment and Prevention Treatment of roseola remains supportive, and neither passive nor active immunization is available.

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Erythema Infectiosum (Fifth Disease) For more than 100 years, physicians have recognized a distinct syndrome named erythema infectiosum (EI) and have endeavored to distinguish it from rubella. At around the turn of the 20th century, 6 common childhood exanthems were described in detail and numbered. EI was the fifth such disease described and thus received its common name, Fifth disease. In 1975, investigators identified a virus designated parvovirus (B19), which in 1983 was identified as the cause of EI (25,26).

Etiology Parvovirus B19, a member of the Parvoviridae family, is a small (20-25 nm in diameter) enveloped virus. A recent study has demonstrated 5 separate genotypes of B19, but no clinical significance has been attached to this finding.

Clinical Manifestations Erythema infectiosum is seen most commonly in children aged 5 to 15 years. Ten percent of cases occur in children younger than 5 years of age, and 20% occur in adults (26a). Because approximately half of all adults have antibody to parvovirus B19 and because few recall having had characteristic disease, it can be assumed that a substantial proportion of primary cases of EI are asymptomatic (26a). Two studies of EI found that 17% to 25% of infections were asymptomatic (25,26b). The incubation period of EI is 4 to 14 days. Approximately half of patients with the disease experience mild prodromal symptoms including malaise, sore throat, coryza, and low-grade fever. A characteristic rash then appears on the cheeks. The cheeks seem erythematous and warm, with an associated circumoral pallor. In the second phase of the illness, the rash spreads to the extremities and is usually morbilliform, annular with central clearing, or reticular. The rash is less likely to involve the trunk, palms, or soles. In this phase of the illness, the rash occasionally is described as petechial or purpuric. In the final phase of the illness, which may last for several weeks, the rash remits and recurs with stress, exercise, or bathing. Associated symptoms in patients with EI vary, but most children feel well. Various other symptoms have been described and include coryza, vomiting, diarrhea, adenopathy, conjunctivitis, and arthritis. Arthralgia, arthritis, and myalgia are seen occasionally in children with EI, but these symptoms occur in half of all infected adults. The role of parvovirus B19 in causing disease in other hosts is summarized in Table 38-4.

Diagnosis The demonstration of parvovirus B19 by culture or polymerase chain reaction remains investigational. Confirmation of infection or documentation of

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Table 38-4 Associated Clinical Syndromes in Parvovirus Infection Host

Syndrome

Chronic hemolytic anemia Pregnancy Immunodeficiency Adults Children

Transient aplastic anemia Spontaneous abortion Chronic anemia Arthritis Encephalitis, Henoch–Schönlein purpura, pneumonitis

immunity rests on serologic methods. Assays for serum IgG and IgM antibodies to the virus are available.

Treatment and Prevention No specific antiviral chemotherapy or vaccine is currently available for EI. Exposure of women of childbearing age to EI is a problem that is encountered not infrequently in clinical practice. Approximately half of all adults are already immune, and immune status can be evaluated in the exposed individual. From 30% to 50% of susceptible exposed individuals become infected, and the risk of fetal death in a pregnant woman (even with primary infection) is approximately 10%. On the basis of these figures, an exposed, susceptible pregnant woman can anticipate an upper-limit risk of fetal death of 1.5% to 2.5% (27). On the basis of currently available information and of the difficulty in obtaining serologic data for EI, it does not seem reasonable to recommend the screening of all pregnant women for susceptibility to the disease. Certain teachers and day care personnel have an increased risk of acquiring EI (28), and physicians must deal with issues of occupational exposure on an individual basis (29).

Varicella and Zoster (Chicken Pox and Shingles) Chicken pox (varicella) is a vesicular exanthematous illness that few children escape unless they are vaccinated against it. Asymptomatic disease occurs rarely, if ever (30), and repeated infection is documented rarely in a normal host. Ninety-five percent of adults are immune to varicella even if they have a negative history for the disease. Varicella is extremely contagious, with 90% of susceptible household contacts developing the disease. Infectivity rates are lower with lessintense exposure, such as in the school setting. Interestingly, cases caused by household exposure are more severe. Adults, neonates born to nonimmune mothers, and immunocompromised patients also have more severe disease.

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After the resolution of clinical disease, the VZV remains latent in cells of the dorsal root ganglia. Reactivation may occur later in life, and shingles (zoster) represents a secondary infection with VZV.

Etiology The VZV that causes both chicken pox and shingles is a member of the herpes virus family, is closely related to herpes simplex virus, and has a double-stranded DNA genome. (CMV and EBV are also members of the herpes virus family.)

Clinical Manifestations After an incubation period of 10 to 21 days, patients with varicella develop mild prodromal symptoms of a low-grade fever, headache, and malaise. The characteristic skin lesions are noted within 24 to 48 hours, usually on the trunk, face, or scalp. The lesions start as papules but rapidly become vesicular, with clear, fluid-filled lesions noted on an erythematous base—the so-called tear drop on a rose petal. These lesions progress to the pustular and then crusted stages. New crops of lesions occur with a centrifugal spread. As new crops of lesions become apparent, papules, vesicles, and pustules all may be present at the same time. Involvement by lesions of mucous membranes, including those of the mouth and eyes, is frequent. The lesions in these sites are intensely pruritic and may become secondarily infected, with a resultant increase in surrounding erythema. The patient may continue to have new lesions for up to 7 days. Besides the pruritus of varicella, patients with the disease are likely to have fever (occasionally as high as 41ºC [106ºF]), malaise, and anorexia that are most pronounced during the first few days of illness. As with varicella, the characteristic skin lesions of shingles (zoster) are also vesicular and occur in a dermatomal distribution, involving 1 or more adjacent dermatomes. New lesions appear for up to 7 days. Zoster in children is milder than that which is seen in adults and is accompanied less often by neuritis or postherpetic neuralgia. The most common complications are related to bacterial coinfection. Severe cellulitis, fasciitis, and toxic shock syndrome caused by Streptococcus pyogenes, when seen in children, frequently follow infection with VZV (31). Other complications of infections with VZV include various hematologic or neurological manifestations, especially ataxia and, rarely, Reye syndrome.

Diagnosis Usually, the diagnosis of VZV is made on clinical grounds alone. The appearance of the typical exanthem in a susceptible host occurring after exposure and an appropriate incubation period usually suggests the

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diagnosis. Identification of the virus in tissue culture with specimens of vesicular fluid can be used to confirm the diagnosis. More rapid confirmation is possible by scraping material from the base of a vesicle and looking for multinucleated giant cells or by the direct immunofluorescence using a monoclonal antibody to VZV. Cytologic methods lack sufficient sensitivity and fail to distinguish VZV from herpes simplex virus infections. Serology with enzyme immunoassay methods is used primarily to assess susceptibility to varicella in adults. These results can help the physician make decisions about active versus passive immunization after exposure to VZV (30). IgM-antibody techniques are generally not useful outside the research setting.

Treatment In certain clinical situations, VZV infections are treated with acyclovir. Generally, VZV infections in immunocompromised hosts require intravenous therapy (32). In all patients, it is imperative to initiate treatment as early as possible. Recommendations for treating VZV infection are listed in Table 38-5 (33).

Prevention A cell-free, attenuated, live-virus vaccine for varicella has been available in the United States for 6 years. This vaccine is highly effective in preventing serious disease but has been underused in the United States (34). Compliance with the recommendation for universal varicella immunization is now approaching 90%. Occasionally, recipients develop a rash, and in rare cases there is transmission of the vaccine strain of the virus to susceptible individuals. The duration of immunity conferred by vaccination seems to be excellent, and the subsequent development of shingles actually occurs less frequently than in individuals otherwise infected with virus. Contraindications for this vaccine are similar to those seen with other live vaccines and include moderate to severe febrile illness, immunocompromise, current steroid therapy in children, pregnancy, recent treatment with immunoglobulin, use of salicylates, or allergy to vaccine components. Passive protection against varicella is possible after exposure to VZV through the use of immune serum globulin, intravenous gammaglobulin, or VZIG (35). VZIG is preferred and indicated for susceptible individuals after a significant exposure. Individuals for whom VZIG should be considered include immunocompromised patients, newborn infants whose mothers had chicken pox between 5 days before to 2 days after delivery, premature infants of more than 28-weeks’ gestation and whose mothers have no history of chicken pox, and premature infants of less than 28-weeks’ gestation regardless of the maternal history. For additional details, consult the Report of the Committee on Infectious Diseases, 24th edition (35a).

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Table 38-5 Therapy for Varicella and Zoster Infections Patient Group Varicella Immunocompetent persons Neonates Children <12 years of age Adolescents and adults Women in last trimester of pregnancy Patients with pneumonitis or other severe infection Immunocompromised persons Corticosteroid therapy, continuous or intermittent high dose Low-dose daily cytotoxic drug use† HIV-infected

Hematologic or solid-organ malignant conditions or transplant recipient Acyclovir-resistant lesions Zoster Immunocompetent persons Age <50 years with mild pain With ophthalmic rash Age ≥50 years or moderate to severe pain Immunocompromised persons Corticosteroid therapy, continuous or intermittent high dose Low-dose daily cytotoxic drug use‡ HIV-infected Hematologic or solid-organ malignant conditions or transplant recipient Disseminated disease Acyclovir-resistant lesions

Treatment Options*

Intravenous acyclovir for 10 days Symptomatic care only; consider 5 days of oral acyclovir Oral valacyclovir,† famciclovir,† or acyclovir for 5 days Oral acyclovir for 5 days Intravenous acyclovir for 7–10 days

Oral valacyclovir,† famciclovir,† or acyclovir for 7 days Oral valacyclovir,† famciclovir,† or acyclovir for 7 days Intraenous acyclovir for 7 days or longer, or oral valacyclovir,† famciclovir† or acyclovir for 7–10 days if symptoms are mild Intravenous acyclovir for 7–10 days Intravenous foscarnet† for 14 days or longer (until healing)

Symptomatic care only Oral famciclovir, valacyclovir, or acyclovir for 7 days; ophthalmologic assessment Oral famciclovir, valacyclovir, or acyclovir for 7 days; consider corticosteroids§ Oral famciclovir, valacyclovir, or acyclovir for 7 days Oral famciclovir, valacyclovir, or acyclovir for 7 days Oral valacyclovir, famciclovir, or acyclovir for 7–10 days Intravenous acyclovir or oral valacyclovir or famciclovir for 7–10 days Intravenous acyclovir for 10 days Intravenous foscarnet† for 14 days or longer (until healing)

* Standard dosages are oral acyclovir, 20 mg/kg five times daily for children or 800 mg five times daily for adults; intravenous acyclovir, 500 mg/m2 every 8 hours for children or 10 mg/kg every 8 hours for adults; oral valacyclovir, 1000 mg three times per day; oral famciclovir, 500 mg three times per day; intravenous foscarnet, 40 mg/kg every 8 hour0s. † Not approved by the Food and Drug Administration for this indication. ‡ Examples include daily oral cyclophosphamide, methotrexate, azathioprine, and 6-mercaptopurine. § Oral prednisone, 30 mg twice per day for 7 days, 15 mg twice per day for 7 days, and 7.5 mg twice per day for 7 days. Republished with permission from Cohen JI, Brunell PA, Strauss SE, Krause PR. Recent advances in Varicella–Zoster Virus Infection. Ann Intern Med. 1999;130:922–932.

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Zoster (shingles) remains a common and debilitating problem especially seen in the elderly. The varicella vaccine has been reformulated into a zoster vaccine, Zostavax. This vaccine contains substantially more plaqueforming units of virus than the vaccine used to immunize against varicella. Both the incidence of zoster as well as the occurrence of postherpetic neuralgia were significantly reduced in the vaccine group (35b). There are several issues to be considered with regard to universal use of this vaccine in adults. With each passing year, more of the population will be immune to VZV as a result of immunization rather than natural disease. Viral burden is less in the ganglia of adults immunized during childhood, which may make occurrence of zoster later in life less. However, with less exposure to disease, and less possibility for subclinical boosts of immunity, the need for a shingles vaccine for adults may be increased. Cost effectiveness of such a vaccine also needs further evaluation. Zostavax is currently licensed for use in the prevention of shingles for individuals 60 years of age and older.

Enteroviruses Enteroviruses (EVs) are ubiquitous agents that are responsible for a wide variety of diseases, of which poliomyelitis is the best known. EVs are spread by the fecal–oral route, and their activity in more temperate climates is most marked in the late summer and early fall (but they occur throughout the year). The exanthems associated with enteroviral disease vary from maculopapular to petechial to vesicular, and consequently these diseases must be included in the differential diagnosis of any disease that causes fever and rash in a child (36).

Clinical Manifestations Infants and children are infected with EV most often. As with poliomyelitis, most disease is clinically unapparent. Infections with EV are often seen as part of outbreaks. Patients with symptomatic disease have a wide range of clinical manifestations that range from mild, nonspecific, febrile disease to more severe disease with associated paralysis or fatal myocarditis. Prodromal symptoms of EV infection include fever, nausea, vomiting, conjunctivitis, or eye irritation. The clinical illness caused by EV is often biphasic, and several associated features help the clinician arrive at the diagnosis. Some patients have an enanthem characterized by the development of vesicular and/or papular lesions (herpangina) in the posterior pharynx or on the soft palate. Aseptic meningitis is a common feature of EV infection. Rash associated with EV disease is most often described as maculopapular, macular, or morbilliform. As in rubella and rubeola, the EV rash starts on the face and neck and spreads downward to involve the trunk and

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extremities. The rash is rarely vesicular but can be confused with varicella under these circumstances. A petechial rash is not uncommon, especially in cases of infection with echovirus 9, and can be confused with the skin manifestations of meningococcemia. Exanthematous disease, which is associated with at least 2 echoviruses (types 16 and 25) has occurred as part of well-defined outbreaks of EV disease, with a rash that appears in many of these patients after defervescence (as occurs with roseola). These patients with Boston or Pittsburgh exanthem exhibit features common to EV disease. Aseptic meningitis is a frequent occurrence. The rash of roseola lasts from 1 to 7 days, and an enanthem of papules or vesicles in the posterior pharynx is not uncommon.

Hand-Foot-and-Mouth Disease As with other diseases caused by EV, hand-foot-and-mouth (HFM) disease is more often seen in the summer and early autumn. After a short incubation period of 2 to 6 days, a brief prodrome of low-grade fever, sore throat, and anorexia appears; within another day, involvement of the oral cavity and/or skin is noted. Generally, the enanthem of HFM disease is thought to be the most common manifestation and is estimated to occur in 90% of patients. The lesions of the enanthem are most often vesicular and are found, in decreasing order of frequency, on the buccal mucosa, tongue, palate, uvula, and/or anterior pillars. These enanthema can be confused with herpetic stomatitis or aphthous ulcers. An exanthem is seen in more than half of patients with HFM disease, with involvement of the hands (52%), feet (31%), and buttocks (31%) noted in one study (36). Lesions on the hands and feet consist of small vesicles and last from 2 to 7 days. Although Coxsackie A16 virus is recovered most often from patients with HFM disease, other Coxsackie viruses of both types A and B have been recovered occasionally.

Diagnosis Confirmation of EV disease usually depends on identification of the virus in tissue culture. Fibroblasts or primary monkey kidney cells are used, and virus is identified in 2 to 10 days. Identification in shell vial culture can be made within 72 hours. Suitable specimens for culture include cerebrospinal fluid, vesicle and pericardial fluid, and blood. Identification of EV in the throat or in stool can be suggestive of disease; however, because of the frequency of asymptomatic shedding of EV (especially in the summer and autumn), these specimens are not preferred. Serology is generally not useful because of the large number of serotypes of EV that are potentially

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involved in causing disease. Recently, the polymerase chain reaction test has been applied to several clinical specimens, especially cerebrospinal fluid, in cases of EV disease. Polymerase chain reaction in a limited number of studies that used cerebrospinal fluid has provided more timely and sensitive results than other assay methods. The diagnosis is confirmed through culture of infected material, which usually is indicated only to distinguish EV disease from other, more serious illnesses that require specific therapy (e.g., meningococcemia, bacterial meningitis).

Treatment and Prevention No specific antiviral chemotherapy is yet available for EV disease. Immune serum globulin has been used in selected immunocompromised patients and has been found to modify the course of disease. Neither active immunization or passive protection with immune serum globulin is now feasible for individuals exposed to nonpolio enteroviruses.

REFERENCES 1. Hinman AR, Eddins DL, Kirby CD, Orenstein WA, Bernier RH, Turner PM Jr., et al. Progress in measles elimination. JAMA. 1982;247:1592-5. 2. Gustafson TL, Lievens AW, Brunell PA, Moellenberg RG, Buttery CM, Sehulster LM. Measles outbreak in a fully immunized secondary-school population. N Engl J Med. 1987; 316:771-4. 3. Edmonson MB, Addiss DG, McPherson JT, Berg JL, Circo SR, Davis JP. Mild measles and secondary vaccine failure during a sustained outbreak in a highly vaccinated population. JAMA. 1990;263:2467-71. 4. Centers for Disease Control (CDC). Measles prevention: Recommendations of the immunization practices advisory committee (ACIP). MMWR Morb Mortal Wkly Rep. 1989;38:1-18. 5. Fulginiti VA, Eller JJ, Downie AW, Kempe CH. Altered reactivity to measles virus. JAMA. 1967;202:101-6. 6. American Academy of Pediatrics. Committee on Child Abuse and Neglect. American Academy of Pediatrics. Committee on Child Abuse and Neglect. Gonorrhea in prepubertal children. Pediatrics. 1998;101:134-5. 7. Gregg NM. Congenital cataract following German measles in the mother. Ophthalmol Soc Aust. 1941;3:35. 8. Lamprecht C, Schauf V, Warren D, Nelson K, Northrop R, Christiansen M. An outbreak of congenital rubella in Chicago. JAMA. 1982;247:1129-33. 9. Orenstein WA, Greaves WL. Congenital rubella syndrome: a continuing problem [Editorial]. JAMA. 1982;247:1174-5. 10. Modlin JF, Brandling-Bennett AD,Witte JJ, Campbell CC, Meyers JD. A review of five years’ experience with rubella vaccine in the United States. Pediatrics. 1975;55:20-9. 11. Ziring PR, Florman AL, Cooper LZ. The diagnosis of rubella. Pediatr Clin North Am. 1971;18:87-97. 12. Sumaya CV. Primary Epstein-Barr virus infections in children. Pediatrics. 1977;59:16-21. 13. Tamir D, Benderly A, Levy J, et al. Infectious mononucleosis and Epstein-Barr virus in childhood. Pediatrics. 1974;53:330-5. 14. Andiman WA. The Epstein-Barr virus and EB virus infections in childhood. J Pediatr. 1979;95:171-82. 15. Patel BM. Skin rash with infectious mononucleosis and ampicillin. Pediatrics. 1967;40:910-1. 16. Mccarthy JT, Hoagland RJ. Cutaneous manifestations of infecitous mononucleosis. JAMA. 1964;187:153-4. 17. Africk JA, Halprin KM. Infectious mononucleosis presenting as urticaria. JAMA. 1969;209:1524-5. 18. Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children. I. Clinical and general laboratory findings. Pediatrics. 1985;75:1003-10.

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19. Grose C, Henle W, Henle G, Feorino PM. Primary Epstein-Barr-virus infections in acute neurologic diseases. N Engl J Med. 1975;292:392-5. 20. Sumaya CV, Ench Y. Epstein-Barr virus infectious mononucleosis in children. II. Heterophil antibody and viral-specific responses. Pediatrics. 1985;75:1011-9. 21. Bender, CE. The value of corticosteroids in the treatment of infectious mononucleosis. JAMA. 1967;199:97-9. 22. Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, et al. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet. 1988;1:1065-7. 23. Pruksananonda P, Hall CB, Insel RA, McIntyre K, Pellett PE, Long CE, et al. Primary human herpesvirus 6 infection in young children. N Engl J Med. 1992;326:1445-50. 24. Hall CB, Long CE, Schnabel KC, Caserta MT, McIntyre KM, Costanzo MA, et al. Human herpesvirus6 infection in children. A prospective study of complications and reactivation. N Engl J Med. 1994;331:432-8. 25. Plummer FA, Hammond GW, Forward K, Sekla L, Thompson LM, Jones SE, et al. An erythema infectiosum-like illness caused by human parvovirus infection. N Engl J Med. 1985;313:74-9. 26. Thurn J. Human parvovirus B19: historical and clinical review. Rev Infect Dis. 1988;10:1005-11. 26a. Anderson LJ. Role of parvovirus B19 in human disease. Pediatr Infect Dis J. 1987;6: 711-8. 26b. Chorba T, Coccia P, Holman RC, Tattersall P, Anderson LJ, Sudman J, et al. The role of parvovirus B19 in aplastic crisis and erythema infectiosum (fifth disease). J Infect Dis. 1986;154:383-93. 27. Centers for Disease Control (CDC). Risks associated with human parvovirus B19 infection. MMWR Morb Mortal Wkly Rep. 1989;38:81-94. 28. Gillespie SM, Cartter ML,Asch S, Rokos JB, Gary GW,Tsou CJ, et al. Occupational risk of human parvovirus B19 infection for school and day-care personnel during an outbreak of erythema infectiosum. JAMA. 1990;263:2061-5. 29. Pickering LK, Reves RR. Occupational risks for child-care providers and teachers [Editorial]. JAMA. 1990;263:2096-7. 30. Gershon AA, Krugman S. Seroepidemiologic survey of varicella: Value of specific fluorescent antibody test. Pediatrics. 1975;56:1005-8. 31. Smith EW, Garson A Jr., Boyleston JA, Katz SL,Wilfert CM. Varicella gangrenosa due to group A beta-hemolytic Streptococcus. Pediatrics. 1976;57:306-10. 32. Shepp DH, Dandliker PS, Meyers JD. Treatment of varicella-zoster virus infection in severely immunocompromised patients. A randomized comparison of acyclovir and vidarabine. N Engl J Med. 1986;314:208-12. 33. Cohen JI, Brunell PA, Straus SE, Krause PR. Recent advances in varicella-zoster virus infection. Ann Intern Med. 1999;130:922-32. 34. Plotkin SA. Varicella vaccine: a point of decision. Pediatrics. 1986;78:705-7. 35. Ross AH, Lenchner E, Reitman G. Modification of chicken pox in family contacts by administration of gamma globulin. N Engl J Med. 1962;627:369-76. 35a. Pickering LK, ed. Red Book 2000: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000. 35b. Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-84. 36. Cherry JD. Newer viral exanthems. In: Schulman I, ed. Advances in Pediatrics. Vol 16. Chicago, IL: Year Book; 1969:233-86.

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Part IX

Immunocompromised-Related Infections

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Chapter 39

HIV Infection JOSEPH C. CHAN, MD RAFAEL E. CAMPO, MD

Key Learning Points 1. After the appropriate counseling for an HIV-positive patient, medical evaluations should be directed towards providing highly active antiretroviral therapy (HAART). Except few nonprogressing individuals, most patients will require HAART. The clinician must determine when to initiate HAART. 2. Once the decision of treatment is made, the clinician must choose the first HAART regimen wisely according to the gender and co-morbidities of the patient. The first regimen has the best chance to succeed for the patient. 3. Any HAART regimen should consist of three effective drugs from at least 2 different classes and protease inhibitors, except nelfinavir, should not be used without enhancement by ritonavir. 4. Most nucleoside reverse transcriptase inhibitors are excreted mainly by the kidneys so the dosage must be adjusted according to renal function. Other oral antiretroviral drugs are mainly metabolized by the liver through the cytochrome P450 system so drug interactions are common. 5. Drug resistance develops because of treatment failure and not the other way around; therefore, the goal of HAART is successful viral suppression to undetectable level for as long as possible to avoid the development of drug-resistance.

I

t has been 25 years since the first description of an outbreak of Pneumocystis jiroveci pneumonia in a small group of gay men in Los Angeles in 1981 (1). That was usually considered as the heralding event of 723

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New Developments in the Management of HIV Infection • A swab of the oral mucosa can be used to screen for HIV infection, and the result

will be available in less than 20 minutes. This can be done in any clinician’s office because it is Clinical Laboratory Improvement Act (CLIA)-waived. Clinicians should no longer ask themselves who should be tested for HIV, they should ask themselves who should not be tested. • Atripla, a tablet containing tenofovir, emtricitabine, and efavirenz is available. Theoretically, many newly diagnosed HIV-infected patients can be controlled successfully on one pill once a day. • Most treatment-experienced patients with triple-class resistant virus can still be successfully suppressed with the introduction of enfuvirtide combined with one of the latest protease inhibitors such as darunavir and tipranavir. • A large international prospective randomly assigned clinical trial has confirmed that treatment interruption can lead to more rapid progression to AIDS and death. Furthermore, patients with interrupted treatment actually developed more hepatic, renal, and cardiovascular complications despite receiving only a third of the HIV drugs compared to the continuous treatment group. The risk of HIV progression far outweighs any concern with drug toxicity. • Valproic acid, a histone deacetylase-1 inhibitor, given with highly active antiretroviral therapy (HAART) and enfuvirtide, was demonstrated to enhance clearance of latently infected CD4+ T-cells in a pilot study of four patients. This finding can pave the way for the eventual HIV eradication with drug treatment alone.

the present worldwide epidemic of the acquired immunodeficiency syndrome (AIDS). The causative agent was discovered in 1983-1984 and was subsequently known as the human immunodeficiency virus type 1 (HIV-1), belonging to the family of Retroviridae. It contains only 9 genes and 15 proteins (2,3). In 1987, within 3 years of the discovery of HIV-1, zidovudine (ZDV) (or azidothymidine [AZT]) was introduced, although the survival benefit was known to be relatively brief (4). Eight years after the introduction of AZT, the true nature of the viral dynamic within an infected individual was clarified, partly as the result of improved technologies to accurately measure the intensity of viremia and partly because of advances in drug development (5). Principles of antiretroviral treatment will continue to evolve because new information on basic virology, immunology, and pharmacology will be incorporated into better clinical trials. This chapter will focus on the up-to-date therapeutic options and dilemmas that a general internist should be aware of while providing care to an adult or adolescent patient infected by HIV-1.

Virology Based on their genetic make-up, HIV-1 viruses are classified into the following three major groups:

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1. Group M: M stands for main, contains nine genetically distinct subtypes or clades (A, B, C, D, F, G, H, J, K) and many recombinant forms (e.g., A/E = CRFO1). 2. Group O: O stands for outliers, which show up to 50% genetic variability from M subtypes of the virus. This group of virus cannot be detected by the usual blood tests. 3. Group N: This comprises the group of nonpandemic strains, mainly found in Africa. Subtype C is the dominant infection worldwide, accounting for 55% to 60% of all human HIV-1 infections. Subtype B predominates in North America, Europe, and Australia. Coinfection with two genetically distinct viruses can lead to new recombinant viruses, and superinfections from different time points of acquisition are well documented. These observations highlighted the difficulty in vaccine development because infected individuals are not protected from another infection. On the practical side, safe sex should be practiced even among infected individuals to keep reexposure to new viral strains to the minimum. HIV type 2 (HIV-2) causes an infection similar to that caused by HIV-1 but usually with less severe destruction of the host immune system and characterized by a less-rapid disease progression and less-efficient sexual and vertical transmission. The HIV-1 life cycle is very complex. The CD4 receptor present on T-lymphocytes, macrophages and dendritic cells is the recognized binding target of the HIV-1 virus. The beta-chemokine receptors (CCR5 and CXCR4) present on the cell surface of these cells act as coreceptors that are necessary to trigger the transformational changes of the viral envelope proteins (gp120 and gp41) so that the fusion event will take place, and the viral core will be released into the cytoplasm. The viral RNA is then transcribed into DNA by the viral reverse transcriptase (RT) enzyme. The resulting linear double-stranded DNA will be transported into the nucleus and integrates into the host’s chromosomal DNA, thereby transforming a host’s cell into a viral producer. The complex gene processing is regulated by many viral genes (tat, rev, nef, vif, vpr, vpu) and many host factors. The formation of new virions requires the assembly of the translated viral proteins and viral RNA near the cell membrane. The viral protease must provide the final proteolytic cleavage of gag-pol polyprotein before the mature infectious virions can egress from the cell.

Epidemiology At the end of 2003, an estimated 1,039,000 to 1,185,000 persons in the United States were living with HIV/AIDS, with 24% to 27% undiagnosed and unaware of their HIV infection. In 2004, there were 42,468 newly diagnosed AIDS cases (31,026 men and 11,442 women) among adults and

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Table 39-1 2004 AIDS cases in the United States by Gender and Exposure History Estimated Number of AIDS Cases in 2004 Exposure Category

Male-to-male sexual contact Injection drug use

Male

17,691 5,968

Male-to-male contact and injection drug use

1,920

Heterosexual contact

5,419

Other Total

Female

Total

17,691 3,184

9,152

7,979

13,128

1,920

298

279

577

31,026

11,442

42,468

adolescents. The distribution of the 2004 AIDS cases by gender and exposure category is listed in Table 39-1. There were also 48 AIDS cases in children younger than 13 years of age.

Natural History of HIV-1 Infection Depletion of the naïve and memory CD4+ T-lymphocyte population is the hallmark of HIV infection, and the level of depletion predicts the risk for an infected individual to develop either an opportunistic infection or an HIV-related complication. The natural history of HIV infection can be summarized by Figure 39-1. Most patients do not have any noticeable symptoms after the initial infection, but up to 10% of the infected individuals can present with an acute viral infection similar to mononucleosis (acute retroviral syndrome). Shortly after the initial infection, the level of the HIV virus in the bloodstream is typically in excess of 10 million particles per milliliter (6). The infected individual has not yet seroconverted so he or she can only be discovered by the direct measurement of HIV-RNA. This period, often referred to as the window period, usually lasts 3 to 6 months after the initial infection, and the patient is highly contagious. The initial HIV-specific CD8+ T-lymphocyte containment of the virus is very important to the control of the infection because the virus is remarkably efficient in evading any neutralizing antibodies. Within the next 3 to 6 months, there is a gradual reduction of viremia caused by the induction of partially effective immune response. The patient then enters the chronic phase of the infection, and the level of viremia (usually 1-2 orders of magnitude below initial viremia) remains relatively constant (the set point). Activated CD4+ T-lymphocytes are the main source of viral production, and these cells are selected for destruction. Unfortunately, the detectable HIVspecific immune responses become inconsequential when the early homogeneous viral population diversifies into many distinct quasi-species that

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HIV Infection

Primary infection

CD4+ T Lymphocyte Count (cells/mm3)

1000 900

Death Opportunistic diseases

Clinical Latency

800

1/512 1/256

Constitutional symptoms

700

1/128

600

1/64

500

1/32

400

1/16

300

1/8

200

1/4

100

1/2

0

0 0

3

6 9 12 Weeks

1

2

3

4

5 6 Years

7

8

9

10 11

107

106

105

104

HIV RNA Copies per ml Plasma

1100

± Acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs

Culturable Plasma Viremia (dilutional titer)

1200

727

103

102

Figure 39-1 The natural history of HIV infection in an individual without any antiviral intervention. The square line represents the changes of CD4+ T-cells, the triangle line represents the fluctuation of the plasma viral load and the circle line can be viewed as the likelihood of clinical symptoms as directly or indirectly related to the HIV infection. During the clinical latent period when the individual has achieved set point of the viral load, the probability of clinical symptoms is quite low. This figure is reproduced with permission from Ann Intern Med. 1996;124:654.

are no longer recognized and targeted by the cytotoxic T-lymphocytes. Ultimately, the immune response in most HIV-infected individuals is incapable of preventing the progression of the disease. The decline of the CD4 cell count, usually averages 50 to 100 cells/year, will eventually reach below 200/mm3, predisposing the patient to opportunistic infections and other complications associated with immune deficiency.

Diagnosis HIV infection can be diagnosed by either serology (the measurement of an antibody response to the virus) or by detecting the presence of HIV-RNA, called the viral load, directly in plasma by polymerase chain reaction (PCR) or by the branched-DNA technology. The standard serologic tests are either the enzyme-linked immunoabsorbent assay (ELISA) or the Western blot (WB). Most states require the ELISA as screening and the WB for confirmation. There are three Food and Drug Administration (FDA)-approved rapid tests: OraQuick Rapid HIV-1, Reveal Rapid Antibody, and UniGold Recombigen HIV (www.cdc.gov/hiv/rapid_testing). Results are available in 20 to 30 minutes. A negative rapid test result is considered a definitive negative unless

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tested in the window period shortly after infection. A positive test should be confirmed by WB. The viral load measurement is not advocated for the usual screening because of the low rate of false-positives, but it can be used to diagnose acute retroviral syndrome when antibody response has not been established in early infection. Once the infection is confirmed, only HIV-RNA measurement is relevant for prognosis and for treatment.

Classification and the Case Definition of AIDS The latest revised Centers for Disease Control (CDC) classification system for HIV-infected adolescents and adults categorizes persons on the basis of clinical conditions associated with HIV infection and CD4+ T-lymphocyte counts. The system is based on three ranges of CD4+ T-cells and three clinical categories and is represented by a matrix of nine mutually exclusive categories (Table 39-2). This 1993 revised HIV-classification system also allows for the use of the percentage of CD4+ T-cells. Persons in the subcategories A3, B3, and C3 meet the immunologic criteria of the surveillance case definition, and those persons in subcategories C1, C2, and C3 with conditions listed in Table 39-3 meet the clinical criteria for surveillance purposes (7).

Initial Counseling and Evaluation Most patients are very apprehensive during their first encounter with a health care provider after they were tested positive for HIV. It is imperative for the health care provider to address the issue of prevention, stigma, and fear with the patient as soon as they get acquainted. A complete history doc-

Table 39-2 Centers for Disease Control AIDS Surveillance Case Definition for Adolescents and Adults* Clinical Categories

CD4 Cell Categories

1. >500/mm3 (≥29%) 2. 200-499/mm3 (14-28%) 3. <200/mm3 (<14%)

A Asymptomatic, persistent generalized lymphadenopathy, or acute HIV infection

A1 A2 A3

B Symptomatic (not A or C) conditions that are attributed C to HIV or indicative AIDS of a defect in cellindicator mediated immunity conditions

B1 B2 B3

C1 C2 C3

* 1993 Centers for Disease Control (CDC) AIDS surveillance case definition for adolescents and adults. The percentages of CD4+ T-cells are also used for the immunologic categorization. Patients belonging to A3, B3, or C3 satisfied the immunologic criteria, and patients belonging to C1, C2, or C3 satisfied the clinical criteria for AIDS.

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Table 39-3 Indicator Conditions in Case Definition of AIDS 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Candidiasis of esophagus, trachea, bronchi, or lungs Cervical cancer, invasive* Coccidioidomycosis, extrapulmonary* Cryptococcosis, extrapulmonary Cryptosporidiosis with diarrhea for more than 1 month Cytomegalovirus of any organ other than liver, spleen, or lymph nodes Herpes simplex with mucocutaneous ulcer for more than 1 month or bronchitis, pneumonitis, esophagitis Histoplasmosis, extrapulmonary* HIV-associated dementia, disabling cognitive and/or motor dysfunction interfering with occupation or activities of daily living HIV-associated wasting: involuntary weight loss of more than 10% of baseline plus chronic diarrhea (≥2 loose stools/day ≥30 days) or chronic weakness and documented enigmatic fever for 30 days or more Isosporosis with diarrhea for more than 1 month* Kaposi sarcoma in patient younger than 60 years of age (or older than 60*) Lymphoma of brain in patient younger than 60 years of age (or older than 60*) Lymphoma, non-Hodgkin of B cell or unknown immunologic phenotype and histology showing small, noncleaved lymphoma or immunoblastic sarcoma Mycobacterium avium or M. kansasii, disseminated M. tuberculosis, disseminated* M. tuberculosis, pulmonary* Pneumocystis jiroveci pneumonia Pneumonia, recurrent bacterial* Progressive multifocal leukoencephalopathy Salmonella septicemia (nontyphoid), recurrent* Toxoplasmosis of internal organ

* Requires HIV serology.

umenting the patient’s knowledge of the disease, sexual behavior, lifestyle, drug allergies, and preexisting conditions that can have potential conflicts with the management of HIV, particularly with respect to potential drug toxicities or drug interactions, is essential. Initial laboratory tests, summarized in Table 39-4, are recommended with the intention that most patients will eventually require the highly active antiretroviral treatment (HAART). It is prudent to uncover all the factors, medical or psychosocial, that can affect the maximum benefit or can increase adverse events by such treatment. Some of the co-illnesses such as tuberculosis, syphilis, chronic hepatitis C, and gastric infection by Helicobacter pylori can require preferential treatment before the initiation of HAART. Sometimes, a negative serology, such as toxoplasma IgG, can trigger the discussion of preventive measures such as avoidance of cats and raw meat. An in-depth discussion of safe sexual practices is critical because few patients recognize the possibility and danger of superinfection by another HIV1 strain that can precipitate a more rapid progression of disease and can also carry drug-resistant mutations (8). Infected or noninfected individuals should therefore exercise the same degree of vigilance to prevent HIV-1 exposure.

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Table 39-4 Initial Laboratory Tests Recommended for Persons with Newly Diagnosed HIV Infection* Test

Indication and Comment

Complete blood counts with platelets

Anemia, thrombocytopenia are common; zidovudine can be avoided Comprehensive chemistry panel Renal insufficiency and abnormal liver enzymes can indicate further workup, can influence choice and dosage of ART Fasting glucose and lipid profile Metabolic complications are common with ART Serologic tests for prior exposure to Can influence the timing and choice of ART, hepatitis A, B, and C vaccination if negative Serologic tests for syphilis, Can require treatment or prophylaxis toxoplasmosis, and cytomegalovirus depending on CD4+ cell count Tuberculin skin test Prophylactic treatment indicated for induration ≥ 5 mm T-lymphocyte subsets and plasma Critical determinations for therapeutic HIV-RNA decision Genotypic test for prior drug resistance Helpful in areas with >5% primary drug resistance Serologic test for Helicobacter Can help to clarify causes of gastritis and pylori infection esophagitis, reduced dependency on PPI that can affect absorption of ATV Cervical and anal PAP smear High incidence of HPV infection, cervical and anal carcinoma Chest radiography For detection of preexisting pulmonary disease and for future comparison Creatine kinase, amylase, lipase Optional depending on choice of ART Urine analysis Screening for proteinuria * These tests should be carried out during the first encounter with an HIV-infected individual and simple reasons are provided in the comment. Abbreviations: ART, antiretroviral therapy; ATV, atazanavir; HPV, human papillomavirus; PPI, proton pump inhibitor.

Early evaluation of any transmitted drug-resistant variants is considered important because these variants can submerge into the latent reservoir and only to be revealed too late in the future when selective drug pressure is placed on them by an inadequate treatment regimen (see the First HAART Regimen).

Treatment The goal of treatment in this disease is to preserve existing CD4+ cells and to replenish any preexisting CD4+ cell loss. The means to accomplish this task is to administer available antiretroviral drugs optimally to reduce viral production to as low as possible for as long as possible. The complete eradication of HIV from an infected individual is not considered possible with available drugs. Emergence of resistance, medication adherence, and drug toxicities are the major obstacles along this overly simplified therapeutic

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roadmap. Long-term success depends on the coordinated efforts from both the clinician and the patient. HIV has an inherent predisposition to produce genetic variants in its offspring because of the poor fidelity of the RT and the enormous number of viral progenies generated daily. Every new generation of virions will attempt to further evade the host immune surveillance and any drug that can be present in their environment. The only effective way to circumvent the development of drug-resistant HIV mutants is to suppress viral replication to the lowest level possible. The clinical correlate to this goal is to consistently reduce the plasma viral load in the patient to the undetectable level. This is usually accomplished with at least three fully effective drugs from two different classes. Once the initial regimen is selected, the patient must follow the scheduled dosing protocol that can involve coordination with dietary intake, sometimes up to three times a day. Better short-term adherence can be achieved by simplifying the HAART regimen to daily dosing, preferably only one tablet at bed time such as the triple coformulation drug, Atripla. Most HIV drugs have early toxicities (during the first 3 months) such as nausea, diarrhea, rash, dizziness, and sleep disturbance. These adverse events are usually predictable, transient, and of low intensity, generally manageable by a well-informed patient provided with some supportive care. Late side effects (> 3 months) of antiretroviral drugs such as anemia, hepatitis, hyperlipidemia, lipoatrophy, peripheral neuropathy, and lactic acidosis, can be permanent, causing stigmatizing disfiguration and sometimes fatality (Table 39-5). Many of these side effects are slowly cumulative, often not amenable to physiologic or pharmacologic intervention, and can require treatment modification or interruption. Although the incidence of serious side effects is low and unpredictable, certain patients can be at increased risk based on their gender, their age, and few other predisposing factors such as obesity, smoking, diabetes, and chronic hepatitis. It is therefore prudent to avoid drugs or drug combinations that are more likely to lead to these complications in a high-risk individual.

Commercially Available Antiretroviral Drugs There are now twenty-one approved antiretroviral agents and six fixed dose coformulation products that can be grouped into four classes (9). Eight drugs are nucleoside or nucleotide reverse transcriptase inhibitors (Table 39-6), and three are nonnucleoside inhibitors for the same enzyme (Table 39-7). Nine drugs are inhibitors for the HIV protease (Table 39-8), and one injectable peptide inhibits the fusion process of the virus with the cell membrane of the CD4+ T-lymphocyte. Some of the previous formulations on a product can no longer be available commercially. They were removed from the market by the manufacturer because of poor bioavailability or poor tolerance. Amprenavir capsule (Agenerase by Glaxo-Smith-Kline), both saquinavir capsules

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Table 39-5 Common Adverse Events of Antiretroviral Drugs* Adverse Event

Anemia (E1) Cardiovascular disease (L2)

Fat atrophy (L)

Fat maldistribution (L)

Glucose intolerance (L)

Hepatitis (E or L)

Hyperbilirubinemia (unconjugated, E→L) Hypercholesterolemia (L)

Hyperlactatemia (E or L)

Hypertriglyceridemia (L)

Nephrotoxicity (L) Pancreatitis (E or L) Peripheral neuropathy (L)

Rash (E)

Ranking of Risk for Adverse Event

Comment/Management

ZDV most drugs except ABC, ATV, FTC, or 3TC, NVP, TDF

Switch drug, erythropoietin Smoking has much higher risk than any drug combination, switch drug, conventional management Switch drug, cosmetic d4T/ddI3 > d4T > ZDV surgery for facial lipoatrophy IDV > other PIs, not ATV; More common in women, d4T > ZDV > ddI control weight, switch drug, metformin, growth hormone or testosterone, liposuction IDV, r-LPV > f-APV > Familial history, obesity, SQV; worse with d4T/ddI dietary control, conventional management, switch drug NVP (E), ATV (E→L) Chronic viral hepatitis, select appropriate CD4 number for NVP according to gender, switch drug ATV > IDV Pharmacogenetic predisposition, switch drug r-IDV > r-LPV > r-APV > Familial history, dietary r-SQV > NLV; EFV > NVP; control, switch drug, d4T/ddI > ZDV/3TC > conventional TDF/FTC management d4T/ddI > d4T > ddI > More common in women, ZDV > ddC > 3TC or FTC possible racial > ABC > TDF difference, switch drug r-LPV > r-IDV > r-APV > More common in women, r-SQV > NLV switch drug, conventional management IDV > TDF IDV from nephrolithiasis, fluid intake ddI/TDF > ddI No alcohol, reduce triglycerides ddC/d4T > ddC > d4T/ddI Avoid other neuropathic > d4T > ddI hydroxyurea drugs, switch drug, antidepressant, analgesic, massage, acupuncture? NVP, ABC > EFV NVP rash usually accompanied by hepatitis, switch drug, never attempt rechallenge, worse with Continued

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Table 39-5 Continued Ranking of Risk for Adverse Event

Adverse Event

Thrombocytopenia (L)

ZDV, hydroxyurea

Comment/Management

steroid. EFV rash may be transient Search for ITP or TTP, switch drug

* Adverse events of antiretroviral agents are commonly divided into early or late. The relative risk is ranked according to descending order of severity or likelihood. Some common combinations are also listed in the ranking. E1 = early or less than 3 months; L2 = late or 3 months or more; d4T/ddI = combination. Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV, atazantavir; d4T, didehydrodideoxythymidine; ddI, dideoxyinosine; ddI3; EFV, efavirenz; f-APV, amprenavir; FTC, emtrictabine; IDV, indinavir; ITP, immune thrombocytopenia; NLV; NVP, nevirapine; PI, protease inhibitor; r-APV; r-IDV; r-LPV; r-SQV; SQV, saquinavir; TDF, tenofovir disoproxil fumarate; TTP, thrombotic thrombocytopenic purpura; ZDV, zidovudine.

Table 39-6 Commercially Available Nucleoside or Nucleotide Reverse Transcriptase Inhibitors* Agent (abbreviation)

Abacavir (ABC)

Trade Name

Elimination

Adult Dose

Available Formulation

Ziagen GlaxoSmith-Kline (GSK)

Hepatic 300 mg PO 300-mg glucuronidation q12h or 600 tablet, 20and carboxymg daily (QD) mg/mL lation solution Didanosine Videx™ and Cellular 400 mg PO QD buffered (ddI) Videx EC metabolism for ≥60 kg or chewable Bristol-Myers250 mg PO tablet and Squibb QD for entericcoat<60 kg ed tablet Emtricitabine Emtriva Gilead Renal 200 mg daily 200-mg (FTC) capsule Lamivudine Epivir GSK Renal 300 mg daily or 150, 300-mg (3TC) 150 mg q12h tablet 10-mg/mL solution Stavudine (d4T) Zerit BristolRenal 40 mg PO 15, 20, 30, Myers-Squibb q12h for 40-mg ≥60 kg and capsule 30 mg PO 1 mg/mL q12h for solution <60 kg Tenofovir (TDF) Viread Gilead Renal 300 mg PO 300-mg daily tablet Zalcitabine Hivid Hoffman- Renal 0.75 mg PO 0.375, 0.75(ddC) LaRoche q8h mg tablet Zidovudine Retrovir GSK Hepatic 300 mg PO 300-mg (ZDV or AZT) glucuronidation q12h tablet 10and renal mg/mL solution/syrup Continued

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Table 39-6 Continued Agent (abbreviation)

Trade Name

Elimination

Adult Dose

ZDV + 3TC Combivir GSK coformulation

See above

1 tablet PO q12h

ABC + 3TC Epzicom GSK coformulation

See above

1 tablet PO daily

ABC + ZDV + 3TC triple formulation

See above

1 tablet PO q12h

See above

1 tablet PO daily

Trizivir GSK

TDF + FTC Truvada Gilead coformulation

Available Formulation

300 mg ZDV 150 mg 3TC fixed dose tablet 600 mg ABC 300 mg 3TC fixed dose tablet 300 mg ABC 300 mg ZDV 150 mg 3TC fixed dose tablet 300 mg TDF 200 mg FTC fixed dose tablet

* There are eight commercially available nucleoside/nucleotide reverse transcriptase inhibitors and four coformulation products. Zalcitabine is rarely used because of its high toxic profile. Generic substitutes are available for zidovudine and didanosine. Abbreviations: h, hour; PO, orally; q, every; QD, daily.

Table 39-7 Non-Nucleoside Reverse Transcriptase Inhibitors and Coformulation* Agent (abbreviation) Trade Name

Elimination

Adult Dose

Formulations

Delavirdine (DLV)

Rescriptor Agouron

Efavirenz (EFV)

Sustiva BristolMyers Squibb

Nevirapine (NVP)

Viramune Boehringer Ingelheim

Tenofovir + Emtricitabine + Efavirenz coformulation

Atripla Gilead and Bristol-MyersSquibb

hepatic P-450 400 mg PO 100, 200-mg q8h tablet hepatic P-450 600 mg PO 50, 100, 200daily (QD) mg capsule, 600 mg tablet hepatic P-450 200 mg PO 200-mg tablet QD × 14 10-mg/mL days, then solution 200 mg q12h or 400 mg QD both renal 1 tablet PO 300-mg TDF and hepatic QHS + 200-mg FTC P-450 + 600-mg EFV

* There are three nonnucleoside reverse transcriptase inhibitors and one coformulation drug containing both NRTI and NNRTI. Delavirdine is seldom used because of its thrice daily dosing. The rate of severe hepatotoxicity of nevirapine is considered too high for women with CD4+ T-cells of >250/mL and for men with CD4+ T-cells > 350/mL. Abbreviations: h, hour; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PO, orally; q, every; QD, daily; QHS, at bedtime.

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Table 39-8 Inhibitors of the HIV Protease Enzyme* Agent (abbreviation) Trade Name

Elimination

Adult Dose

Formulation

Atazanavir (ATV)

Reyataz Bristol- hepatic P-450 400 mg PO QD 100, 150, 200Myers-Squibb or 300 mg mg capsule with 100 mg ritonavir PO QD Darunavir (DNV) Prezista hepatic P-450 600 mg with 300-mg tablet Tibotec 100 mg ritonavir PO q12h Fosamprenavir Lexiva Glaxo- hepatic P-450 1400 mg PO 700-mg tablet (f-APV) Smith-Kline q12h or 700 mg with 100 mg ritonavir PO q12h Indinavir (IDV) Crixivan Merck hepatic P-450 800 mg PO 100, 200, 333, renal q8h or 800 mg 400-mg with 100 mg capsule ritonavir PO q12h Lopinavir + ritonavir Kaletra Abbott hepatic P-450 Two tablets PO 200-mg coformulation q12h, or 5 mL lopinavir (r-LPV) solution PO 50-mg q12h ritonavir fixed dose tablet, 80mg lopinavir 20-mg ritonavir per mL solution Nelfinavir (NFV) Viracept hepatic P-450 1250 mg PO 250, 625-mg Agouron q12h tablet Ritonavir (RTV) Norvir Abbott hepatic P-450 600 mg PO 100-mg q12h capsule 80mg/mL solution Saquinavir (SQV) Invirase hepatic P-450 1000 mg with 500-mg tablet Hoffman100 mg LaRoche ritonavir PO q12h Tipranavir (TPV) Aptivus hepatic P-450 500 mg with 250-mg Boehringer200 mg capsule Ingelheim ritonavir PO q12h * There are nine commercially available protease inhibitors. Ritonavir is almost never used alone because of its high rate of intolerance at therapeutic dose. It is used mainly to enhance the levels of other protease inhibitors except nelfinavir. Only products that are presently marketed in the United States are shown in the table. Abbreviations: h, hour; PO, orally; q, every; QD, daily.

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(Invirase and Fortovase by Hoffman-LaRoche) and the ritonavir (Norvir by Abbott) liquid were replaced by better products. The gel-cap coformulation of lopinavir/ritonavir (Kaletra by Abbott) was recently replaced by a new tablet.

HIV Targets for Antiretroviral Agents The reverse transcriptase (RT), the protease, and the envelope protein GP120 have been successfully targeted for drug development during the last 20 years. Two classes of drugs have been developed to block the function of RT: nucleoside or nucleotide (nucleoside monophosphate) analog RT inhibitors (NRTIs), which act to short-circuit DNA chain elongation and act as competitive inhibitors of RT; and nonnucleoside RT inhibitors (NNRTIs), which bind to the catalytic site of RT and act as noncompetitive antagonists of enzyme activity. All four normal nucleoside substrates (adenosine, cytosine, thymidine, and guanidine) are being targeted by inhibitory analogues (Table 39-9). NRTIs that compete with the same nucleoside substrate should not be administered together because the combinations tend to be antagonistic (AZT and didehydrodideoxythymidine [d4T]), mutually exclusive (lamivudine [3TC] and emtricitabine [FTC]), or potentially toxic (tenofovir disoproxil fumarate [TDF] and dideoxyinosine [ddI]). In general, combining two analogues targeting different nucleoside substrates reduces viral production more effectively than any one alone. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) include compounds with widely divergent chemical structures (see Table 39-7). They do not require phosphorylation or intracellular processing. They inhibit RT function by binding at sites distinct from the NRTIs. These drugs do not have activity against HIV-2. Combining drugs of this class (two NNRTIs simultaneously) does not result in more effective antiviral activity (10). The HIV protease is a 99-amino acid aspartyl proteolytic enzyme that exists as a homodimer to give a symmetrical structure. Most of the approved protease inhibitors (PIs) (see Table 39-8) are synthetic peptide mimetics containing the phenylalanine-proline sequence designed to com-

Table 39-9 Nucleoside or Nucleotide Analogue that Inhibits the HIV-1 Reverse Transcriptase Enzyme* Adenosine Didanosine (ddI) Tenofovir2 (TDF)

Cytosine Zalcitabine (ddC) Lamivudine (3TC) Emtricitabine (FTC)

Thymidine Zidovudine (ZDV1) Stavudine (d4T)

Guanosine Abacavir (ABC)

* These drugs compete with the normal nucleoside substrates for the reverse transcriptase during viral DNA synthesis. Combining analogues that target different substrates provides synergistic activity, but combining analogues that target the same substrate can be detrimental. 1 ZDV is often used interchangeably with AZT. 2 Tenofovir is a nucleotide or a nucleoside monophosphate.

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pete with one of the eight cleavage sites within the gag-pol polyprotein precursor (11). These drugs do not require any additional processing in the body, and the serum trough level must exceed the level necessary to inhibit at least 50% of the virus by in-vitro assays. This inhibitory concentration (IC50) measurement is quite similar to the concept of minimum inhibitory concentration (MIC50) in bacteriology. It has been established by clinical trials that the higher the inhibitory quotient, defined as the ratio of the trough level of a PI over the IC50 of a viral isolate, the more effective is the drug against that particular virus. Among resistant HIV isolates, the IC50 can be many folds higher than that of a wild type virus. The process of HIV-1 entry into host cells is complex and consists of several distinct steps, each of which forms a separate target for inhibition. Enfuvirtide (T-20 or Fuseon by Hoffman-LaRoche) is a 36-amino-acid synthetic peptide that acts as a competitive decoy that disrupts the formation of a six-helix configuration by the exposed transmembrane gp41 protein, a process that is essential for the fusion of the viral envelope and the host cell membrane (12). It has similar activity against HIV-1 strains that use different coreceptors (chemokine receptor 5 [CCR5] or chemokine-related receptor [CXCR4]), but it has no activity against HIV-2. With subcutaneous injections at a dose of 90 mg (1 mL) for an adult, the half-life of the drug is 3.8 hours, necessitating two administrations daily. Enfuvirtide is available as a powder in single-use vials and must be reconstituted with sterile water immediately before each administration. Resistance to the drug is correlated with mutations of the HR1 coding region of the gp41 protein.

Principles of Optimal Highly Active Antiretroviral Therapy (HAART) Some principles on the selection and application of HAART have emerged since 1996 through many clinical trials and expert consensus (9). They can be summarized as follows: ●

●

At least three fully effective antiretroviral drugs should be administered together for a drug-naïve patient as the first regimen. They should be selected from two different classes of agents. Classsparing strategy with triple NRTIs has been shown to be less reliable. A four-drug combination initially has not been shown to be more effective in achieving undetectable viral load or CD4+ recovery. It is not necessary to combine three classes of drugs in the first triple HAART regimen regardless of the plasma level of HIV-RNA. Exposing a patient to three classes of drugs early in the treatment time course can restrict subsequent choices because drug resistance usually crosses over to other drugs within the same class.

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●

●

●

●

When a patient develops virologic failure while on his or her first regimen (usually defined as greater than 1000 copies of HIV-RNA despite 12 weeks of HAART or reemergence after being undetectable previously), the virus can remain fully susceptible if the patient took less than 50% of the prescribed doses. It is advisable to modify the HAART regimen according to in-vitro resistance tests (see Drug Resistance). Simple addition of a new drug to a failing regimen will often be inadequate to suppress the viral load to undetectable level and will likely lead to more resistance. However, most early failure is the result of viral resistance against only one or two drug components of the triple regimen. Therefore, some drugs can still be included or reusable in the next regimen. A second HAART regimen is more likely to be successful if it consists of at least one new drug from a different class; such as a PI if the first regimen had two NRTIs plus one NNRTI, or an NNRTI if the first regimen had two NRTIs plus a PI. There are only four classes of antiretroviral agents available at present; therefore, the patient can use up all the class options after the third regimen. If a patient develops intolerable adverse events while remaining fully suppressed, it is acceptable to change only the offending drug without interrupting the treatment. Treatment interruption must take into account the different drug half-lives to avoid exposing the virus to a single drug with low genetic barrier to resistance development. This is often the case with two NRTIs and efavirenz (very long half-life). Most experts recommend substituting efavirenz with a PI for 5 to 7 days before the final discontinuation. The trough level of any PI correlates well with viral suppression; therefore, enhancing the trough level of a PI by inhibiting its hepatic metabolism has been shown to be a successful strategy. This is often accomplished by administering a PI with ritonavir, a powerful inhibitor of hepatic cytochrome P-450 enzymes. The only exception is nelfinavir because of its unique pathway of metabolism.

Drug Resistance Development of Drug Resistance HIV has a very high propensity to generate genetic variants because of the enormous number of virions turning over daily in a single patient and the notoriously error-prone RT transcribing viral RNA into DNA. On the average, a mistake is likely to be introduced after each genome transcribed. Most errors are base substitutions but deletion, insertion, duplication, and combinations

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of these processes have been demonstrated. Even in a treatment-naïve patient, the likelihood of a tiny population of viruses that have already mutated to be a single drug-resistant genotype at random is high. Drug resistance actually develops quite readily in situations where the drug combination was insufficient to reduce viral replication to an undetectable level but sufficient enough to apply selective pressure on the still replicating viruses (13). Contrary to common misconception, drug resistance is the consequence of treatment failure and not the cause. Treatment failure was the norm before the HAART era. At present, virologic failure occurs when a patient is nonadherent to the dosing protocol, or drug interactions that can reduce therapeutic drug levels were not suspected by the prescribing clinician. Inadequate HAART regimens should be rare if the clinician follows the recommended treatment guidelines (9,14). Signature or key mutations for most drugs have been described, and they can be detected easily by appropriate commercially available resistant genotype tests. Because the transmission of resistant HIV has been increasing in urban areas with large infected-patient populations, it is advisable to request a resistant genotype assay before initiating the first regimen. Clinical failure is far more costly than any resistance assay.

Commercial Resistance Assays Drug resistance generally increases with the accumulation of mutational changes within the various drug targets so it develops gradually over a range of drug concentrations and over time. When a patient develops virologic failure because of a few mutations in the RT or the protease gene, resistance has not reached maximal levels. Additional mutations associated with further increase in resistance can occur without any change of the treatment regimen. Therefore, it is recommended to change the failing regimen early to avoid more cross-resistance to develop within the same class of drugs. Because cross-resistance is common, selection of a new regimen cannot be made on the simple assumption that other drugs of the same class as the failing regimen remain effective. In an effort to facilitate the selection of an efficacious alternative regimen, tests have been developed to determine the susceptibility of HIV to each individual drug. Two types of assays are currently available: genotypic assays, which detect the presence of resistance mutations; and phenotypic assays (Phenosense by Mongram, South San Francisco, CA), which measure the susceptibility of the virus to various drugs in tissue-culture systems. VirtualPhenotype (by Virco, Mechelen, Belgium) is a commercially available interpretation tool based on computer matching of the patient’s genotype with a large database of genotype-phenotype pairs. Clinical correlations have shown that these tests are more reliable in predicting treatment failure than treatment success (13).

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When to Initiate Antiretroviral Therapy in HIV-1–Infected Adults One of the most controversial topics in the medical management of HIV disease is the optimal time to initiate HAART in HIV-1–infected adults. This controversy applies not only to an individual but also to a society. Premature treatment can lead to more resistant viruses and more unwanted toxicities whereas delayed treatment can lead to reduced therapeutic benefit and wider spread of the epidemic (15). Almost everyone agrees that HAART should not be given for an asymptomatic patient with 350 CD4+ cells or more (the early group) (Figure 39-2). Most also agree that HAART should be given for any symptomatic patients, for any patient with less than 200 CD4+ cells (the late group), and for a woman who is pregnant. Two key areas of uncertainty involve asymptomatic patients with HIV-RNA greater than 100,000 copies/mL

HIV-infected adult

CD4 & HIV RNA

Symptomatic

Asymptomatic

CD4 <200

CD4 200-350

Monitor monthly proceed if

CD4 >350

Monitor every 3 months except with other risks

CD4 <20%, VL >105, age >50, rapid rate of CD4 decline (>15/m), no pre-existing resistance, low CV and metabolic risk, readiness, psychosocial stability, coinfection with hepatitis C, no alcohol, no drug

Initiate HAART

Figure 39-2 The decision to initiate highly active antiretroviral therapy is often difficult and should be made individually rather than strictly adhering to published guidelines.

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and those patients with CD4+ cells between 200 and 350 (the intermediate group). More recent clinical trials with more potent HAART regimens did not find any difference in the proportion of patients achieving undetectable level even if the baseline HIV-RNA was greater than 100,000 copies (16). The difference of disease progression between the early group and the intermediate group was significant from observational cohorts on no therapy. However, the relative risks for disease progression for both groups after HAART were so low that observational studies could not determine the optimal timing of initiation. The lack of a randomly assigned clinical trial to address this issue directly has resulted in the substantial variability among international consensus guidelines about the optimal timing of HAART initiation (9,15). There are other risk factors besides the absolute CD4+ cell count that can influence the decision on the timing of initiation. A flow chart is presented to assist clinicians to individualize their decision (Figure 39-3). Those patients

Candidate for HAART

CD4 <50: PI may result in higher CD4 recovery

Chronic hepatitis: avoid NVP & ATV, see text

Opportunistic infections or malignancy, see text

Substance abuse: avoid drug interaction, anticipate sequencing

Renal insufficiency: avoid fixed-dose combination & possible TDF

No other risk

Female

Male: NVP only if CD4 <350

Nonreproductive: NVP only if CD4 <250, avoid d4T

High CV risk: prefers TDF, ABC, 3TC/FTC, NVP, EFV, ATV; avoid ritonavir/PI, d4T/ddI

Reproductive: beware of contraceptive failure, no EFV

High psychiatric risk: avoid EFV

Dependency on proton pump inhibitor: avoid ATV

Figure 39-3 Among the 48 possible triple combinations of drugs to be used as the first HAART regimen, some are considered contraindicated because of the gender and the preexisting co-illnesses of the patient. The clinician must choose the first regimen wisely.

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with low risk of potential adverse events and treatment failure, in accordance to their readiness, male gender, healthy lifestyle without substance abuse, stable psychosocial background, and excellent cardiovascular status, can be considered candidates for earlier treatment. Patients coinfected with hepatitis C can sometimes require earlier treatment because hepatic progression to cirrhosis is accelerated in coinfected patients not receiving HAART. Delaying HAART until the completion of treatment for a preexisting co-illness is sometimes considered a sound approach. Both the CDC and the World Health Organization (WHO) recommend delaying initiation of HAART for 8 weeks while patients are under intensive treatment for tuberculosis to avoid drug interaction with rifampin unless the patient’s CD4+ cell count is less than 50 (17,18). The final decision on initiation should be made with mutual understandings by both the patient and the clinician.

The First HAART Regimen All the clinical trials have confirmed that the proportion of patients achieving undetectable viral load (defined as < 50 copies/mL) with antiretroviral therapy is highest among the drug-naïve population. Therefore, the first regimen is the best regimen for an HIV-infected patient. The regimens of choice from both the Department of Health and Human Services (DHHS) and the International AIDS Society (IAS) panels of experts are mainly based on the clinical efficacy and the general tolerability of the regimen (9,14). Recommendations from these panels are designed to be flexible enough to accommodate many individual differences. The actual regimen should be selected according to personal preferences and known co-illnesses, but most importantly, according to preexisting resistance (Figure 39-4). Transmission of drug-resistant strains of HIV, regardless of the actual route (sex parenteral or vertical), has been well described in newly infected individuals (19). The prevalence of drug-resistant virus in naïve individuals increased dramatically during the second 5-year period after the introduction of HAART. Between 2003 and 2004, among 539 newly diagnosed patients from 65 sites in 5 different states, the CDC found 15.2% had genetic evidence of resistance against at least 1 antiretroviral agent and 3.2% had resistance against more than 1 antiretroviral class. Resistance to NNRTIs occurred with the greatest frequency, at a rate of 9.1% (20). In addition, several studies have documented greater resistance in chronically infected naïve individuals, indicating the persistence of these resistant mutations. Even if the drug-resistant mutation is no longer detectable in serum, the drugresistant variant can persist in the latently infected CD4+ memory T-cell pool. These resistant mutants will rapidly emerge under the selective pressure of HAART. Thus, the early identification of the transmitted resistant variants before they submerge into the latent pool can improve the subsequent selection of the first-line antiretroviral treatment (20).

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Selection of HAART in Patients with Very Low Initial CD4+ Cell Count The recovery of the CD4+ cells can be less complete in patients with very low CD4+ nadir before HAART (21). A recent review of 49 clinical trials involving 13,147 individuals found that the ritonavir boosted PI-based triple regimens resulted in significantly higher CD4+ cell recovery compared to NNRTI-based triple combinations even though there was no difference in proportion of patients achieving less than 50 copies of HIV-RNA (22). The boosted-PIs block HIV replication not only by inhibiting the protease but also by blocking toll-like receptor (TLR)- and tumor necrosis factor-alpha (TNF-alpha)-mediated NF-kappa-B activation and proinflammatory cytokine production (23). These findings can help to explain the immunomodulatory effects of PI and the potential advantage of PI-based regimens in patients with more severely depleted CD4+ cell population.

Selection of HAART for Women The proportion of women among cumulative U.S. AIDS cases has increased from 6.7% in 1986 to 18% in 2002 with women now representing 26% of all new AIDS diagnoses. Heterosexual contact surpassed injection drug use as the predominant method of exposure among new cases of AIDS in women. Observations from the Multicenter AIDS Cohort (MAC) and the Women’s Interagency HIV Study (WIHS) did not find any sex-based difference in response to HAART (24); however, there can be a sex-based difference in tolerability such as fat maldistribution, dyslipidemia, hyperglycemia, and bone disorders. Rash associated with nevirapine was shown to be much higher in women than men, especially in those women having more than 250 CD4+ cells at the beginning of the nevirapine treatment (25). Fatal cases of lactic acidosis have been reported more often in women, especially among those women treated with stavudine and didanosine during pregnancy (9). Efavirenz is rated category D by the FDA because of reported cases of myelomeningocele in newborns whose mothers took the drug during the first trimester of pregnancy. It should be prescribed with great caution for any women of childbearing potential. It has been known that oral contraceptive drugs can fail because their serum levels can be reduced by some antiretroviral agents. The most relevant of these interactions are described in Table 39-10. In general, alternative or additional methods of contraception should be used in women of child-bearing potential who are on highly active antiretroviral therapy. Two related but distinct problems arise in a patient infected with HIV who wishes to become pregnant: management of pregnancy in an HIV-positive woman and management of HIV infection in a pregnant woman. The first problem is not within the scope of this chapter but pregnancy in an HIVpositive woman tends to have more complications. HIV management in a

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Table 39-10 Interactions between Oral Contraceptives and Antiretroviral Agents* Antiretroviral Agent

Interactions with Oral Contraceptives

Lopinavir, ritonavir, nelfinavir, nevirapine, tipranavir

Decrease plasma concentrations of oral contraceptives with the potential for reduced contraceptive efficacy Increase plasma concentrations of oral contraceptives; clinical significance not known Oral contraceptives decrease serum concentrations of amprenavir with the potential for decreased antiretroviral efficacy No data

Atazanavir, efavirenz, delavirdine Amprenavir, fos-amprenavir

Saquinavir

* Family planning should be part of the routine recommendation provided to HIV-infected women; therefore, the effects of antiretroviral drugs on oral contraceptives should be discussed in detail. Alternative contraceptive methods should be provided if necessary.

Table 39-11 Mother-to-Child HIV Transmission Rates Maternal RNA

>30,000 copies/ML 10,00-29,999 3500-9999 400-3499 <400

Transmission Rate

Maternal Treatment

23.4% 14.7% 9.3% 5.3% 1.0%

None Zidovudine alone Dual-drug therapy HAART

Transmission Rate

20.0% 10.4% 3.8% 1.2%

* Mother-to-child transmission rates are listed according to maternal HIV-RNA copies at the time of delivery and the treatment for the mother before delivery. Abbreviation: HAART, highly active antiretroviral therapy.

pregnant woman should be directed at improving maternal health and reducing mother-to-child transmission. Maximizing viral suppression by the time of delivery is the primary objective because transmission rates substantially lower as maternal plasma levels of HIV-RNA decrease (Table 39-11). Because the risk associated with exposing the fetus to antiretroviral agents during the period of organogenesis is unknown, clinicians can choose to defer initiation of treatment until the second trimester of pregnancy. Data on antiretroviral toxicity and teratogenicity are available through the Antiretroviral Pregnancy Registry (www.apregistry.com) and are also summarized in the treatment guidelines (9). With limited options for NNRTIs because of potential toxicity, the use of PIs for prevention of mother-to-child transmission is increasing. The American College of Obstetricians and Gynecologists recommends offering the option of cesarean delivery to women whose viral load could not be suppressed to less than 1,000 copies/mL at 38 weeks. Most infants born to mothers who are HIV-positive are treated with a 6-week course of oral zidovudine syrup initiated as soon as possible after birth. Alternative therapy should be used if zidovudine resistance in the mother is known or suspected. Serial testing for HIV and evaluations for symptoms of HIV infection and toxic effects of drugs should be scheduled by the pediatrician (26).

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Selection of HAART for Highly Experienced Patients There are high levels of cross-resistance within the three orally available classes of drugs, and it can be difficult to construct a successful regimen without relying on the injectable fusion inhibitor enfuvirtide when the patient has already failed twice (27). With greater treatment experience and drug-resistance, patients can reach a point when complete virologic suppression is not achievable. In this situation, the goal is to delay CD4+ T-cell decline while preserving as many partially active drugs as possible until other new effective agents become available. Unfortunately, complete treatment interruption was associated with increased incidence of AIDS-related illness, especially among patients with CD4+ T-cells at 250 or less (28). Partial treatment interruption keeping the failing NRTIs, especially 3TC or FTC but stopping all NNRTIs and PIs, similar to a holding regimen, seems to be able to maintain stable levels of viremia with preservation of immunologic function for up to 24 weeks (29). Recent evidence indicated that there is a strong inverse relationship between the degree of partial viral suppression and the magnitude of immunological benefit (30). The immunological benefit can be derived from many factors: the residual activity of drugs against the resistant variants; the selective maintenance of a viral population with reduced replicative capacity; preserved intrathymic T-cell production; decreased peripheral T-cell activation; and a sustained level of HIV-specific T-cells. Highly treatment-experienced patients are probably best managed by highly experienced HIV providers.

Drug Interactions One of the most challenging aspects of clinical care for HIV-infected patients is the appropriate management of all the potential interactions between antiretroviral agents. The field becomes increasingly more complex as new medications are added to the antiretroviral armamentarium, particularly because it is difficult to comprehensively study all possible drug-drug interactions before the launch of a new agent. Thus, the clinician is sometimes faced with the daunting task of trying to predict the levels of individual drugs when the patient is taking more than three drugs with different interaction potentials. Frequently, the pharmacokinetic profiles of new combinations can become unpredictable when nonantiretroviral drugs are also included. In general, PIs are inhibitors of cytochrome P-450 enzyme (CYP) 3A4, although some of them are also inducers of their own metabolism (e.g., ritonavir). The inhibition of CYP 3A4 has important pharmacokinetic implications. Administration of low doses of ritonavir leads to such a marked inhibition of the metabolism of other PIs that their plasma levels can be significantly enhanced. In fact, this intervention has led to a complete revolution in the field of PI therapy.

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Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used and are considered highly effective in the treatment of dyslipidemia. Because of the metabolic changes brought about by some of the antiretroviral agents, it is likely that HIV-infected patients can require statin therapy at some point in time. Most statins are metabolized through the cytochrome P-450 system, and potent metabolic inhibitors such as protease inhibitors can lead to elevated statin levels. Muscle toxicity that can range from asymptomatic elevations of CPK to significant rhabdomyolysis has been reported in patients taking both classes of drugs (31). Some statins are less affected than others; therefore, caution should be exercised when using these two drug classes simultaneously (Table 39-12). There is less of an interaction between NNRTIs and statins. However, efavirenz can accelerate the metabolism of atorvastatin, and simvastatin and lead to decreased levels and efficacy (32). On the contrary, delavirdine can inhibit the metabolism of lovastatin, simvastatin, and atorvastatin with the potential for higher serum levels and higher rate of toxicity. There are no known significant interactions between statins and NRTIs. It has been reported recently that acid-reducing agents (ARA) such as antacids, H2-receptor antagonists, proton pump inhibitors, and even buffered medications, can lead to inadequate gastric absorption of atazanavir by decreasing gastric acidity. Decreased clinical efficacy has been reported when atazanavir was used with proton pump inhibitors (33). Thus, efforts should be directed at cautioning patients about the concomitant use of these classes of medications because many ARAs can be purchased over the counter without physician knowledge or supervision. Widely used calcium-channel blockers such as diltiazem and amlodipine, and highly popular erectile dysfunction drugs such as sildenafil, vardenafil, and tadalafil are metabolized by cytochrome P-450. The serum levels of these drugs can be increased by the various PIs. It has been described that the use of indinavir and ritonavir is associated with increased bioavailability of both diltiazem and amlodipine with the potential for greater vascular dilatation and decreased cardiac conductivity (34). There is some preliminary information that suggests that this can also happen with atazanavir and diltiazem. When it is necessary to use these two classes of drugs simultaneously with a protease inhibitor, it is advisable to lower their doses to avoid toxicity.

Table 39-12 Interactions between Statins and Protease Inhibitors* Statin

Comments

Atorvastatin Fluvastatin Lovastatin Pravastatin Simvastatin

Can be used with caution Can be used with caution Should not be used Safe to use Should not be used

* Hyperlipidemia is very common with antiretroviral agents, but the most commonly prescribed statins can have drug interactions.

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It has been known for many years that the popular St. John’s Wort (Hypericum perforatum) is a potent inducer of cytochrome P-450. Significant pharmacokinetic interactions are possible between this common home remedy and many medications. Its use can lead to significantly enhanced PI and NNRTI metabolism with correspondingly lower plasma levels (35). Patients on antiretroviral therapy should be warned against its use. Grapefruit juice is also known to be a P-450 inhibitor, and its use has been associated with increased levels of saquinavir (36).

Lifelong Use of HAART When effective antiretroviral therapy first became available in the mid1990s, the expectation was that effective viral suppression would eventually lead to eradication of HIV infection. Even the state-of-the-art therapy has important limitations. Some of these limitations are better recognized because of advances in our knowledge of antiretroviral therapy over the last 10 years. It is now known that HIV infection becomes latent in longlived resting memory CD4+ T-lymphocytes, and that this reservoir of infected cells decays very slowly with an estimated half-life of approximately 44 months (37). This slow decay rate essentially guarantees lifetime persistence of infected latent T-lymphocytes with replication competent virus. Even with only one out of every million resting CD4+ T-lymphocytes having latent HIV infection, HAART would have to be given for more than seven decades to achieve viral eradication (38,39). Antiretroviral therapy is designed to interrupt the replication cycle of HIV; it has no effect against dormant, chromosomally integrated HIV. In the absence of antiretroviral therapy and on immune stimulation, these resting T-lymphocytes can become activated and will produce virus. Thus, even after years of effective viral suppression, discontinuation of HAART is promptly followed by a recurrence of viremia. It has become evident that this latently infected pool of T-lymphocytes makes viral eradication within the lifetime of HIV-infected individuals extremely unlikely. Thus, antiretroviral therapy will most likely be required throughout the lifetime of an HIV-infected patient. With lifelong therapy, any potential adverse events related to HAART, that can seem insignificant in short-term clinical trials, will be magnified many folds years later. Metabolic disturbances associated with some of the HIV drugs pose particular concerns to most HIV health care providers.

Adherence to Treatment Because HAART can be lifelong and any deviation from the prescribed treatment regimen can result in inadequate viral suppression, strict adherence to the treatment protocol is the key to long lasting success. Adherence to HAART

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is a challenge for even the most motivated individual. It has been identified that the five main obstacles to perfect adherence are: forgetfulness, antiretroviral regimen complexity, medication adverse effects, inadequate understanding of the significance of adherence, and social and physical environment (40). Patients can be reminded to take their pills by electronic devices or by direct phone calls. One-way cell phones can be provided to patients if they cannot afford a common cell phone on their own. Treatment complexity can be simplified with once daily regimens, and most adverse events can be prevented or minimized if the correct regimen was chosen first. If the provider has a good relationship with his or her patients, inadequate understanding of the significance of adherence is uncommon. The last but the biggest hurdle to adherence continues to be the social and physical environment of the patient. Social prejudice and poverty remains untouchable to the best clinician. Directly observed treatment, especially with an outreach team, can assist those few patients who have a known address and who are willing to cooperate. Short of incarceration, some of the patients who live at the fringes of our society remain out of reach regardless of the efforts from the health care providers.

Treatment Failure Treatment failure in HIV can be defined in three ways: virologic failure, immunologic failure, or clinical failure. Virologic failure is defined as the failure to achieve less than 400 copies of HIV-RNA or less than 50 copies of HIV-RNA after 24 weeks or 48 weeks of HAART respectively. Immunologic failure is defined as progressive decline in CD4+ T-lymphocytes, and clinical failure is defined as progression of clinical disease, especially the development of a new AIDS-defining illness (see Table 39-3). In clinical practice, virologic failure is more relevant in the selection of HAART. Although discordance of responses can occur, a maximally suppressed patient is not failing therapy simply because of a poor immune recovery or a new clinical event because a new HAART regimen would not have resulted in a different outcome. A rare exception is the potential CD4+ T-cell suppression caused by a drug combination such as TDF/ddI (41). Clinical approach to virologic failure should be guided by the reason for failure. Nonadherence, drug toxicity, or pharmacokinetic factors must be addressed accordingly. If the virologic failure is suspected to be the result of development of drug resistance, resistance assays are appropriate for a virologic rebound greater than 1,000 copies. Many clinical trials have demonstrated that a virologic rebound can occur in a patient without the development of any resistance mutation. A negative resistance assay can uncover subtherapeutic drug levels caused by nonadherence or other pharmacokinetic factors. Low level viremia, those between 50 and 400 copies/mL, are sometimes called blips, and these blips are not necessarily associated with virologic

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failure or evolution of drug resistance. In many cases, blips are not true viremia but laboratory variability, especially with the ultrasensitive viral load assays. False-positive viral load can occur because of incorrect handling of blood specimens. It has also been suggested that blips can sometimes be caused by the release of virus from the latent reservoirs (42). The challenge for clinicians is to decide whether a small detectable viral load is caused by blips or early development of true virologic resistance.

Patients with HIV and Chronic Kidney Disease Chronic kidney disease (CKD) is an important complication of HIV infection. Most HIV-associated nephropathy (HIVAN) is caused by a collapsing form of focal glomerulosclerosis with tubulointerstitial injury presenting as a nephrotic syndrome. Kidney function is abnormal in up to 30% of HIVinfected patients, and 1.5% (range 0.3%-3.4%) of dialysis patients were reported to have HIV infection in 2000 (43). It is recommended that all HIVinfected patients should be screened for existing kidney disease with a screening urine analysis for proteinuria and a calculated estimate of renal function. Patients at high risk for CKD (e.g., African American persons, those with CD4+ cell <200/uL, those with diabetes mellitus, hypertension or chronic hepatitis C) should be rescreened annually (44). There is evidence of direct intrarenal HIV infection in the pathogenesis of HIVAN; therefore, HAART should not be withheld regardless of renal function. In addition to being effective in treating established HIVAN, HAART can decrease the actual incidence of de-novo HIVAN. Recent data from the United States Renal Data System (USRDS) has demonstrated that the death rates for patients with HIVAN have improved compared with death rates in the pre-HAART era. The rates are now approaching the death rates in the general end-stage renal disease (ESRD) population. The benefit of angiotensin-converting enzyme (ACE) inhibition has been shown, and the benefit can be related to alleviated renal hemodynamic, reduced proteinuria, or cytokine modulation. However, calcium-channel blockers of both dihydropyridine and nondihydropyridine classes should be used with caution because of their potential interaction with PIs, which can result in hypotension and possibly in conduction delays. All the NRTIs except abacavir (ABC) are primarily excreted by the kidneys; therefore, dosage should be adjusted in those patients with impaired renal function (44). NRTIs can be easily removed by dialysis; therefore, they should be administered after dialysis (although an extra dose to supplement the loss during dialysis is not required). Fixed dose combinations should be avoided because the two or three drug components can require different adjustments. NNRTIs, PIs, and enfuvirtide do not require dose adjustments because they are primarily metabolized by the liver. Nephrolithiasis is a major side effect of indinavir therapy because of its pH-based solubility in

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the urine. This complication can be more common with ritonavir-boosted indinavir regimen, and it can be prevented by a daily intake of at least 1.5 L of water. Indinavir should not be withheld in patients with severe kidney disease for fear of increased risk of nephrolithiasis because little of the drug will actually reach the collecting system. Tenofovir belongs to the acyclic nucleoside phosphonate class of medications, including adefovir and cidofovir. Renal toxicity of this class of drugs is caused by proximal tubular accumulation of the excreted unchanged compound which seems to be concentration dependent. Nephrotoxicity is characterized by the Fanconi syndrome (hypokalemia, hypophosphatemia, metabolic acidosis, albuminuria/proteinuria, glucosuria, and calciuria). The incidence of renal dysfunction with tenofovir has been quite low, on the order of 0.5% to 1.5% in clinical trials, but patients with preexisting renal impairment were excluded.

Patients with Concurrent AIDS-Defining Illnesses Depending on the clinician’s practice setting, a significant proportion of patients requiring initiation of HAART can have substantially advanced HIV infection by the time they come to medical attention. In such patients, CD4+ cell counts can be low enough (e.g., <100 cells/mm3) that AIDSdefining infections or malignancies can be present. Under these circumstances, treatment of the opportunistic infection or a life-threatening malignancy (e.g., central nervous system lymphoma) is imperative and takes precedence over other interventions. However, as soon as the patient can reliably tolerate oral medications, antiretroviral therapy should be initiated. It has been shown that in patients with advanced AIDS and recent opportunistic infections, initiation of HAART is safe, well-tolerated, and, most importantly, effective in controlling viral replication and beginning the process of immune restoration (45). In fact, for certain infections such as progressive multifocal leukoencephalopathy for which there is no specific therapy, prompt initiation of HAART can be the best and only therapeutic intervention available (46,47). The therapy for many common opportunistic infections such as Pneumocystis jiroveci pneumonia, central nervous system toxoplasmosis, cytomegalovirus ocular or gastrointestinal disease, and candida esophagitis does not pose a challenge with respect to immediate initiation of antiretroviral therapy other than the patient’s willingness and ability to begin the latter. The one significant exception to this is infection with Mycobacterium tuberculosis. Among the drugs used for first-line therapy of M. tuberculosis disease, rifampin has important interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors because of their common metabolism through the cytochrome CYP 3A4 isozyme (48). Specifically, rifampin administration leads to such an enhancement of the metabolism of these two drug

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classes that their plasma levels are decreased below concentrations where reliable antiretroviral activity can be expected. Thus, PIs and NNRTIs should not be used in patients receiving rifampin. The strategy of using single-class treatment with either triple or quadruple nucleosides (with or without nucleotide) regimens was considered unacceptable because of high rates of virologic failures with these regimens. In HIV patients with active tuberculosis for whom rifampin must be given, antiretroviral therapy should be delayed until treatment of tuberculosis is completed. The other treatment strategy is to substitute rifampin with rifabutin, an analogue of rifampin that retains significant antimycobacterial activity with less induction of CYP 3A4. However, the interactions between rifabutin and antiretroviral agents are complex (48). Because NNRTIs increase rifabutin clearance, concomitant use of these medications requires an increase in the total daily dose of rifabutin from 300 mg to 450 mg. Interactions with PIs are more complex. Lopinavir, ritonavir, atazanavir, or fos-amprenavir all decrease rifabutin clearance, and their use requires a decrease in the total daily dose of rifabutin to 150 mg. Indinavir and nelfinavir decrease rifabutin clearance at the same time that rifabutin increases their clearance; thus, when used simultaneously, doses of these PIs have to be increased although the dose of rifabutin has to be decreased.

Hepatic Diseases and HAART Progressive liver disease is one of the leading causes of illness and death in the HIV-infected patient population (49). Liver toxicities related to HAART can be highly variable, from asymptomatic elevation of aminotransferases to fulminant hepatic failure, from early idiosyncratic hepatitis to late immunerestoration injury. Liver enzyme elevations have been reported in both randomly assigned clinical trials and cohort observational studies (50,51). Unconjugated hyperbilirubinemia associated with indinavir and atazanavir are usually not considered to be true liver injury because it resembles Gilbert syndrome clinically. These two PIs directly inhibit the activity of the hepatic enzyme uridine diphosphate (UDP)-glucuronosyltransferase (UGT) leading to a reversible indirect hyperbilirubinemia. HIV significantly modifies the natural history of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection by accelerating the risk of cirrhosis (52, 53). HCV infection, especially among active injection drug users, was shown to be an important factor in the illness and death rates of HIV-1–infected patients, possibly through impaired recovery of CD4+ cell levels (54). On the contrary, cases of liver deterioration paralleling the immune restoration or CD4+ cell recovery in HIV/HCV and HIV/HBV coinfected patients have been reported (55,56). This paradoxical effect of HAART on chronic hepatitis, sometimes referred to as the immune reconstitution syndrome (IRS), calls attention to the question of temporal sequence of HIV and HCV treatment.

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For those patients with relatively intact CD4+ T-cell and a favorable HCV serotype (II or III), it is advisable to eradicate the HCV infection before initiating HAART to avoid additive drug toxicities or the paradoxical hepatic deterioration from immune restoration. Three antiretroviral drugs, 3TC, emtricitabine, and tenofovir, also have excellent activity on HBV (57). Sequential treatment of HBV and HIV is not feasible given the overlapping drug activities and the potential for the development of resistance by either virus. Therefore, the strategy and management of HBV in HIV-infected patients must take into consideration both viral infections together.

Immune Reconstitution Syndrome Some patients had clinical deterioration after the initiation of HAART, and the pathogenesis of their illness is thought to be the consequence of their restored ability to effectively mount an immune response against an occult or preexisting infection. This phenomenon has been IRS, or immune restoration syndrome, or immune reconstitution inflammatory syndrome (IRIS). The clinical manifestation varies widely, depending on the organ that is targeted by the restored immune system. Most cases present with fever and lymphadenitis, and the clinical course is usually self-limiting; however, deaths have been reported in cases with progressive multifocal leukoencephalopathy (PML), cryptococcal or tuberculous meningitis. The incidence can be up to 25% of patients whose CD4+ cells were less than 50/mm3 at the time of their first HAART. The following case definition of IRS was recently proposed by a group from the University of Cincinnati: a clinical entity with the presence of symptoms of infection or inflammatory disease; presence of symptoms occurring after the initiation of antiretroviral therapy; demonstration of adequate virologic response to therapy (1 log10 decrease in viral load); and presence of symptoms not explainable by a newly acquired infectious or inflammatory condition. The requirement of an increase in CD4+ cells was not included because it was thought that plasma cell number does not always reflect function (58). The infectious conditions most frequently found in association with the syndrome are mycobacterial (M. tuberculosis and M. avium complex), viral (cytomegalovirus, herpes zoster, hepatitis B and C, genital herpes, varicella zoster, and PML), and fungal (Pneumocystis and cryptococcal) diseases. Other noninfectious and autoimmune processes such as thyroiditis, Grave disease, and sarcoidosis have all been reported to be associated with IRS.

Recurrent Acute Retroviral Syndrome A relatively rare phenomenon that is seen after abrupt discontinuation of antiretroviral treatment is a syndrome similar to that seen at the time of acute HIV

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infection. This has been described in patients on therapy for both acute and chronic HIV infection a few days to a few weeks after they have discontinued HAART (59,60,61). The syndrome is characterized by a marked rebound of the viral load, fever, generalized lymphadenopathy, and a skin rash. It can also be accompanied by a precipitous decrease in the CD4+ cell levels. Anecdotal experience seems to suggest that these symptoms, just like those of the acute retroviral syndrome seen with primary HIV infection, are selflimiting. However, reinitiation of HAART frequently leads to resolution of symptoms, resuppression of viral RNA, and restoration of CD4+ cell counts.

Metabolic Syndrome and Cardiovascular Risk in HIV-Infected Adults Morphologic changes such as subcutaneous lipoatrophy (especially involving the face and the limbs), and relative or absolute accumulation of central fat have been seen in up to 50% of HIV-infected adults receiving HAART. These morphologic changes were strongly associated with changes of the lipid profile and the development of hyperinsulinemia among affected individuals. The largest prospective study of the prevalence of dyslipidemia and the associated cardiovascular (CV) risk with antiretroviral therapy is the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study (62). Hypercholesterolemia (total cholesterol level >240 mg/dL) was found in 27% and hypertriglyceridemia (triglyceride level >200 mg/dL) in 40% of individuals receiving a treatment regimen consisting of both NRTI and PI, as compared with 8% and 15% respectively among untreated patients. This study also found that the rate of myocardial infarction increased with longer PI exposure time, and the relative risk of MI per year of HAART exposure was 1.26 (95% CI, 1.09-1.41). The mechanisms of increased vascular disease in HIV-infected patients are not known but are not simply related to prolonged exposure to antiretroviral drugs. HIV patients can have a higher incidence of CV disease because of chronic viral infection, acute-phase reactants, circulating cytokines, and impaired fibrinolysis. A recent report from a large randomly assigned treatment interruption trial found that HIV-infected adults who were randomly assigned to receive continuous antiretroviral treatment had less CV complication than those patients who were given only a third of the drug exposure because of predetermined treatment interruption according to CD4+ T-cell counts (62). Hyperinsulinemia, a surrogate measure of insulin resistance, is commonly seen in association with lipoatrophy and central fat accumulation. Among HIV-infected adults with those changes, diabetes mellitus was seen in 7%, and impaired glucose tolerance was seen in 35% as compared with 0.5% and 5% respectively of otherwise healthy control individuals matched for age and body-mass index (63). The rate at which impaired glucose tolerance progresses to overt diabetes mellitus is not known.

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In all HIV-infected patients, all the traditional risk factors for CV disease and diabetes mellitus should be assessed. Fasting lipid, glucose, and insulin levels should be measured annually before HAART is initiated, and within 1 to 2 months after any change in the treatment regimen. Anthropometric measurements of truncal and limb fat, including measurement of waist, hip, and thigh circumferences periodically can provide additional information about lipoatrophy and metabolic risks from HAART. Whenever possible, the antiretroviral medications least likely to worsen lipid levels should be selected for patients with high CV risk (see Table 39-5). In general, a HMG-CoA reductase inhibitor (statin) should be used to treat isolated hypercholesterolemia, and a fibrate should be used to treat isolated hypertriglyceridemia. Combined statin-fibrate therapy can be considered when the response is incomplete, provided that there is appropriate safety monitoring. Until more specific recommendations become available, National Cholesterol Education Program (NCEP) guidelines are considered equally applicable to HIV patients. In patients with central obesity and hyperinsulinemia, metformin 500 mg twice daily has been shown to alleviate insulin sensitivity, decreased visceral adiposity and CV risk markers, but lactate levels, hepatic, and renal functions must be monitored (64). Metformin can reduce subcutaneous fat, it should be avoided for those patients with significant lipoatrophy. Thiazolidinediones such as rosiglitazone were found to be beneficial on insulin resistance and one study also showed improvement on limb fat. However, rosiglitazone was associated with increased total cholesterol and low-density lipoprotein (LDL)-cholesterol levels (65). Cessation of therapy with the thymidine nucleoside analogue stavudine or zidovudine generally leads to substantial improvements in limb-fat mass. Other strategies such as lifestyle modification and dietary changes should also be incorporated to achieve maximum benefit from pharmacologic intervention (66).

Management of Occupational and Nonoccupational HIV Exposure Estimates of the probability of HIV transmission after a single occupational or nonoccupational exposure are shown in Table 39-13. The actual risk from any specific exposure situation is dependent on so many variables that it can be quite different from the average estimates shown. The role of the clinician is to assess the risk of HIV transmission after a careful history of the exposure event and to provide appropriate counseling and follow-up care if necessary. The decision to provide postexposure prophylaxis (PEP) for HIV is measured by the assessed risk, the source individual if available, and the previous serological status of the involved individual (Table 39-14). Clinicians should advise the patient that there is no proof that antiretroviral treatment decreases the risk of HIV infection after occupational or nonoccupational exposures. There is only sound biologic plausibility, positive

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Table 39-13 Estimated Odds of HIV Transmission After a Single Exposure* Exposure Method

Odds

Hollow needle stick Receptive anal intercourse Receptive vaginal intercourse Insertive vaginal intercourse Insertive anal intercourse Receptive oral fellatio with ejaculation Sharing needles

1 1 1 1 1 1 1

in in in in in in in

300 100 1000 2000 1600 2500 150

* These estimates apply to an individual who engages in certain unprotected activity. The device is presumed contaminated, and the sexual partner is presumed seropositive.

Table 39-14 Indications for HIV Postexposure Prophylaxis if Source Is Positive or Unavailable* Occupational Exposure

Nonoccupational Exposure

Deep injury by hollow needles Visible blood on the sharp device Prior insertion of the device into an artery or vein Contamination by blood, body fluid, CSF, seminal fluid, vaginal secretion, amniotic fluid on mucosal surface, or nonintact skin Suture needle injury on ungloved hand High viral titer in the source patient

Unprotected receptive anal intercourse Sharing needles or using a discarded needle Unprotected receptive vaginal intercourse Unprotected insertive anal intercourse

Rape victim Unprotected receptive fellatio with ejaculation

* Not all occupational or nonoccupational exposures require prophylaxis. The exposures listed in the table are considered high risk and prophylaxis should be provided. Abbreviation: CSF, cerebrospinal fluid.

observation from animal studies, and supportive evidence from perinatal transmission (67). There was only one retrospective non-randomly assigned case-control trial demonstrating that PEP with zidovudine alone was associated with an 81% reduction in the odds of HIV transmission with a percutaneous exposure in the occupational setting, but there are also documented cases of PEP failure in health care workers (68). Similarly, there are no data showing any benefit of PEP after sexual and injectiondrug use exposure, but common medical practices have accepted PEP in the nonoccupational settings. Wound care should follow basic first aid principles. Douching or other local cleansing methods after sexual exposures is not known to be beneficial. The source should be tested by a rapid HIV-antibody test (if permission is granted) to provide results within 20 minutes (69). Many states have specific regulations pertaining to the situation when the source declines to be tested. If the patient meets any of the indications listed in Table 39-14, PEP

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should be initiated as soon as possible and no later than 72 hours after the exposure. Free consultation is available from The National Clinicians’ Postexposure Prophylaxis Hotline (PEPline) 24 hours a day at www.ucsf. edu/ hivcntr or 1-888-HIV-4911. PEPline is run by the University of California San Francisco and the San Francisco General Hospital staff, with the support from the CDC. Because the only PEP study used zidovudine as monotherapy, many experts prefer the inclusion of ZDV or AZT in the PEP regimen regardless of the drug-resistance information from the source individual. Dual NRTI regimen, especially using the fixed dose coformulation, is considered safe and convenient unless a third drug is deemed necessary. The addition of a third drug is often considered for those individuals who suffered a high-risk exposure, or there are known drug-resistance to a dual NRTI regimen (67). The routine reliance on triple combinations for patients with long-standing infection can not apply to prophylaxis because the viral inoculum associated with any exposure is much smaller than the viral burden of an infected patient. Abacavir and efavirenz seem to be reasonable alternatives as a third drug in PEP; however, the potential hypersensitivity reaction with ABC and the high prevalence of drug resistance with efavirenz (EFV) raise caution for their selection. Nevirapine has been associated with severe liver toxicity in PEP for health care workers, and it should be avoided (70). A protease inhibitor will be a preferable third choice. In our institution, the combination of TDF/FTC is the preferred dual NRTI, and the combination of LPV/RTV is the preferred PI for PEP, because of their tolerability and low prevalence of resistance. The principles of postexposure management are summarized in Table 39-15.

Table 39-15 Principles of Management of Occupational and Nonoccupational HIV Exposure 1. Assess the risk of transmission of HIV and other blood-borne viruses caused by the exposure event. 2. Discuss with the patient the risks and benefits of postexposure prophylaxis. 3. If the decision of treatment is made, choose an appropriate regimen, and prescribe for 28 days. 4. Screen for other medical conditions that can complicate treatment such as anemia and renal insufficiency. 5. Counsel patients about the importance of sexual abstinence during postexposure prophylaxis (PEP) and adherence to the protocol. 6. Discuss guidelines and procedures that will reduce future exposure and safe sexual practices. 7. Follow patients for potential adverse events from PEP and surveillance for symptoms suggestive of the acute-HIV syndrome. 8. Repeat HIV test for seroconversion in appropriate time intervals. 9. Reinforce counseling messages.

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REFERENCES 1. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med. 1981;305:1425-31. 2. Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al. Isolation of a Tlymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983;220:868-71. 3. Popovic M, Sarngadharan MG, Read E, Gallo RC. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS. Science. 1984;224:497-500. 4. Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317:184-91. 5. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995;373:123-6. 6. Rosenberg ES,Altfeld M, Poon SH, Phillips MN,Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523-6. 7. 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS among Adolescents and Adults. MMWR Recomm Rep. 1992, December 18;41:RR-17. 8. Goulder PJ, Walker BD. HIV-1 superinfection—a word of caution [Editorial]. N Engl J Med. 2002;347:756-8. 9. DHHS. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available at: http://AIDSinfo.nih.gov. Accessed April 2005. 10. 2NN Study team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004;363:1253-63. 11. Flexner C. HIV-protease inhibitors. N Engl J Med. 1998;338:1281-92. 12. Kilby JM, Eron JJ. Novel therapies based on mechanisms of HIV-1 cell entry. N Engl J Med. 2003;348:2228-38. 13. Clavel F, Hance AJ. HIV drug resistance. N Engl J Med. 2004;350:1023-35. 14. International AIDS Society-USA panel. Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel. JAMA. 2006;296:827-43. 15. Wood E, Hogg RS, Harrigan PR, Montaner JS. When to initiate antiretroviral therapy in HIV-1infected adults: a review for clinicians and patients. Lancet Infect Dis. 2005;5: 407-14. 16. King MS, Bernstein BM, Walmsley SL, Sherer R, Feinberg J, Sanne I, et al. Baseline HIV-1 RNA level and CD4 cell count predict time to loss of virologic response to nelfinavir, but not lopinavir/ritonavir, in antiretroviral therapy-naive patients. J Infect Dis. 2004; 190:280 4. 17. Centers for Disease Control, ATS, IDSA. Treatment of tuberculosis. Available at: www.cdc. gov/mmwr/preview/mmwrhtml/rr5211a1.htm. 18. Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. Lancet Infect Dis. 2005;5:415-30. 19. Little SJ, Holte S, Routy JP, Daar ES, Markowitz M, Collier AC, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002;347:385-94. 20. Bennett D, McCormick L, Kline R, et al. U.S. surveillance of HIV drug resistance at diagnosis using HIV diagnostic sera. Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections; February 22-25, 2005; Boston, Massachusetts. Abstract 674. 21. Kaufmann GR, Furrer H, Ledergerber B, et al. Characteristics, determinants, and clinical relevance of CD4 T-cell recovery to <500 cells/uL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Disease. 2005;41:361-72. 22. Bartlett J, Fath M, DeMassi R, et al. An updated meta-analysis of triple combination therapy in antiretroviral-naïve HIV-infected adults. 12th conference of retroviruses and opportunistic infections, February 22-25, 2005; Boston, Massachusetts. Abstract 586. 23. Equils O, Shapiro A, Madak Z, Liu C, Lu D. Human immunodeficiency virus type 1 protease inhibitors block toll-like receptor 2 (TLR2)- and TLR4-Induced NF-kappaB activation. Antimicrob Agents Chemother. 2004;48:3905-11. 24. Giordano TP,Wright JA, Hasan MQ,White AC Jr., Graviss EA,Visnegarwala F. Do sex and race/ethnicity influence CD4 cell response in patients who achieve virologic suppression during antiretroviral therapy? Clin Infect Dis. 2003;37:433-7. 25. Wong KH, Chan KC, Lee SS. Sex differences in nevirapine rash [Letter]. Clin Infect Dis. 2001;33:2096-8.

Tan ch39.qxd 10/12/07 5:27 PM Page 758

758

Expert Guide to Infectious Diseases

26. Riley LE,Yawetz S. Case records of the Massachusetts General Hospital. Case 32-2005. A 34year-old HIV-positive woman who desired to become pregnant. N Engl J Med. 2005;353:1725-32. 27. Nelson M, Arastéh K, Clotet B, Cooper DA, Henry K, Katlama C, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr. 2005;40:404-12. 28. Montaner J, Harris M, Hogg R. Structured treatment interruptions: a risky business [Editorial]. Clin Infect Dis. 2005;40:601-3. 29. Deeks SG, Hoh R, Neilands TB, Liegler T, Aweeka F, Petropoulos CJ, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis. 2005;192:1537-44. 30. PLATO Collaboration. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet. 2004;364:51-62. 31. Adult AIDS Clinical Trials Group Cardiovascular Subcommittee. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37:613-27. 32. AIDS Clinical Trials Group A5108 Team. Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr. 2005;39:307-12. 33. Antoniou T, Yoong D, Beique L, Chirhin S, Rachlis A, Gough K, et al. Impact of acid-suppressive therapy on virologic response to atazanavir-based regimens in antiretroviral-experienced patients: a case series [Letter]. J Acquir Immune Defic Syndr. 2005;39:126-8. 34. Adult AIDS Clinical Trials Group A5159 Protocol Team. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers. Clin Pharmacol Ther. 2005;78:143-53. 35. Henderson L,Yue QY, Bergquist C, et al. St John’s Wort (Hypericum perforatum): Drug interactions and clinical outcomes. Br J Clin Pharmacol. 2002;54349-56. 36. Kupferschmidt HH, Fattinger KE, Ha HR, Follath F, Krähenbühl S. Grapefruit juice enhances the bioavailability of the HIV protease inhibitor saquinavir in man. Br J Clin Pharmacol. 1998;45:355-9. 37. Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9:727-8. 38. Simmons R, Siliciano RF. Can antiretroviral therapy ever be stopped? An update. AIDS Read. 2004;14:435-8, 441-2. 39. Siliciano RF. Scientific rationale for antiretroviral therapy in 2005: viral reservoirs and resistance evolution. Top HIV Med. 2005;13:96-100. 40. Roberts KJ. Barriers to and facilitators of HIV-positive patients’ adherence to antiretroviral treatment regimens. AIDS Patient Care STDS. 2000;14:155-68. 41. Negredo E, Bonjoch A, Paredes R, Puig J, Clotet B. Compromised immunologic recovery in treatment-experienced patients with HIV infection receiving both tenofovir disoproxil fumarate and didanosine in the TORO studies. Clin Infect Dis. 2005;41:901-5. 42. Tokars JI, Frank M,Alter MJ,Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2000. Semin Dial. 2002;15:162-71. 43. Gupta SK, Eustace JA, Winston JA, Boydstun II, Ahuja TS, Rodriguez RA, et al. Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2005;40:1559-85. 44. Sungkanuparph S, Kiertiburanakul S, Manosuthi W, Kiatatchasai W, Vibhagool A. Initiation of highly active antiretroviral therapy in advanced AIDS with CD4 < 50 cells/mm3 in a resource-limited setting: efficacy and tolerability. Int J STD AIDS. 2005;16:243-6. 45. GESIDA 11/99 Study Group. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis. 2003;36:1047-52. 46. Giudici B,Vaz B, Bossolasco S, Casari S, Brambilla AM, Lüke W, et al. Highly active antiretroviral therapy and progressive multifocal leukoencephalopathy: effects on cerebrospinal fluid markers of JC virus replication and immune response. Clin Infect Dis. 2000;30:95-9.

Tan ch39.qxd 10/12/07 5:27 PM Page 759

HIV Infection

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47. Finch CK, Chrisman CR, Baciewicz AM, Self TH. Rifampin and rifabutin drug interactions: an update. Arch Intern Med. 2002;162:985-92. 48. Soriano V, García-Samaniego J,Valencia E, Rodríguez-Rosado R, Muñoz F, González-Lahoz J. Impact of chronic liver disease due to hepatitis viruses as cause of hospital admission and death in HIV-infected drug users. Eur J Epidemiol. 1999;15:1-4. 49. Spengler U, Lichterfeld M, Rockstroh JK. Antiretroviral drug toxicity—a challenge for the hepatologist? J Hepatol. 2002;36:283-94. 50. Becker S. Liver toxicity in epidemiological cohorts. Clin Infect Des. 2004;38(suppl 2): S49-55. 51. Gilson RJ, Hawkins AE, Beecham MR, Ross E,Waite J, Briggs M, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS. 1997;11:597-606. 52. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-Infected Person. Ann Intern Med. 2003;138:197-207. 53. Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet. 2000;356:1800-5. 54. Zylberberg H, Pialoux G, Carnot F, Landau A, Bréchot C, Pol S. Rapidly evolving hepatitis C virusrelated cirrhosis in a human immunodeficiency virus-infected patient receiving triple antiretroviral therapy. Clin Infect Dis. 1998;27:1255-8. 55. Fowkes FG, Leng GC, Donnan PT, Deary IJ, Riemersma RA, Housley E. Serum cholesterol, triglycerides, and aggression in the general population. Lancet. 1992;340:995-8. 56. Dore G J, Cooper DA, Barrett C, Goh LE,Thakrar B,Atkins M. Dual efficacy of lamivudine treatment in human immunodeficiency virus/hepatitis B virus-coinfected persons in a randomized, controlled study (CAESAR). The CAESAR Coordinating Committee. J Infect Dis. 1999;180:607-13. 57. Robertson J, Meier M,Wall J,Ying J, Fichtenbaum C J. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis. 2006;42:1639-46. 58. Kilby JM, Goepfert PA, Miller AP, Gnann JW Jr., Sillers M, Saag MS, et al. Recurrence of the acute HIV syndrome after interruption of antiretroviral therapy in a patient with chronic HIV infection: A case report. Ann Intern Med. 2000;133:435-8. 59. Kilby JM, Goepfert PA, Miller AP, Gnann JW Jr., Sillers M, Saag MS, et al. Recurrence of the acute HIV syndrome after interruption of antiretroviral therapy in a patient with chronic HIV infection: A case report. Ann Intern Med. 2000;133:435-8. 60. Daar ES, Bai J, Hausner MA, Majchrowicz M,Tamaddon M, Giorgi JV. Acute HIV syndrome after discontinuation of antiretroviral therapy in a patient treated before seroconversion. Ann Intern Med. 1998;128:827-9. 61. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349:1993-2003. (Erratum, N Engl J Med. 2004;350:955.) 62. Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis. 2001;32:130-9. 63. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA. 2000;284:472-7. 64. Hadigan C,Yawetz S,Thomas A, et al. Metabolic effects of rosiglitazone in HIV lipodystrophy: A randomized, controlled trial. Ann Inter Med. 2004;140:786-4. 65. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352:48-62. 66. Katz MH, Gerberding JL. Management of occupational and nonoccupational postexposure HIV prophylaxis. Current HIV/AIDS Reports. 2004;1:159-65. 67. Cardo DM, Culver DH, Ciesielski CA Srivastava PU, Marcus R, Abiteboul D, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med. 1997;337: 1485-90. 68. Centers for Disease Control and Prevention. Notice to readers: approval of a new rapid test for HIV antibody. MMWR Recomm Rep. 2002;51:1051-2. 69. Centers For Disease Control And Prevention. Serious Adverse Events Attribute To Nevirapine Regimens For Postexposure Prophylaxis After HIV Exposures—Worldwide, 1997-2000. MMWR Morb Mort Wkly Rep. 2001;49:1153-6.

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Chapter 40

Opportunistic Infections in Patients with AIDS MICHAEL J. TAN, MD

Key Learning Points 1. Pneumocystis jiroveci pneumonia commonly occurs in patients with CD4 T cell counts less than 200 cells/mm3. Treatment and prophylaxis are primarily with TMP-SMX based therapies. 2. Patients with cerebral toxoplasmosis are often diagnosed and treated on clinical and radiographic grounds. Biopsy of suspicious lesions should be performed in the setting of treatment failure. 3. Cryptococcosis and cryptococcal meningitis are readily diagnosed through cryptococcal antigen assays and clinical suspicion. Treatment courses are typically protracted with high likelihood of recurrence. 4. Mycobacterium avium complex (MAC) infection can be focal or disseminated infection. Extra consideration should also be given to immune reconstitution inflammatory syndrome that may be seen in AIDS patients with rapidly recovering CD4 T cell counts. 5. Cytomegalovirus (CMV) infection most commonly manifests as retinitis but often may also affect the pulmonary and gastrointestinal organs. There is significant toxicity associated with the antiviral therapy modalities.

A

cquired immune deficiency syndrome (AIDS) is the clinical syndrome that represents the late stage of infection with human immunodeficiency virus type 1 (HIV-1). HIV infection over time causes a progressive decline in CD4 T lymphocytes. Currently, AIDS is defined as an HIV-positive patient with CD4 T-lymphocyte counts less than 760

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New Developments in the Management of Opportunistic Infections in Patients with AIDS ●

●

●

●

Pneumocystis jiroveci is specific to human disease. Previously known as Pneumocystis carinii, the name is now reserved for Pneumocystis specific to rodents. DNA testing can aid Mycobacterial species identification to help differentiate tuberculous and non-tuberculous mycobacterium. Polymerase Chain Reaction testing for CMV DNA aids in detection and diagnosis even with low levels of CMV. Due to its superior gastrointestinal absorption, valganciclovir replaces oral ganciclovir in most situations where therapy for CMV is indicated and oral equivalents may be employed.

200 cells/mm3, a CD4 T lymphocyte less than 14%, or presentation with any of several AIDS-defining diagnoses listed in Table 40-1 (1). Loss of CD4 T-lymphocyte cell-mediated immunity leaves the host susceptible to many opportunistic infections or neoplasms. Opportunistic infections are those infections that arise primarily in the setting of an immune compromised host. Although the incidence of opportunistic infections has decreased dramatically since the beginning of the highly active antiretroviral therapy (HAART) era, opportunistic infections are still significant causes of illness in patients with undiagnosed and late stage AIDS (2). An exhaustive review of all of the opportunistic infections that occur in patients with AIDS is beyond the scope of this chapter. Thus, this chapter will review characteristics of the most common opportunistic infections in patients with AIDS. It will also address diagnosis, treatment, and prevention of each entity.

Pneumocystis jiroveci Pneumonia Formerly known as Pneumocystis carinii, the taxonomy has changed, P. carinii now refers only to Pneumocystis that infect rodents. Pneumocystis jiroveci is specific to the individual species that infects humans. Before the advent of the HIV epidemic, P. jiroveci pneumonia (PCP) was seen only sporadically in immunocompromised hosts. Patients usually had hematologic malignancies or organ transplants, or received high-dose corticosteroids. Because of HAART and appropriate PCP-prophylaxis therapy, the incidence of PCP has decreased more than 20% between 1992 and 1998. Nearly half of the cases of PCP were in patients who were not previously receiving medical care (2). Of the 39% of patients who receive a diagnosis of AIDS as a result of AIDS-defining opportunistic infection, 24% have a definitive diagnosis of PCP and 14% have a presumptive diagnosis; it is the most commonly presenting AIDS-defining opportunistic infection (3).

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Table 40-1 Conditions Included in the 1993 AIDS Surveillance Case Definition ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ● ● ● ● ● ● ● ●

Bacterial infections, many or recurrent (children younger than 13 years of age) Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal Cervical cancer, invasive Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 mo duration) Cytomegalovirus disease other than retinitis, liver, spleen, lymph nodes Cytomegalovirus retinitis with loss of vision Encephalopathy, HIV related Herpes simplex, with esophagitis, pneumonitis, or chronic mucocutaneous ulcers Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal Kaposi sarcoma Lymphoid interstitial pneumonia and/or pulmonary lymphoid hyperplasia Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Mycobacterium avium-intracellulare or Mycobacterium kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site Mycobacterial disease, other mycobacterium, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrent Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome caused by HIV Immunosuppression, severe HIV related, CD4 T cell count >200 or CD4 percentage younger than age 14 years in adults/adolescents who meet the AIDS surveillance case definition

Abbreviation: mo = month.

Organism and Etiology Pneumocystis jiroveci is a ubiquitous organism classified as a fungus but that shares biologic characteristics with protozoa. Its classification is a continued point of debate. Initial infection with Pneumocystis occurs during childhood, and two thirds of healthy children have antibodies to P. jiroveci by 2 to 4 years of age (4). PCP is thought to result from reactivation of latent infection or new exposure to the organism through airborne acquisition (5). Deficiency of cell-mediated immunity is the most significant predisposing factor for P. jiroveci infection.

Clinical Manifestations Patients with PCP most commonly present with fever, nonproductive cough, dyspnea, and chest pain. Clinical course is often subacute with gradual worsening of symptoms over several weeks before diagnosis is established. Lung auscultation is often normal, but diffuse crackles should

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not be unexpected. Extrapulmonary sites may also be present and include lymph nodes, bone marrow, spleen, and liver.

Diagnosis Chest radiographs that demonstrate diffuse bilateral interstitial infiltrates can be suggestive of PCP in the appropriate clinical setting but is by no means pathognomonic. Typically, chest radiographs will have diffuse bilateral interstitial infiltrates. Occasionally, focal or nodular infiltrates may be present. Cavitation, blebs, bullae, and cysts have also been reported. Pneumothorax occurs in a small percentage of patients, and in the presence of AIDS, should be presumed to be associated with PCP (6). CD4 cell counts are typically less than 200 cells/mm3; however, PCP can occur with any CD4 count. Arterial blood gas measurements often reveal hypoxemia or an increased alveolar-arterial (A-a) oxygen gradient. Although nonspecific, serum lactate dehydrogenase (LDH) level is increased in as many as 90% of patients with PCP (7). Demonstration of characteristic cyst forms in respiratory specimens stained with Gomori methenamine silver, toluidine blue, or periodic acidSchiff stain is generally required for diagnosis of PCP. Expectorated sputum alone is often unsatisfactory and generally not submitted for staining; induced sputum specimens may have sensitivities of 55% to 95% (8). Bronchoscopy with bronchoalveolar lavage is often the preferred method for obtaining deep respiratory specimens and optimizing diagnostic yield.

Treatment Treatment of PCP is generally with trimethoprim-sulfamethoxazole (TMPSMX) 15 to 20 mg/kg per day in 3 to 4 divided doses for 21 days with the route of administration dependent on whether or not the patient can be given oral or intravenous medication. For patients with mild to moderate disease, oral TMP-SMX is effective. Patients with more severe disease, who are acutely ill, or have a room air PO2 less than 70 mm Hg are generally given intravenous therapy. In addition, use of corticosteroids within the first 72 hours of anti-PCP treatment has been shown to be effective in patients with severe disease (5). The recommended regimen of prednisone (or intravenous equivalent) is 40 mg twice daily for 5 days, followed by 40 mg daily for 5 days, then 20 mg daily for 11 days or until PCP therapy is completed (9,10). PCP therapies are summarized in Table 40-2 (9).

Prevention Prevention of PCP in HIV-infected individuals is indicated for patients with 1) CD4 count less than 200 cells/mm3, 2) unexplained oropharyngeal candidiasis in an HIV patient regardless of the CD4 count, or 3) unexplained fever for 2 weeks. Table 40-3 summarizes recommendations for

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Table 40-2 Drug Therapies for Pneumocystis jiroveci Pneumonia Mild to Moderate Disease* Drug

Dosage

First-line therapy: TMP-SMX

TMP PO 15-20 mg/kg/d Rash, fever, bone marrow in 3-4 divided doses for 21 d suppression, hepatotoxicity ● TMP PO 15-20 mg/kg/d ● TMP: rash ● Dapsone: hemolysis in 3-4 divided doses ● Dapsone PO 100 mg/d (especially G6PD for 21 d deficiency), methemoglobinemia ● Clindamycin 300-450 mg ● Clindamycin: diarrhea, PO q6-8h Clostridium difficile ● Primaquine base 15 mg/d colitis ● Primaquine: hemolysis for 21 d (especially G6PD deficiency), methemoglobinemia ● Rash 750 mg PO bid for 21 d ● Fever ● GI disturbance ● Hepatotoxicity

Alternative: TMP + dapsone

Alternative: Clindamycin + primaquine

Alternative: Atovaquone

Adverse Effects

Moderate to Severe Disease† Drug

Dosage

Adverse Effects

First-line therapy: TMP-SMX

TMP 15-20 mg/kg/d IV in 3-4 divided doses for 21 d

●

Alternative: Pentamidine

4 mg/kg/d IV for 21 d

Alternative: Clindamycin + primaquine

●

●

Clindamycin 600-900 mg IV q8h Primaquine base 15-30 mg/d PO for 21 d

Alternative: Trimetrexate 45 mg/m2 (with leucovorin 20 mg/m2 IV or PO q6h) for 21 d

Rash Fever ● Bone marrow suppression ● Hepatotoxicity ● Hypotension ● Hypoglycemia ● Hyperglycemia ● Pancreatitis ● Neutropenia ● Nephrotoxicity ● Cardiac arrhythmias ● Clindamycin: diarrhea, Clostridium difficile colitis ● Primaquine: hemolysis (especially G6PD deficiency), methemoglobinemia Bone marrow suppression ●

* Defined as not acutely ill, able to take oral medications, room air PO2 > 70 mm Hg. † Defined as acutely ill and room air PO2 < 70 mm Hg. Abbreviations: d = day; G6PD = glucose-6-phosphate-dehydrogenase; GI = gastrointestinal; h = hour; IV = intravenous; PO = by mouth; q = every; TMP-SMX = trimethoprim-sulfamethoxazole.

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Table 40 -3 Prophylaxis for Pneumocystis jiroveci Pneumonia Drug

Dosage

First-line: TMP-SMX Alternative: TMP-SMX Alternative: Dapsone Alternative: Dapsone + Pyrimethamine + Leucovorin

1 DS or SS PO qd 1 DS PO 3× qwk ● 50 mg PO 2 × d ● 100 mg PO qd ● Dapsone 50 mg PO qd ● Pyrimethamine 50 mg PO qwk ● Leucovorin 25 mg PO qwk or ● Dapsone 200 mg PO qwk ● Pyrimethamine 75 mg PO qwk ● Leucovorin 25 mg PO qwk 300 mg nebulized qmo 1500 mg PO qd

Aerosolized pentamidine Atovaquone

Abbreviations: d = day; DS = double strength; mo = month; q = every; PO = by mouth; SD = single strength; TMP-SMX = trimethoprim-sulfamethoxazole; wk = week.

prevention (11). It should be considered that aerosolized pentamidine is only efficacious for PCP and not extrapulmonary Pneumocystis. Patients diagnosed with PCP should continue prophylaxis beyond the treatment period. However, unless patients have had PCP with a CD4 cell count greater than 200 cells/mm3, secondary prophylaxis is generally safe to discontinue with immune reconstitution of a CD4 cell count greater than 200 cells/mm3 for more than 3 months on HAART (12). Patients without a diagnosis of PCP may discontinue prophylaxis should their CD4 counts increase to more than 200 cells/mm3 for at least 3 months (11).

Cerebral Toxoplasmosis Cerebral toxoplasmosis is the most common mass lesion of the central nervous system (CNS) in patients with AIDS. It occurs in up to 40% of patients with advanced immunosuppression and is most commonly seen in patients with CD4 less than100 cells/mm3 and latent Toxoplasma gondii infection (13). Approximately 4% of patients who present with an AIDS-defining illness present with a definitive or presumptive diagnosis of cerebral toxoplasmosis (3).

Organism and Etiology Toxoplasma gondii is an obligate intracellular protozoan. Humans are generally infected by ingestion of the cysts found in undercooked meats or the ingestion of the oocysts excreted by cats. Human cells are invaded after hematogenous and lymphatic dissemination with resulting inflammation and necrosis of involved tissues. The infection incidence increases with age. In the healthy host, the infection is generally asymptomatic (14). In the United

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States, the seroprevalence is approximately 15% with a range of 10% to 40% (5,15). Patients with immunosuppression caused by hematologic malignancy, transplant, of AIDS are at much higher risk than the general population for developing Toxoplasma encephalitis. It has been reported in 1% to 5% of AIDS patients (14). In patients with advanced immunosuppression in the pre-antiretroviral therapy (pre-ART) era, the 12-month incidence of toxoplasmosis was approximately 33% (5).

Clinical Manifestations AIDS patients with cerebral toxoplasmosis present with a focal encephalitis with headache, confusion, motor weakness, and fever. Common symptoms include headache (55%), confusion (52%), fever (47%), lethargy (43%), and seizures (29%). Focal neurological signs were present in 69% of patients; the most common were hemiparesis, ataxia, and cranial nerve palsies (16).

Diagnosis Most patients with cerebral toxoplasmosis have a CD4 count less than 100 cells/mm3, and most patients with HIV have a reactive anti-Toxoplasma IgG. Patients without detectable Toxoplasma IgG are not likely to have active disease; however, the absence of antibodies does not exclude the diagnosis. Polymerase chain reaction testing of cerebrospinal fluid has limited utility because of its low sensitivity; however, it is highly specific. Computed tomography (CT) of the brain usually demonstrates a single or many ring-enhancing lesions; at least 2 lesions should be present to make a diagnosis. Magnetic resonance imaging (MRI) of the brain with gadolinium-67 enhancement is more sensitive for cerebral toxoplasmosis and should be used either as the initial test, or for follow-up of a CT with less than 2 lesions (15,16). Many lesions are more suggestive of cerebral toxoplasmosis than CNS lymphoma, which often presents with a solitary mass lesion. Biopsy of the lesions in question may be necessary for a definite diagnosis. Alternatively, most patients will have clinical and radiographic improvement within 2 weeks after start of treatment; follow-up MRI demonstrating resolution of the CNS lesions is often sufficient to make a diagnosis of cerebral toxoplasmosis. If there is no clinical or radiographic improvement, biopsy should be done to rule out abscess or malignancy.

Treatment For patients with an appropriate clinical history and suggestive radiographic findings, treatment may be initiated before a definite diagnosis is made. Treatment regimens for cerebral toxoplasmosis are outlined in Table 40-4 (16-19). Again, biopsy should be considered in patients who do not respond to therapy.

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Table 40-4 Drug Therapies for Cerebral Toxoplasmosis First-Line Therapy (4-6 wk)

Pyrimethamine 100-200 mg PO (loading dose) then 50-100 mg PO d plus Leucovorin 10 mg PO d plus Sulfadiazine 1-2 g PO q6h Alternative Therapies (4-6 wk)

Pyrimethamine 100-200 mg PO (loading dose) then 50-100 mg PO d plus Leucovorin 10 mg PO d plus 1 of the following: Clindamycin 600-1200 mg IV q6h or 300-450 mg PO q6h Azithromycin 1200-1500 mg PO d Clarithromycin 1g PO 2×d Atovaquone 750 mg PO q6h Note: Corticosteroids are usually used adjunctively if significant edema or mass effect is present. Abbreviations: d = day; h = hour; IV = intravenously; PO = orally; q = every; wk = week.

Prevention Patients who have no evidence of cerebral toxoplasmosis and do not have detectable antibodies to Toxoplasma should be counseled about avoiding exposure to Toxoplasma. Patients who have CD4 counts of less than 100 cells/mm3 should be started on prophylaxis (Table 40-5). Patients whose CD4 counts have recovered to greater than 200 cells/mm3 for more than 3 months may discontinue prophylaxis. Patients who have been diagnosed with cerebral toxoplasmosis who are asymptomatic and have completed a full course of therapy may discontinue their maintenance therapy if their CD4 counts have increased to more than 200 cells/mm3 for at least 6 months. Patients whose CD4 counts have not recovered on HAART and have completed a full course of therapy should be continued on a maintenance regimen until they have sufficient immune reconstitution (19,20). Secondary prophylaxis is outlined in Table 40-5 (21).

Table 40-5 Prophylaxis for Toxoplasma Infection Indication

First Line

Alternative

Primary IgG antibody to TMP-SMX 1 DS PO d Prophylaxis Toxoplasma species and CD4 < 100 cells/mm3

TMP-SMX 1SS PO qd Dapsone 50 mg PO qd + pyrimethamine 50 mg PO qwk + leucovorin 25 mg PO qwk Secondary Maintenance Pyrimethamine Pyrimethamine 25-75 Prophylaxis therapy after 4-6 wk 25-75 mg PO d + mg PO qd + treatment for acute leucovorin 10-25 mg leucovorin 10-25 mg disease PO d + sulfadiazine PO qd + clindamycin 500-1000 mg PO 4×d 300-450 mg PO q6-8h Abbreviations: d = day; DS = double strength; PO = by mouth; q = every; wk = week.

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Cryptococcosis Cryptococcosis is a relatively common fungal disease that affects AIDS patients. It is responsible for approximately 5% of all patients presenting with an AIDS-defining illness (3). Before ART, approximately 5% to 8% of HIV-1–infected patients developed cryptococcosis. Most patients affected by cryptococcosis have CD4 counts less than 50 cells/mm3.

Organism and Etiology Cryptococcus neoformans is encapsulated yeast and is ubiquitous. Most cases found in the United States are associated with C. neoformans–variety neoformans. Most commonly associated with bird excreta, C. neoformans can remain infectious for several years because of its thick capsule. Infection with C. neoformans arises from inhalation of the organisms that subsequently germinate in the lungs. When the fungal inoculum is high or there is impaired host immunity, the organism can hematogenously disseminate with a particular predilection toward the central nervous system (22).

Clinical Manifestations The most common presentation of cryptococcosis is a subacute meningitis or meningoencephalitis with fever, malaise, and headache. Meningismus and photophobia are relatively uncommon, occurring in less than one third of all patients. Other symptoms may include seizures and focal neurological deficits. Although less common, altered mentation may also be present. Disseminated disease is relatively common with or without meningitis. AIDS patients with disseminated disease are more likely to have pulmonary involvement. Pulmonary disease may manifest with cough, dyspnea, and abnormal radiographic imaging. Cutaneous and ocular lesions are also possible. CNS and pulmonary cryptococcomas are relatively uncommon (5,22,23).

Diagnosis In addition to the clinical presentation, cryptococcal antigen detection by latex agglutination is highly sensitive and specific and can be done on CSF and serum. Cerebrospinal fluid findings usually demonstrate a mildly elevated protein, a normal or low glucose, and few lymphocytes. Organisms are often visible on India ink of the CSF and are often cultured from blood or CSF samples. The opening pressure is usually very high.

Treatment The treatment of cryptococcosis is still somewhat controversial. Currently, the recommended initial treatment of cryptococcal meningitis is amphotericin B with flucytosine for 2 weeks, followed by an additional 8 weeks of oral

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Table 40-6 Preferred Treatment Options for Central Nervous System Cryptococcal Infection Induction and Consolidation ●

● ● ● ● ● ● ● ●

AmB 0.7-1.0 mg/kg/d + flucytosine 100 mg/kg/d for 2 wk, then fluconazole 400 mg/d for 8 wk ABLC/AmB 4 mg/kg/d for 2 wk, then fluconazole 400 mg/d for 8-10 wk ABLC/AmB 5 mg/kg/d × 6-10 wk AmB 0.7-1.0 mg/kg/d + flucytosine 100 mg/kg/d for 6-10 wk AmB 0.7-1.0 mg/kg/d for 2 wk then fluconazole 400 mg/d for 8-10 wk AmB 0.7-1.0 mg/kd/d for 6-10 wk Fluconazole 400-800 mg/d + flucytosine 100-150 mg/kg/d for 6-10 wk Fluconazole 400-800 mg/d for 10-12 wk Itraconazole 400 mg/d for 10-12 wk

Maintenance ● ●

Fluconazole 200-400 mg PO qd for life Itraconazole 200 mg PO 2 × d for life

Abbreviations: ABLC = amphotericin B lipid complex; AmB = Amphotericin B; d = day; PO = orally; q = every; wk = week.

fluconazole. Lipid formulations of amphotericin B are also acceptable. Other potential regimens are listed in Table 40-6 (24,25). Patients who have relatively mild disease with a low CSF cryptococcal antigen titer, normal mental status, and a normal CSF leukocyte count may be considered for initial oral therapy with fluconazole; however, in patients with AIDS, cryptococcosis tends to be much more difficult to eradicate and likely to relapse; intravenous treatment with amphotericin B should be considered the first-line agent. Patients on amphotericin B should be monitored for nephrotoxicity and electrolyte abnormalities, and patients receiving flucytosine should be monitored for bone marrow suppression. Patients with symptomatic elevations in intracranial pressure should have daily lumbar puncture done to normalize the pressure. Follow-up lumbar puncture to ensure the clearing of the organism and monitoring of the serum cryptococcal antigen are generally not useful. CSF cryptococcal antigen monitoring may be beneficial to monitor response; however, this requires repeated lumbar puncture and is generally not recommended (5). Consultation with an infectious disease specialist experienced in treatment of cryptococcosis should be obtained.

Prevention AIDS patients who have completed a course of therapy for cryptococcosis should be maintained on lifelong suppressive therapy with fluconazole 200 mg daily to prevent recurrence. Some authorities note that secondary prophylaxis may be discontinued in patients with sustained immune reconstitution with CD4 counts greater than 100 to 200 after 6 months on ARV, who have completed a full course of therapy for cryptococcosis, and who have no signs or symptoms of the disease. However, no guidelines have been established (5,26). Should the CD4 count decrease to less than 100 to

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200, secondary prophylaxis should be reinitiated (5). Although primary prophylaxis is generally not recommended, in select AIDS populations with CD4 cells less than 50 where the risk of cryptococcosis is high, fluconazole 100 to 200 mg daily is acceptable.

Mycobacterium avium Complex Infection caused by Mycobacterium avium complex (MAC) is fairly common in the HIV population. In patients without prophylaxis for MAC organisms and without active ART, the incidence of disseminated MAC is approximately 20% to 40%. The incidence is dramatically reduced in patients with a suppressed viral load and MAC chemoprophylaxis (5).

Organism and Epidemiology Mycobacterium avium complex organisms are ubiquitous in the environment. They are acid-fast nonpigmented bacilli typically found in water, soil, and food and are carried by various animal species (27). Transmission is thought to be through inhalation or ingestion. Household contacts are not at increased risk for experiencing disease caused by MAC, and personto-person transmission is unlikely. Disease caused by MAC is generally seen in patients whose CD4 T cell count is less than 50 cells. Other factors associated with disseminated MAC disease include previous opportunistic infections, previous colonization or infection with MAC, and high HIV viral load (more than 100,000 copies) (5).

Clinical Manifestations Disease caused by MAC is generally disseminated with multiorgan involvement. Typical symptoms include fever, night sweats, weight loss, fatigue, abdominal pain, and diarrhea. Also seen is an immune reconstitution inflammatory syndrome (IRIS) primarily involving patients with AIDS who have a rapid increase in CD4 cells with the initiation of ART. This syndrome typically includes fever and focal lymphadenitis that may be rapidly progressing. These patients may not have mycobacterial bacteremia. Because of the availability and use of more effective and potent antiretrovirals, IRIS is becoming a more common syndrome and should be considered in any patient with rapid response to HAART. Other clinical manifestations of disseminated MAC disease include pneumonitis, pericarditis, osteomyelitis, skin and soft tissue abscess, genital ulcers, and CNS infection (5). Physical examination findings are often limited; however, lymphadenopathy, hepatomegaly, and splenomegaly are not uncommon. Radiographs may demonstrate lymph node enlargement. Common lab abnormalities include anemia and elevated alkaline phosphatase. Other

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exam findings may correlate with regional signs and symptoms mentioned previously (5).

Diagnosis In conjunction with an appropriate clinical presentation, diagnosis may be confirmed by the isolation of MAC organisms from suspected culture sites. Bacteremia is direct and definitive. Biopsy and culture of suspect sites such as lymph nodes may also yield mycobacterial organisms. Sputum and stool specimens are often positive for acid fast organisms; however, the clinical context must be considered because these organisms often colonize the respiratory and gastrointestinal tract. Specific species identification can often be done with DNA or biochemical tests (27).

Treatment The preferred initial treatment of disseminated MAC infection is with clarithromycin 500 mg twice daily and ethambutol 15 mg/kg daily or azithromycin 500 mg daily and ethambutol 15 mg/kg daily. Occasionally, rifabutin 300 mg daily is added to this regimen. Fluoroquinolones and intravenous amikacin are also effective alternatives (27). Clofazimine is generally viewed as ineffective for MAC therapy (28). Duration of therapy is unclear; however, 6 months to 1 year is accepted. Antiretrovirals should be initiated soon after the initiation of MAC therapy.

Prevention Patients with CD4 T cell counts less than 50 should receive chemoprophylaxis for MAC infection. Azithromycin 1200 mg weekly or clarithromycin 500 mg twice daily are acceptable regimens. Rifabutin 300 mg daily is an acceptable alternative as long as infection with M. tuberculosis is not suspected. Prophylaxis should not be initiated if patients demonstrate signs or symptoms suggestive of disseminated disease; mycobacterial disease should be ruled out before initiating prophylaxis. In general, patients who have been diagnosed with disseminated MAC infection should remain on lifelong prophylaxis with 1 of the aforementioned agents. However, discontinuation of primary and secondary prophylaxis in asymptomatic patients whose CD4 counts have recovered to greater than 100 cells for at least 6 months is generally considered safe (20).

Cytomegalovirus Cytomegalovirus (CMV) is a common viral opportunistic infection in patients with AIDS. Most infections arise from reactivation of latent infection in patients with advanced immunosuppression (5).

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Organism and Epidemiology Cytomegalovirus is a double-stranded DNA virus in the herpesvirus family. Disseminated or local end-organ disease may result from reactivation of latent infection. Before ART, approximately 30% of AIDS patients had CMV retinitis. End-organ disease tends to occur in patients whose CD4 T cell count is less than 50 or who have failed to respond to ART. Other risk factors include previous history of opportunistic infection, MAC disease, and high HIV viral load (5).

Clinical Manifestations Cytomegalovirus may present with many manifestations in patients with AIDS. CMV retinitis is the most common clinical manifestation of CMV end-organ disease. Retinitis may be unilateral or bilateral, peripheral, or central. Peripheral disease may be asymptomatic or present with floaters, scotomata, or peripheral visual field defects. Central retinal lesions are associated with central visual field defects or diminished visual acuity. Patients with CMV colitis may present with fever, weight loss, anorexia, abdominal pain, and persistent diarrhea. Gastrointestinal hemorrhage and perforation are potential complications. Esophagitis may present with fever, odynophagia, nausea, and mid-epigastric or retrosternal discomfort. Pneumonitis is less common but may cause shortness of breath, cough, and hypoxemia. Chest radiographs may have interstitial infiltrates. CMV neurologic disease, dementia, ventriculoencephalitis, and ascending polyradiculomyelopathy have also been described (5).

Diagnosis Cytomegalovirus may be detected by standard viral or shell vial culture; however, CMV is most readily detected by PCR of serum or end-organ samples. CMV antibody titers are usually not helpful; negative CMV IgG does not exclude CMV viremia, especially in patients with advanced immunosuppression. Tissue biopsy of end-organ disease with characteristic histopathologic changes is acceptable means of diagnosis. Direct funduscopic examination by an experienced examiner may reveal characteristic ophthalmologic changes (29).

Treatment Antivirals such as oral valganciclovir, intravenous ganciclovir, cidofovir, and foscarnet are effective treatments for CMV retinitis. Treatment options for CMV retinitis are summarized in Table 40-7 (29). Ganciclovir intraocular implants in addition to valganciclovir is also effective and seems to be superior to once-daily oral valganciclovir at preventing relapse (30). In most cases where oral therapy is indicated, valganciclovir is preferred more than

IV Ganciclovir + IV foscarnet

IV Foscarnet

Induction: 5 mg/kg q12h for 14-21 d Maintenance: 5 mg/kg/d Induction: 90 mg/kg q12h for 14-21 d Maintenance: 90-120 mg/kg/d (500-1000 mL 0.9% saline with each dose)*

IV Ganciclovir

Adverse Effects

Advantages

Disadvantages

Median Time to Retinitis Progression

Opportunistic Infections in Patients with AIDS

Continued

Neutropenia, Systemic therapy, Hematologic toxicity; 47-104 d thrombocytopenia, anti-HSV activity requires daily infusions, line sepsis indwelling catheter Nephrotoxicity, Systemic therapy, Nephrotoxicity; requires 53-93 d electrolyte abnormalities, anti-HSV activity daily infusions, indwelling anemia, nausea, genital (including acyclovir catheter, supplemental ulceration, line sepsis -resistant strains) hydration, a prolonged infusion time, and infusion-pump/ controlled-rate device For prior ganciclovir: Same as ganciclovir and Same as ganciclovir Same as ganciclovir 129 d Induction: ganciclovir foscarnet; toxicity of and foscarnet and foscarnet; additive 5 mg/kg/d for 14-21 d + ganciclovir and or synergistic toxicity of foscarnet 90 mg/kg foscarnet may be these agents together is q12h for 14-21 d additive or synergistic significant; generally, Maintenance: ganciclovir if used together using an alternative agent 5 mg/kg/d + foscarnet to previous therapy 90-120 mg/kg/d should be considered first For prior foscarnet: Induction: ganciclovir 5 mg/kg q12h for 14-21 d + foscarnet 90-120 mg/kg/d for 14-21 d Maintenance: ganciclovir 5mg/kg/d + 90-120 mg/kg/d

Dosage

Treatment

Table 40-7 Treatment Options for Cytomegalovirus Retinitis

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Disadvantages

216-226 d

160 d

Systemic therapy; no Requires probenecid and 64-120 d indwelling catheter IV hydration; probenecid required; infrequent toxicity, nephrotoxicity dosing (may be prolonged)

Systemic therapy, Hematologic toxicity oral administration, good oral bioavailability Longest time to Increased risk of disease retinitis progression in other eye and of in treated eye; no extraocular disease IV dosing or catheter required

Advantages

Abbreviations: d = day; HSV = Herpes simplex virus; IV = intravenous; mo = month; q = every; PO = by mouth; wk = week. * May require dosage adjustment for renal insufficiency. ** All doses given with probenecid and IV fluids.

IV Cidofovir

Intraocular ganciclovir implant

Induction: 900 mg Neutropenia, nausea, q12h for 14-21 d diarrhea Maintenance: 900 mg q24h Surgical implantation: Surgical complications 4.5 mg implant releasing (e.g., transient blurred 1 µg/h vision, infection, Duration: 6-8 mo; replace hemorrhage) q5-8mo Recommended concomitant systemic therapy: ganciclovir 4500 mg/d PO in 3 divided doses Induction: 5 mg/kg/wk Nephrotoxicity, for 2 wk neutropenia, uveitis, Maintenance: 5 mg/kg alopecia, hypotonia every 2 wk** Probenecid adverse effects: rash, fever, nausea, fatigue

PO Valganciclovir

Adverse Effects

Dosage

Median Time to Retinitis Progression

774

Treatment

Table 40-7 Continued

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ganciclovir because of ganciclovir’s poor bioavailability. Appropriate ART with sufficient immune reconstitution may be sufficient at controlling retinitis; however, immune reconstitution uveitis has been seen. Nonocular cytomegalovirus infections may be treated with ganciclovir, foscarnet, or oral valganciclovir. Patients on any therapy for cytomegalovirus should be monitored closely for side effects. Ganciclovir and valganciclovir are associated with neutropenia, thrombocytopenia, nausea, diarrhea, and renal dysfunction. Foscarnet has been associated with anemia, nephrotoxicity, electrolyte abnormalities, neurologic dysfunction, and genital ulceration. Cidofovir is associated with nephrotoxicity and hypotony. Ganciclovir and foscarnet have also been associated with seizures. Optimized HAART therapy should also be instituted (5).

Prevention Chronic lifelong prophylaxis is recommended for patients with CMV retinitis unless they have significant immune reconstitution with ART with sustained CD4 T cell counts greater than 100. The role of maintenance therapy for gastrointestinal and pulmonary CMV has not been established. Primary prophylaxis is not indicated. Secondary prophylaxis can be discontinued in patients with a CD4 T cell count greater than 100 to 150 for more than 6 months if proper ophthalmologic exams can be done regularly (5,30).

REFERENCES 1. Centers for Disease Control and Prevention. 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep. 1992;41(RR-17):1-19. 2. Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;30 Suppl 1:S5-14. 3. Centers of Disease Control and Prevention. HIV/AIDS Surveillance Report. 1997; 9 (No. 2):18. 4. Pifer LL, Hughes WT, Stagno S, Woods D. Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children. Pediatrics. 1978;61:35-41. 5. Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK. Treating opportunistic infections among HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Clin Infect Dis. 2005;40:S131-235. 6. Sepkowitz KA,Telzak EE, Gold JWM, et al. Pneumothorax in AIDS. Ann Intern Med. 1991;114455-9. 7. Zaman MK,White DA. Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia. Diagnostic and prognostic significance. Am Rev Respir Dis. 1988;137: 796-800. 8. Santamauro JT, Stover DE. Pneumocystis carinii pneumonia. Med Clin North Am. 1997;81:299-318. 9. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:343-5. 10. Bozzette SA, Sattler FR, Chiu J,Wu AW, Gluckstein D, Kemper C, et al. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990;323:1451-7. 11. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:41-3.

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12. Eight European Study Groups. Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups. N Engl J Med. 2001;344:168-74. 13. Luft BJ, Remington JS. AIDS commentary. Toxoplasmic encephalitis. J Infect Dis. 1988; 157:1-6. 14. Couvrer J, Leport C. Toxoplasma gondii. In: Yu V, Weber R, Raoult D, eds. Antimicrobial Therapy and Vaccines. New York, NY: Apple Tree Productions; 2003:1679-93. 15. Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis. 1992;15:211-22. 16. Porter SB, Sande MA. Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med. 1992;327:1643-8. 17. Dannemann B, McCutchan JA, Israelski D,Antoniskis D, Leport C, Luft B, et al. Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group. Ann Intern Med. 1992;116:33-43. 18. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:348-50. 19. Murray HW, Katlama C. Toxoplasmosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy. Philadelphia, Pa: Churchill Livingstone; 2003:419-37. 20. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:44-5. 21. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:348-50. 22. Nguyen MH, Clancy CJ, Ecevit IZ. Cryptococcus neoformans. In: Yu V, Weber R, Raoult D, eds. Antimicrobial Therapy and Vaccines. New York, NY: Apple Tree Productions; 2003:1045-57. 23. Aberg JA, Powderly WG. Cryptococcosis. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy. Philadelphia, Pa: Churchill Livingstone; 2003:498-510. 24. Saag MS, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis. 2000;30:710-8. 25. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:310-3. 26. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:47. 27. Korvick J. Mycobacterium Avium Complex. In: Yu V, Weber R, Raoult D, eds. Antimicrobial Therapy and Vaccines. New York, NY: Apple Tree Productions; 2003: 807-20. 28. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:329-31. 29. Polis MA. Cytomegalovirus Disease. In: Dolin R, Masur H, Saag MS, eds. AIDS Therapy. Philadelphia, Pa: Churchill Livingstone; 2003:582-603. 30. Bartlett JG, Gallant JE. Medical Management of HIV Infection. Baltimore, Md: Port City Press; 2004:314-9.

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Chapter 41

Opportunistic Infections in the Immunocompromised Host DAVID A. BOBAK, MD ROBERT A. SALATA, MD

Key Learning Points 1. Primary care providers are increasingly involved in various aspects of care for immunocompromised patients (IP) 2. A large variety of clinical syndromes are associated with specific qualitative and/or quantitative defects in host immune response or defense 3. Infections in IP often have subtle and non-specific presentation 4. In many instances, understanding the nature of the immunologic or host defense defect in an IP helps to identify the most likely pathogens that may be causing the infection 5. Practitioners will often need to begin appropriate empiric therapy for infections in IP while awaiting a definitive diagnosis

P

aradoxically, continued advances in medicine have contributed significantly to the frequency, type, and severity of infection occurring in immunocompromised patients (1). Developments such as stem cell transplantation, new and more intensive chemotherapeutic and immunosuppressive regimens, and an increased number of solid organ transplants have created more challenging and significant states of immunosuppression. Technological advances, such as long-term indwelling catheters or ports, and more sophisticated methods of monitoring and ventilation have also created a milieu in which infections are a major complication. Furthermore, many intravenous therapies are undertaken in the ambulatory setting. These developments have increased the number of immunosuppressed patients dramatically and brought them to the outpatient arena. Consequently, primary care physicians now more frequently begin the initial management of various medical issues arising in 777

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New Developments in the Management of Opportunistic Infections in Immunocompromised Patients ●

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Newer immunosuppressant drugs and biologicals are expanding the variety of immune and/or host defense defects in an ever-increasing population of patients. In recent years, more patients who are elderly or have significant co-morbid diseases are undergoing aggressive immunomodulating regimens and/or organ/hematologic transplantation, increasing the risk for infections in these populations. Efforts are increasing to use rapid-response, molecular-based assays to definitively diagnose specific types of infections in IP. Growth-factors, cytokines, intravenous immunoglobulins, and granulocyte transfusions are among the non-antimicrobial adjuvants used in increased frequency in the treatment of infections in IP. The use of newer antimicrobial agents combined with novel approaches to prophylaxis or pre-emptive therapy is an emerging trend in efforts to prevent infections in IP.

immunocompromised patients. Beyond this, the advent of HIV infection has brought about the emergence of new opportunistic infections as well as the resurgence of old diseases. Thus, it is essential to be able to recognize, diagnose, and treat infections occurring in the immunocompromised patient. This chapter will first detail the nature of the immune defects in immunocompromised patients, an understanding of which can help prioritize infectious agents and syndromes in this patient population. Thereafter, the discussion will focus on selected types of immunocompromised patients frequently encountered in primary care practice and will detail the epidemiology, cause, and approaches to the diagnosis and management of associated infections in this group. A discussion of HIV-related infections is beyond the scope of this chapter; however, HIV-related infections are covered in Chapter 39, Diagnosis and Treatment of HIV Infection, and Chapter 40, Opportunistic Infections in Patients with AIDS.

Host-Defense Mechanisms The type and extent of immunosuppression can often predict the spectrum of organisms that cause infections in immunocompromised patients. Hence, it is important to first become familiar with the types of immunodeficiencies and the defects they cause in host-defense mechanisms (1,2). These mechanisms include 1) mechanical defense barriers, 2) innate immunity and cellular host defense, 3) humoral immunity (HI), and 4) cell-mediated immunity (CMI) (1-8). Once the type of an immunodeficiency is identified, the most likely causes of infections can be established and the approach to diagnosis and management of these infections can then be more specifically directed.

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It should also be remembered that most immunocompromised hosts will have more than 1 type of defect of host defense and immune function.

Mechanical Defense Barriers The skin and mucosal surfaces, in conjunction with many other nonspecific mechanisms of defense, such as ciliary activity, gastric acid, and intestinal motility, are considered the primary mechanical defense barriers (4,9,10). In a normal host, brief disruption of these mechanisms rarely results in infection. However, when the secondary mechanisms of defense, such as cell-mediated and humoral immunity, are impaired, even transient disruptions of mechanical barriers may result in illness and death. These disruptions can be secondary to invasive procedures such as surgery, trauma, burns, the use of long-term intravenous catheters, or local destruction of the mucosa by infections (e.g., influenza or oral herpes simplex) and cytotoxic chemotherapeutic agents. Because certain bacteria such as coagulase-negative staphylococci and Staphylococcus aureus colonize the skin and mucosal surfaces, disruptions in these barriers can provide a port of entry for these organisms in particular. In patients who have had prolonged or several hospital stays, have been treated with broad-spectrum antibiotics, and/or received parenteral nutrition, the skin flora may be replaced by more resistant and less common organisms, including yeasts, and can subject these patients to infections that are often more challenging to diagnose and more difficult to eradicate (1,9). In these situations, effective therapy often requires appropriate antibiotic drug use and resolution of the source of infection. The latter usually refers to a definitive surgical procedure, removal of a long-term catheter or treatment of the cause of mucosal breakdown.

Cell-Mediated Immunity Cell-mediated immunity involves a complex series of interactions between T lymphocytes and other effector cells (5). Through different mechanisms, antigen-specific T-cells can either act directly on target cells or can secrete cytokines that recruit other, less specific cells such as macrophages and natural killer cells to act on the target cell. A defect in this system can result either from a primary (congenital immunodeficiency) or secondary process. Because CMI is responsible for the control of many types of infections, a deficiency in this type of immunity increases the risk of certain bacterial, fungal, viral, and parasitic infections (Table 41-1). Primary disorders of CMI commonly involve both B and T-cell abnormalities (1,2,5). This is often a result of congenital diseases such as severe combined immunodeficiency disease, Wiskott-Aldrich syndrome, ataxiatelangiectasia, and certain purine pathway enzyme deficiencies. As expected

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Table 41-1 Causes of Cell-Mediated Immunity and Related Infections* Causes Congenital Severe combined immunodeficiency Wiskott-Aldrich syndrome Ataxia-telangiectasia Chronic mucocutaneous candidiasis DiGeorge syndrome X-linked agammaglobulinemia Nezelof’s syndrome

Bacterial infections

Fungal infections

Viral infections

Other infections

Mycobacterium tuberculosis Nontuberculous mycobacteria Listeria monocytogenes Nocardia species Legionella pneumophilia Salmonella species Streptococcus pneumoniae

Histoplasma capsulatum Coccidioides immitis Cryptococcus neoformans Candida species Pneumocystis jiroveci Aspergillus Zygomycetes

Cytomegalovirus Varicella–zoster virus Herpes simplex virus Human herpesvirus-6 Human herpesvirus-8

Toxoplasma gondii Cryptosporidium parvum Leishmania donovani Giardia lamblia Strongyloides stercoralis

Malignancies Hairy-cell leukemia, Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Mycosis fungoides T-cell lymphomas Other solid tumors Infections HIV Cytomegalovirus Epstein–Barr virus Respiratory syncytial virus Varicella–zoster virus Measles Syphilis Malaria Typhoid fever Filariasis Tuberculosis Histoplasmosis Leprosy Drugs Alkylating agents (e.g., cyclophosphamide) Antimetabolites (e.g., methotrexate, azathioprine) Calcineurin/cyclophillin inhibitors (e.g., cyclosporine A, tacrolimus) Cytotoxic antibiotic derivatives (e.g., daunorubicin, mitoxantrone)

Continued

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Table 41-1 Continued Causes

Bacterial infections

Fungal infections

Viral infections

Other infections

Glucocorticoids (e.g., prednisone) Tyrosine kinase inhibitors (e.g., imatinib) Other/Misc (e.g., mycophenolate mofetil) Biologicals Anti-CD3 polyclona antibodies (e.g., antithymocyte globulin) Anti-CD3 monoclonal antibodies (e.g., muromab-CD3) Anti-CD11a monoclonal antibodies (e.g., efalizumab) Anti-CD20 monoclonal antibodies (e.g., basiliximab, daclizumab) Anti-IL-2 monoclonal antibodies (e.g. basiliximab, daclizumab) IL-1 receptor antagonist (anakinra) Anti-TNF monoclonal antibodies (e.g., infliximab, adalimumab) Soluble TNF receptors (e.g., entanercept) Miscellaneous Protein-calorie malnutrition Diabetes mellitus Sarcoidosis Renal and hepatic failure Cushing’s disease Radiation therapy * Related infections can be found in association with any of the listed causes.

with congenital diseases, infections in cases of such primary disorders of CMI often appear early, are frequently severe, and can be recurrent throughout the first few years of life. Because depression of humoral immunity is commonly also involved, these early infections are often caused by encapsulated organisms. However, because of their T-cell abnormalities, these hosts are at

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special risk for opportunistic infections by organisms such as Pneumocystis jiroveci and Candida species and for various human herpes virus infections. Later in life, secondary processes, including malignant and nonmalignant hematologic diseases such as hairy-cell leukemia, Hodgkin and nonHodgkin lymphoma, T-cell malignancies such as mycosis fungoides and lymphoma, and other advanced solid tumors, such as lymphoma, can result in defects of CMI (1,2,5). Often, treatment of these underlying diseases with chemotherapeutic agents or radiation worsens the immunologic defects, resulting in a more severe and generalized immunocompromised state. Many infectious diseases can compromise CMI (1,2,5). The infection that causes the most severe compromise is HIV infection. Various other infections have also been associated with varying degrees of CMI deficiency, including those caused by certain viruses (measles, varicella, cytomegalovirus, Epstein-Barr virus, respiratory syncytial virus, hepatitis B, influenza), bacteria (typhoid fever, syphilis, tuberculosis), fungi (histoplasmosis, coccidioidomycosis), and parasites (malaria and filariasis). Certain live vaccines (e.g., mumps, measles, rubella, yellow fever) may disorder host CMI as well. Fortunately, the resultant defect in CMI in most of these syndromes is short lived. Noninfectious causes of deficiency in CMI also occur and are generally not severe (e.g., chronic malnutrition, diabetes mellitus, sarcoidosis, certain autoimmune diseases, and renal failure). Corticosteroids are the most notable of the pharmacologic agents associated with abnormalities of CMI (11,12). Corticosteroid therapy is commonly used to treat various common disorders and conditions. A large number of cytotoxic agents, other immunosuppressive agents and/or radiation therapy used in the treatment of malignancy, organ transplantation, and autoimmune diseases can significantly impair CMI as well. As with corticosteroid use, the degree of CMI depression directly correlates with the dose and duration of therapy (discussed further later in this chapter).

Humoral Immunity The antibody response produced by cells of the B lymphocyte lineage is the most important component of HI (6,13). Depending on whether the stimulating antigen is a protein or a nonprotein, such as a polysaccharide or lipid, the humoral immune response can be classified as either T-cell dependent or independent. T-cell–dependent antibodies produced in response to protein antigens are usually more specialized, with long-lived memories, whereas Tcell–independent responses to nonprotein antigens are mediated largely by low-affinity IgM and some IgG, with little generation of memory cells. T-cell–dependent antibody responses occur as either primary or secondary responses (1,2,6,13). Primary responses result in activation of naive B cells after the initial exposure to an antigen, such as a vaccine. A repeat exposure to that same antigen results in a secondary response, which

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involves the stimulation of previously stimulated, already expanded clones of memory B cells. This adaptive mechanism enables the secondary response to develop more rapidly and result in larger amounts of antigenspecific antibodies than are produced in the primary response. The most common T-cell–independent antigens are bacterial cell-wall polysaccharides, glycolipids, and nucleic acids (1,2,6,13). Although they are not recognized by helper T-cells, these antigens can activate B cells directly by initially eliciting an IgM antibody response, followed by an IgG response. Individuals with a congenital or acquired deficiency in HI, such as common variable immunodeficiency, chronic lymphocytic leukemia, lymphosarcoma, many myeloma, nephrotic syndrome, major burns, asplenia or a functional asplenic state, and protein-losing enteropathy are therefore at high risk for life-threatening infections by encapsulated organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae (Table 41-2) (2,13). Many of the pharmacologic agents that induce defects in CMI (see above) will also depress humoral immunity. In addition, certain newer biological agents, such as monoclonal antibody rituximab, markedly deplete B cells. Another important component of the humoral immune system is the complement system, which is largely considered an effector mechanism of HI as well as a means of amplification of antibody responses (7). Complement deficiencies can be present in either the classic or alternate pathway. Deficiencies of the early classic complement components (C1, C2, and C4) have been described. Although unexplained, C2 and C4 deficiencies are seen in more than 50% of patients with systemic lupus erythematosus (SLE). Surprisingly, infection rarely occurs in individuals with early classic complement component deficiencies, most likely because the alternate pathway of complement activation remains intact (1,2,7).

Table 41-2 Causes of Humoral Immune Deficiency and Common Associated Infections Causes

Organisms

Common variable hypogammaglobulinemia Nezelof’s syndrome Ataxia telangiectasia Wiskott–Aldrich syndrome Chédiak-Higashi syndrome Chronic lymphocytic leukemia Lymphosarcoma Multiple myeloma Asplenia or hyposplenia Systemic lupus erythematosus Sickle cell disease Major burns Nephrotic syndrome Protein-losing enteropathy C1-9 deficiencies

Streptococcus species Staphylococcus species Salmonella species Neisseria meningitidis N. gonorrhoeae Haemophilus influenzae

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In contrast, individuals with inherited deficiencies of C3 and C5 and Chédiak-Higashi syndrome have significant impairment of opsonization that leads to defective neutrophil chemotaxis, aggregation, and phagocytosis (1,2,7). This can result in severe infections by encapsulated organisms, enteric gram-negative bacteria, and staphylococci, illustrating the importance of these complement components in bacterial lysis. Deficiencies of the late complement components (C5b, C6, C7, C8, and C9) are most common. Because they prevent development of a membrane attack complex for lysing foreign organisms, these deficiencies are associated with infections by N. meningitidis and Neisseria gonorrhoeae (1,2,7). Anyone with recurrent Neisseria infections should be investigated for complement deficiency. One of the most common clinical conditions causing deficient HI is asplenia or hyposplenia (14,15). Because the spleen is a major source of antibody production, these states result in an immunoglobulin-deficient state that puts the patient at unusually high risk for infection by encapsulated organisms. This is especially true for patients with sickle cell anemia, because not only are these patients hyposplenic and antibody deficient but they are also complement deficient because complement is depleted by the stroma of the sickled erythrocytes (16). This condition impairs effective opsonization of encapsulated organisms, increasing the frequency and severity of infection with these organisms (discussed in detail later in this chapter).

Polymorphonuclear Leukocytes Polymorphonuclear leukocytes (PMNs; neutrophils) represent the most important component of the cellular host defense system against most bacterial and certain fungal infections (8,17-21). Both quantitative and qualitative abnormalities in PMN can lead to a predisposition to recurrent infections. Conditions that can cause such abnormalities are many and typical examples are outlined in Table 41-3. There are many diseases (e.g., myelodysplasia, paroxysmal nocturnal hemoglobinuria, genetic diseases such as chronic granulomatous disease, Job syndrome) that can result in neutrophil dysfunction (8,17-21). Each syndrome may cause PMN dysfunction by various different mechanisms. For example, chronic granulomatous disease and myeloperoxidase deficiency each result in an intrinsic defect of the neutrophil oxidative metabolism (17,18,19-21). These defects result in the failure of these PMN to generate an effective oxidative burst in response to certain pathogenic organisms. Patients with oxidative defects are particularly susceptible to infection from catalase-producing organisms such as staphylococci, Serratia, Nocardia, and Aspergillus. Various immunosuppressive medications, including corticosteroids, can also profoundly inhibit PMN functions (11,12). In these settings, even though the circulating PMN count may be normal or even increased, PMN functions are qualitatively dysfunctional, especially with regards to chemotaxis and killing.

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Table 41-3 Causes of Decreased Function or Numbers of Polymorphonuclear Cells and Common Associated Infections Causes

Organisms

Myelodysplasia Paroxysmal nocturnal hemoglobinuria Chronic granulomatous disease Job’s syndrome Chédiak-Higashi syndrome Myeloperoxidase deficiency Peroxidase deficiency G-6-PD deficiency “Lazy” leukocyte syndrome Aplastic anemia Hypersplenism Felty’s syndrome Sarcoidosis Circulating immune complexes Alcohol Corticosteroids Immunosuppressive and chemotherapeutic agents

Streptococcus species Staphylococcus species Serratia species Pseudomonas aeruginosa Escherichia coli Klebsiella species Enterobacter species Nocardia Aspergillus Candida species

Infections in Patients with Neutropenia Neutropenia, defined as an absolute neutrophil count of fewer than 500 cells/µL, is among the most important risk factors for life-threatening infections (1,3,18). Most commonly, it is caused by malignancies and their treatment with cytotoxic agents, especially in conjunction with bone marrow or peripheral stem cell transplantation (1,3,18,22,23). There is a direct correlation between the degree of neutropenia and the risk of infection. The risk of infection begins to increase significantly when the granulocyte count decreases to less than 1000 cells/µL, is even greater below 500 granulocytes/µL, and is essentially universal with counts less than 100 granulocytes/µL. In addition to the absolute granulocyte count, the duration of neutropenia, and whether the neutrophil count is rising or decreasing also profoundly influence the risk of infection. Other risk factors for infection are also commonly present in patients with neutropenia and include the patient’s underlying disease; immunosuppressive therapy; and alterations in the integrity of physical defense barriers by mucositis, indwelling catheters, or invasive procedures.

Epidemiologic Resistance Patterns Neutropenia primarily predisposes patients to bacterial and fungal infections. Over the past several decades, the typical pathogens associated with neutropenia in patients with hematologic malignancies have shifted with the rapid development of different antibiotic resistance patterns (1,3,18,22-27). In the 1960s, gram-positive organisms such as Staphylococcus aureus were the

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predominant infecting organisms. In the 1970s, however, this shifted largely to gram-negative organisms (Escherichia coli, Klebsiella species, Pseudomonas aeruginosa, Enterobacter species), most likely in relation to the use of broadspectrum antimicrobial drugs and newer, more aggressive chemotherapy. Most recently, both resistant as well as more unusual gram-negative organisms have emerged, owing primarily to the changing resistance patterns of the organisms as well as a more universal use of antimicrobial prophylaxis and early broad-spectrum therapy given to high risk patients (24-27).

Treatment Because a high percentage of neutropenic patients can develop fulminant, life-threatening infections, it is recommended that all febrile neutropenic patients, or afebrile neutropenic patients with signs or symptoms suggestive of infection, receive an empiric and broad-spectrum antimicrobial regimen (1,22,23,24,28). Selection of an empirical antibiotic regimen depends on many factors including the extent and duration of neutropenia, the status of the patient’s cellular and humoral immune system, the underlying illness, alteration of physical defense barriers, the patient’s endogenous microbial flora (hospital or community), and the frequency and resistance patterns of pathogens encountered in the treating institution. Most organisms causing infections of neutropenic hosts are part of the microbial flora that colonize the gastrointestinal tract, oropharynx, or skin (22-24,28). In particular, this includes Enterobacteriaceae, gram-negative nonfermenters such as P. aeruginosa, as well as Staphylococcus and Streptococcus species. Under certain conditions the patient is predisposed to infection by certain organisms. For example, a vascular access device (subcutaneous ports, indwelling central line) provides a port of entry for organisms that are part of the skin flora, such as S. aureus and coagulasenegative staphylococci. In these circumstances, an attempt to sterilize the vascular access device can be made with a trial of antibiotic therapy administered through the ports (10). However, if the bacteremia fails to clear after 72 hours of antibiotic administration, and/or the patient remains persistently febrile, has a tunnel infection or local cellulitis, develops a pulmonary complication (septic or bland pulmonary emboli), has evidence of endocarditis, develops central septic thrombophlebitis, or has an infection of fungal cause, removal of the prosthesis must be pursued (10,22,28). Investigation with ultrasound or angiography is helpful for diagnosing suppurative complications in these instances. Pulmonary infiltrates in the febrile, neutropenic patient require immediate and special attention (1,22,24,28). Although noninfectious etiologies must be considered for such infiltrates (hemorrhage, radiation- or drug-induced pneumonitis, fluid overload, thromboembolic disease), a lobar infiltrate is most likely to be pyogenic. Depending on the duration and trend of the neutropenia and the patient’s antibiotic regimen, many infectious agents must be con-

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sidered. Among the most common and virulent organisms are gram-negative bacteria, which are of major concern and should be well covered by empiric antimicrobial therapy. Timing of the development of a pulmonary infiltrate is also important; pulmonary infiltrates appearing during granulocyte recovery may not represent a new infection. In contrast, new and progressive pulmonary infiltrates that develop during antibiotic therapy and prolonged neutropenia are likely to have a fungal cause. Ideally, bronchoscopic or open biopsies should be done early in the clinical course of disease. The overall yield of such biopsies, especially those done by means of bronchoscopy, is often frustratingly low. Nevertheless, a definitive diagnosis should always be pursued when feasible and empiric therapy, including antifungal when appropriate, should be always be instituted while awaiting the results of diagnostic tests (1,22,24,28). Various empiric antimicrobial regimens have been studied and recommended (1,22-24,28). The choice of specific agents cannot be generalized between institutions and must reflect the endogenous microbial resistance patterns (25-27). In most cases, a single broad-spectrum antimicrobial agent with antipseudomonal activity is adequate (ceftazidime, carbapenems, or extended-spectrum penicillins), especially if the degree of neutropenia is not profound and the expected duration of neutropenia will be short. If a resistant gram-negative organism is suspected as the pathogen, an aminoglycoside or fluoroquinolone can be added. If a clinical syndrome implicating methicillin-resistant staphylococci is present (e.g., cellulitis or catheterassociated infection), vancomycin should be added. Clinically significant infections with vancomycin-resistant enterococci (VRE) have continued to increase, especially in association with catheter- or bloodstream-associated infections (22,24,27,28). In seriously ill neutropenic patients known to be colonized with VRE, empiric use of agents such as linezolid or daptomycin may be necessary on occasion. The duration of antimicrobial therapy for infections in neutropenic patients is not well defined (1,22-24,28). Regardless of whether the patient is febrile or afebrile, it is recommended that at least a 5- to 7-day course of antimicrobial therapy be completed. Because the single most important determinant of duration of therapy is recovery of the neutrophil count, it is generally considered safe to stop empiric intravenous antibiotic administration 3 or 4 days after the neutrophil count reaches 500 cells/mL in the absence of definite infection. However, if profound neutropenia is persistent, and there are continuous signs of possible infection (tachycardia, tachypnea, hypotension, and mucous membrane lesions) after 3 days of intravenous antibiotic therapy, a meticulous evaluation for alternative causes of fever must be undertaken and empiric antifungal therapy should be added (22,28-31). Unfortunately, for most febrile episodes, no definitive infection is established. Because chemotherapy, transplant, and prophylaxis regimens are continually refined, the frequency and severity of the risk of infection varies almost down to the individual patient. Improvements in risk

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assessment and antimicrobial prophylaxis allows for the identification of a lower risk strata of neutropenic patient, and modifications to the classic antibiotic management guidelines are beginning appear (32,33). Alternative causes of infection to consider include a bacterial infection resistant to the antibiotic drug(s) in use, viral infections, inadequate dosing of antibiotics, drug fever, or alternate sites of infection such as abscesses or catheter-associated infection. Increasingly, various viral pathogens, including herpesvirus family members, as well as newly appreciated respiratory viruses, are being recognized as causes of infection during neutropenic periods in patients with hematologic malignancies or stem cell transplants (22,23,34-36). However, no general recommendation is given for empiric antiviral therapy in such patients, unless a specific viral infection is documented or highly suspected.

Colony-Stimulating Factors In situations in which a delay is expected in the recovery of the bone marrow, a worsening course is predicted, or profound neutropenia persists, administration of granulocyte growth factors (e.g., granulocyte colonystimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF] is often considered (37,38). In some centers, such therapy is now standard practice, but there is no clear consensus recommendation about the use of agents. Administration of such agents in cases of severe infection; infection with molds; and/or prolonged, severe neutropenia may be beneficial. Use of granulocyte transfusions has varied in popularity over the last 20 years. Currently, there seems to be resurgence in the interest for this therapy, primarily because of improved mechanisms for collection, ability to decrease spontaneous apoptosis of the harvested cells, and concurrent use with growth factors (39).

Infections in Patients with Diabetes Mellitus Recent data provide compelling evidence that tight glucose control can delay or prevent diabetic microvascular complications such as retinopathy, microalbuminuria, renal insufficiency, and neuropathy. In addition, in vitro studies strongly suggest that hyperglycemia inhibits many aspects of the host defense (40). In addition, hyperglycemia and acidosis, along with microvascular compromise also help predispose diabetic patients to an increased incidence of infection (40,41). It is well established that diabetic patients are prone to various infections including chronic osteomyelitis of the foot, rhinocerebral mucormycosis, emphysematous cholecystitis, pyelonephritis, and soft-tissue infections (42-44). Other clinical evidence for an association of hyperglycemia and infection includes the increased incidence of catheter-

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related infections among intensive-care-unit patients receiving total parenteral nutrition compared with enterally fed patients (41). Except for S. aureus and Mucormycosis, no organisms occur more often in diabetic patients than in the general population (42,43). The increased rate of infection with S. aureus is partly attributed to higher rates of skin and mucosal staphylococcal colonization in diabetic patients. Diabetic patients who were regular injection-insulin users had the highest colonizing rates of S. aureus. This supports studies showing diabetes as an underlying disease in up to 36% of patients with staphylococcal bacteremia (42,43). Patients who develop chronic renal failure from diabetic nephropathy and require hemodialysis have a high rate of vascular infection and bacteremia caused by repetitive manipulation (42,43,45,46). Again, S. aureus is frequently found, causing 40% to 70% of cutaneous- and intravenous infusion-related bacteremias in these patients (42,43). Rhinocerebral mucormycosis is a condition known to be particularly associated with poorly controlled diabetes and especially in patients with recurrent episodes of diabetic ketoacidosis (42,43). The relatively acidic environment in this situation is believed to support the growth of mucormycosis. The peripheral vascular disease and neuropathy seen in most chronically diabetic patients also make foot ulcers a common infectious complication in this population (44). (See Chapter 36 for recommendations for medical and surgical management of diabetic foot infections). To decrease the incidence of infections in diabetic patients, it would be prudent to maintain tight glycemic control, keep a vigilant watch for signs of infections, and conduct regular podiatric and vascular evaluations (4044). In dealing with a possibly infected diabetic patient, it is important to remember that immune compromise may result in a physiologic response to infection that is not typical of a normal host. Diagnostic investigations should be directed toward the most common sites of infection. In choosing an antimicrobial regimen, strong consideration should be given to the probable pathogens.

Infections in Patients with Asplenia Overwhelming postsplenectomy infection (OPSI) in children was initially described in 1952. Since then, it has been recognized that the asplenic patient represents a unique compromised immunologic state, involving nearly all aspects of host defense (47-49). The spleen plays a critical role in host defense through several mechanisms. Its microcirculation facilitates mechanical clearance of organisms (bacteria and parasites) that have been ineffectively opsonized by components of complement. The spleen also synthesizes and regulates production of a variety of soluble mediators such as antibodies (especially IgM), complement components, and tuftsin, which are critical in the defense against organisms with polysaccharide capsules.

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Asplenia can be the result either of autosplenectomy (sickle cell disease, congenital asplenia, splenic atrophy) or surgical splenectomy. These patients suffer from an increased incidence of septicemia, pneumonia, or meningitis (14,15,47-52). The risk of infection seems to be the greatest in the first few years after splenectomy. Thereafter, the cumulative incidence is linear for approximately 7 years, after which the occurrence of infection begins to decrease significantly. However, it is important to note that cases of life-threatening infection have been reported as late as 40 years after splenectomy. The major pathogen associated with asplenia is S. pneumoniae; and this organism has been associated with serious invasive disease including bacteremia, endocarditis, meningitis, and pneumonia (14,47-53). Other frequently seen organisms in asplenic individuals are listed in Table 41-4. Worth noting is the fastidious organism Capnocytophaga canimorsus. Although this organism rarely causes sepsis in the normal host, it is recognized as a cause of serious infection after dog bites in asplenic people. Infection with certain protozoan parasites (e.g., malaria, Babesia) also seems to increase in frequency and severity among the asplenic population.

Clinical Manifestations The initial clinical presentation of infection in an asplenic individual can be subtle and nonspecific. Symptoms suggesting a viral illness, such as fever, sore throat, myalgia, diarrhea, and malaise, are common. Clinical clues to absent or impaired splenic function include an abdominal scar suggesting a previous splenectomy, or the presence of Howell-Jolly bodies in the peripheral blood smear, indicating impaired splenic function. After the prodrome, most severe cases will progress to a fulminant course, leading to bacteremia, meningitis, pneumonia, or overwhelming sepsis (14,47,48,52,53). Refractory hypotension, respiratory distress, disseminated intravascular coagulation, peripheral gangrene, Waterhouse-Friderichsen syndrome, hypofibrinogenemia, and hypocomplementemia can be complications. Despite appropriate and aggressive antibiotic therapy accompanied by intensive medical management, the death rate remains high in many instances.

Table 41-4 Common Bacterial Causes of Infection in Asplenic Patients Streptococcus pneumoniae

Pseudomonas species

Haemophilus influenzae Staphylococcus aureus Clostridium species Escherichia coli Group B and D Streptococcus Klebsiella species Enterobacter species

Neisseria species Proteus species Serratia species Acinetobacter species Bacteroides species Salmonella species Capnocytophaga canimorsus

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Treatment Given the large number of possible etiologic organisms of infection in hyposplenic or asplenic individuals, it is recommended that empirical antimicrobial therapy be directed toward the most likely organisms, such as pneumococcus and other encapsulated organisms. In addition, because the clinical course of infection can be rapidly fatal, the liberal use of early empirical antibiotic therapy can be of significant benefit to the asplenic or hyposplenic patient and requires coverage of penicillin-resistant pneumococcus as well as gram-negative organisms. Once the infectious agent is identified and its antibiotic susceptibility pattern is measured, treatment should be modified appropriately.

Prophylaxis Efforts aimed at decreasing illness and death in the patient at risk for OPSI have focused on antibiotic prophylaxis and vaccination (14,47,49,51,52-56). Prophylactic antibiotic use has been suggested as a method of reducing the incidence of infection. However, short-and long-term drug adherence issues are almost always encountered, especially because the risk of infection has been known to persist for up to 40 years after splenectomy. In addition, the issue of antibiotic resistance becomes significant when the asplenic individual develops a life-threatening infection despite antibiotic prophylaxis. Nevertheless, data exist to support the use of antibiotic prophylaxis in children with sickle cell disease (49,51-56). In these children, prophylactic penicillin regimens can significantly reduce the rate of pneumococcal infection. With the emergence of penicillin-resistant pneumococci, however, reevaluation of prophylaxis strategies is ongoing and newer antimicrobial agents will need to be evaluated (51,53). A more practical and cost-effective approach to preventing serious infection in the asplenic individual is through immunization against encapsulated bacteria, that is, using the pneumococcal, meningococcal, and H. influenzae type B vaccines. These confer the most protection when administered before splenectomy and should be recommended to all patients who expect a splenectomy (49,51,53,55,56). The Advisory Committee on Immunization Practices of the American Medical Association recommends administration of the vaccines at least 2 weeks before elective splenectomy whenever possible (57). Although data suggest that there is suboptimal antibody production in splenectomized individuals, these vaccines seem to confer some protective effect even when given after splenectomy. However, because these vaccinations do not confer 100% protection, OPSI must still be considered in any acutely ill asplenic patient who has been previously vaccinated. Use of the newer, protein-conjugated pneumococcal and meningococcal vaccines hold a potential for improved rates of antibody response and protection.

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Infections in Patients with Multiple Myeloma A high incidence of bacterial infection has been historically noted in myeloma patients, accounting for a significant proportion of deaths in this patient population (58,59). Both humoral and cell-mediated immunity seem to be severely dysregulated in patients with multiple myeloma (60). Most myeloma patients also demonstrate decreased complement activity, even in the absence of identifiable decreases in complement components. Granulocyte function has also been found to be defective in patients with myeloma as well. As compared with humoral and cell mediated immune defects, it is unclear whether these particular abnormalities alter the incidence of infection. Despite the advances in relatively nontoxic chemotherapy for myeloma, a significant proportion of patients with the disease still die as a result of infections (58,59). Serious and life-threatening infections are predominantly bacterial. Historically, the most common site of infection was noted to be in the lower respiratory tract, with infection related to S. pneumoniae, followed by urinary tract infection (UTI) with E. coli. More recently, the frequency of resistant gram-positive infections has begun to increase and the incidence of gram-negative infections (Enterobacteriaceae and P. aeruginosa) has risen significantly, especially in patients with advancing, refractory disease. This finding likely reflects a higher rate of nosocomial infections with more resistant hospital-acquired organisms. The risk of infection seems to increase during 3 specific phases of myeloma (58-60). The first phase is in the first 3 months after diagnosis, during initial chemotherapy. It is during this period that viral and fungal infections are more likely to occur. The second phase is the stable-disease phase, which is mainly associated with bacterial infection as a result of the persistence of dysfunctional HI. The last phase is during relapses of myeloma, when additional chemotherapy is given. This usually signifies a progression of the disease and is complicated by infections with a wide variety of organisms, suggesting a more generalized dysfunction of the entire immune system. More recently, there has been a dramatic increase in the interest and use of hematologic stem cell transplantation for treatment of certain forms of multiple myeloma (58,61). This therapeutic trend will likely increase the frequency and severity of infections for these types of patients even further.

Prophylaxis Interventions intended to prevent infection in patients with multiple myeloma have largely been directed at vaccination, with the best-studied vaccine being the pneumococcal vaccine (58,60). Effectiveness of this strategy is somewhat limited, however, because of the suboptimal response to immunization in these patients. As with asplenic patients, protein-conjugate vaccines hold hope for improved protection in this group. Although the use

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of prophylactic antimicrobial therapy has been considered for preventing infection in patients with myeloma, it is not currently recommended. Although prophylactic antibiotic use may be reasonable for the patient who develops recurrent infections with the same organism, general use of such treatment is not recommended because of the high likelihood of its leading to infection with resistant organisms. As with other immunocompromised patients, empiric antibiotic therapy for an infected patient should be directed against the most likely source of infection. Prophylaxis with intravenous γ-globulin therapy (IVIg) seems to decrease the risk of lifethreatening and recurrent infections in certain patients with myeloma (58,60). Monthly infusion of IVIg should be considered for myeloma patients, especially those individuals who had a poor pneumococcal IgG antibody response to pneumococcal vaccine.

Infections in Patients with Systemic Lupus Erythematosus As with multiple myeloma, infection has been recognized as a major cause of illness and death in patients with systemic lupus erythematosus (SLE) (62-64). This increased rate of infection reflects the extensive immunologic dysregulation that is the hallmark of SLE combined with the use of potent immunosuppressive agents. As a result, the lupus patient is at an extraordinary risk for various types of potentially life-threatening opportunistic infections. Many types of immune defects are associated with SLE (62,63). Macrophage and neutrophil defects have been documented and include cytopenias, diminished phagocytic activity, decreased superoxide generation, and decreased production of proinflammatory cytokines. Neutropenia is common and usually correlates with the presence of complement-activating antineutrophil antibodies. Defective phagocytosis and chemotaxis has also been documented in untreated individuals. Excessive concentrations of circulating immune complexes, which are present during the active phase of the disease, result in persistent activation of neutrophils, which in turn causes subsequent defective responses to secondary stimuli. Defects in CMI most commonly result in CD4 lymphopenia and decreased in vitro production of various cytokines important for T-cell–mediated cytolytic activity. Defects of humoral immunity seem largely to come from nonspecific polyclonal B-cell activation and hypergammaglobulinemia. This is accompanied by significant deficiency of complement components, which may be caused by the consumption of complement proteins by circulating and tissue-fixed immune complexes. Although it is uncommon, functional asplenia, with a high incidence of bacterial septicemia, has also been reported in SLE. The most common infections seen in lupus patients are infections of the central nervous system (CNS), pneumonia, skin and soft-tissue infections, and UTIs (62-64). The diagnostic possibilities in each of these organ systems

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depend on whether the patient is receiving corticosteroid or immunosuppressive therapy, which determines the spectrum of likely pathogens. Common organisms causing UTI include E. coli, Proteus mirabilis, and to a lesser extent enterococci and Staphylococcus saprophyticus. Skin and soft tissue infections are more common in lupus patients; however, they are generally caused by common skin organisms such as S. aureus and Streptococcus species. Treatment of these infections should be the same as for normal hosts. Lupus patients who are receiving corticosteroid or immunosuppressive therapy may not manifest typical signs and symptoms of infections. In such circumstances, common infectious problems, such as UTIs or soft-tissue infections, may develop a rapidly progressive course if not promptly recognized and treated with appropriate antimicrobial drugs. Fungal UTIs with Candida, and fungal infections (histoplasmosis, Cryptococcus), should also be considered in the febrile lupus patient who is receiving immunosuppressive therapy. Infections of the CNS are difficult to diagnose in lupus patients, because there are many causes of CNS disease in this population (62-65). Lupus cerebritis is often confused with meningitis. Patients with cerebritis usually do not have signs of meningeal irritation. However, severe headache with fever and meningismus is common and mandates that a diagnosis of cerebritis be considered only after an infectious cause has been excluded. The only reliable way to rule out a CNS infection is with analysis of cerebrospinal fluid (CSF) and appropriate cultures. Patients with lupus cerebritis may have hypoglycorrhachia accompanied by mild pleocytosis with a predominance of PMN. Radiologic imaging with MRI may also be helpful in differentiating the diagnosis. In addition to the standard bacterial causes of meningitis, SLE patients can have CNS infection caused by less common or opportunistic pathogens such as Listeria monocytogenes, Mycobacterium tuberculosis, Cryptococcus neoformans, Toxoplasma gondii, cytomegalovirus, and herpes simplex virus (65). Empiric therapy should be aimed at the more likely organisms based on clinical presentation and local epidemiology with an aggressive approach toward establishing a specific diagnosis.

Infections Related to Use of Corticosteroids and Other Immunosuppressive Agents As mentioned earlier, corticosteroids are commonly used for many medical conditions (11,12,66). It has long been known that corticosteroids affect the immune response through impairment of both T-cell and phagocytic function. Corticosteroids impair neutrophil chemotaxis, phagocytosis, microbicidal effects, and antibody-dependent cytotoxicity. The degree by which these functions are depressed depends strongly on the dose and duration of corticosteroid therapy. For example, chronic low-dose corticosteroid

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therapy (10 mg per day or less of prednisone) is unlikely to have a significant effect on T-cell function. However, higher doses of corticosteroids given for 3 weeks of duration or greater have been shown to cause significant impairment of T-cell–mediated immunity. This risk of immunosuppression is especially high with a daily dose of at or more than 40 mg of prednisone and/or a split daily dosing of the drug (11,12,66). Because corticosteroids can profoundly depress cell-mediated immunity, the patient receiving prolonged high-dose corticosteroid therapy is at risk for a spectrum of infections that can include bacterial, fungal, viral, and mycobacterial infections (11,12,66). A significant relationship also exists between chronic corticosteroid use and atypical presentations of infections. In particular, viral infections, such as with cytomegalovirus and herpes simplex virus, as well as M. tuberculosis and fungal infections, can present in a disseminated fashion. Classic Pneumocystis jiroveci pneumonia often presents shortly after the discontinuation or during the tapering of steroid therapy because removal of the immunosuppressive drug permits an enhanced inflammatory response to the organism (67-69). This is because corticosteroids blunt the inflammatory response to the high concentration of lysed organisms. This is also true for certain forms of M. tuberculosis infection, such as meningitis, pericarditis, and overwhelming pneumonitis, in which treatment of the infection may increase inflammatory response to tubercular antigens. A large variety of immunosuppressive agents are used for a multitude of therapeutic indications (12). These agents include both drugs as well as biological agents (Table 41-5). A detailed discussion of the risk of infection induced by each of these agents is beyond the scope of this chapter. However, the anti–tumor necrosis factor (anti-TNF) antibodies are 1 class of biological modifiers that deserves special mention. Anti-TNF agents have had a marked increase in use in recent years for several common diseases, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis (70,71). Although opportunistic infection in this population is relatively

Table 41-5 Common Microorganisms Causing Infection in Systemic Lupus Erythematosus No Immunosuppressive Therapy

On Immunosuppressive Therapy

Staphylococcus aureus Escherichia coli Streptococcus pneumoniae Haemophilus influenzae Mycoplasma pneumoniae Salmonella species Neisseria species Klebsiella pneumoniae Pseudomonas aeruginosa Enterobacter species Legionella pneumophila

Herpes zoster Cytomegalovirus Mycobacterium tuberculosis Listeria monocytogenes Pneumocystis carinii Cryptococcus neoformans Nocardia species Disseminated Aspergillus Candida species Toxoplasma gondii Histoplasma capsulatum

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rare, there is an increased risk in these patients for serious, and even fatal, forms of invasive or disseminated infections, especially as caused by M. tuberculosis or certain fungi (70,71). Pneumonia is one of the more common infectious syndromes in patients receiving immunosuppressive therapies such as corticosteroids or anti-TNF agents. Community-acquired causes of pneumonia in these patients is often caused by the same pathogens found in normal hosts and agents such as S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, Chlamydia species, and Legionella species. However, because these agents predominantly alter CMI, other causes including cytomegalovirus, Nocardia species, C. neoformans, H. capsulatum, C. immitis, and P. jiroveci should be considered. Because the clinical syndromes associated with these opportunistic organisms are somewhat similar, a definite diagnosis almost always requires the assistance of bronchoscopy with bronchoalveolar lavage or biopsy or even open lung biopsy. Because of the wide spectrum of potential pathogens, as well as the often life-threatening aspect to the pneumonia, an aggressive approach to diagnosis is almost always warranted.

Summary Infections in the immunocompromised host are difficult to diagnose. Immunocompromising conditions may be associated with many defects in host defenses that predispose to infections. These defects lead to characteristic infections atypical of a normal host. Therefore, a general understanding of the immune system and its possible defects in any given patient are essential to the diagnosis and treatment of infection in immunocompromised hosts. This should be accompanied by a high index of suspicion, especially because infections in the immunosuppressed hosts often have an atypical clinical course. Whenever feasible, the diagnosis of infection should be pursued aggressively, because of the importance to outcome of establishing a definitive cause of infection. Prophylaxis against future infections should focus on measures such as immunization and, in some patients, the selected use of prophylactic antimicrobial drugs.

REFERENCES 1. De Pauw BE, Donnelly JP. Infections in the immunocompromised host: General principles. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:3421-32. 2. Akira S, Uematsu S,Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783801. 3. Holland SM, Gallin JI. Evaluation of the patient with suspected immunodeficiency. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:149-60. 4. Liévin-Le Moal V, Servin AL. The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clin Microbiol Rev. 2006;19:315-37.

Tan ch41.qxd 10/12/07 10:28 AM Page 797

Opportunistic Infections in the Immunocompromised Host

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5. Glickman MS, Pamer EG. Cell-mediated defense against infection. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:117-39. 6. Kelsoe G. Studies of the humoral immune response. Immunol Res. 2000;22:199-210. 7. Denson P. Complement. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:68-93. 8. Nathan C. Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol. 2006;6:173-82. 9. Lee SY, Kuti JL, Nicolau DP. Antimicrobial management of complicated skin and skin structure infections in the era of emerging resistance. Surg Infect (Larchmt). 2005;6:283-95. 10. Infectious Diseases Society of America. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis. 2001;32:1249-72. 11. Franchimont D, Kino T, Galon J, Meduri GU, Chrousos G. Glucocorticoids and inflammation revisited: the state of the art. NIH clinical staff conference. Neuroimmunomodulation. 2002;10:247-60. 12. Glück T, Kiefmann B, Grohmann M, Falk W, Straub RH, Schölmerich J. Immune status and risk for infection in patients receiving chronic immunosuppressive therapy. J Rheumatol. 2005;32:1473-80. 13. Baumgarth N, Tung JW, Herzenberg LA. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol. 2005; 26:347-62. 14. Lutwick LI. Life threatening infections in the asplenic or hyposplenic individual. Curr Clin Top Infect Dis. 2002;22:78-96. 15. Newland A, Provan D, Myint S. Preventing severe infection after splenectomy [Editorial]. BMJ. 2005;331:417-8. 16. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364:1343-60. 17. Roos D, van Bruggen R, Meischl C. Oxidative killing of microbes by neutrophils. Microbes Infect. 2003;5:1307-15. 18. Nauseef WA, Clark RA. Granulocytic phagocytes. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill Livingstone; 2005:94-117. 19. Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol. 2003;15:578-84. 20. Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med. 2000;343:1703-14. 21. Andrews T, Sullivan KE. Infections in patients with inherited defects in phagocytic function. Clin Microbiol Rev. 2003;16:597-621. 22. Busca A, Locatelli F, Barbui A, Ghisetti V, Cirillo D, Serra R, et al. Infectious complications following nonmyeloablative allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2003;5:132-9. 23. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103:1103-13. 24. Rolston KV. Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients with cancer and neutropenia. Clin Infect Dis. 2005;40 Suppl 4:S246-52. 25. Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med. 2006;119:S3-10; discussion S62-70. 26. McDonald LC. Trends in antimicrobial resistance in health care-associated pathogens and effect on treatment. Clin Infect Dis. 2006;42 Suppl 2:S65-71. 27. Rice LB. Antimicrobial resistance in gram-positive bacteria. Am J Med. 2006;119:S11-9; discussion S62-70. 28. Hughes WT,Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730-51. 29. Strasfeld L, Weinstock DM. Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents. Expert Rev Anti Infect Ther. 2006;4:457-68. 30. Patterson TF. Advances and challenges in management of invasive mycoses. Lancet. 2005;366:1013-25. 31. van Burik JA. Role of new antifungal agents in prophylaxis of mycoses in high risk patients. Curr Opin Infect Dis. 2005;18:479-83. 32. Kern WV. Risk assessment and treatment of low-risk patients with febrile neutropenia. Clin Infect Dis. 2006;42:533-40.

Tan ch41.qxd 10/12/07 10:28 AM Page 798

798

Expert Guide to Infectious Diseases

33. Viscoli C,Varnier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis. 2005;40 Suppl 4:S240-5. 34. Kumar D, Humar A. Emerging viral infections in transplant recipients. Curr Opin Infect Dis. 2005;18:337-41. 35. Fouchier RA, Rimmelzwaan GF, Kuiken T, Osterhaus AD. Newer respiratory virus infections: human metapneumovirus, avian influenza virus, and human coronaviruses. Curr Opin Infect Dis. 2005;18:141-6. 36. Ison MG, Fishman JA. Cytomegalovirus pneumonia in transplant recipients. Clin Chest Med. 2005;26:691-705, viii. 37. Heuser M, Ganser A. Colony-stimulating factors in the management of neutropenia and its complications. Ann Hematol. 2005;84:697-708. 38. National Comprehensive Cancer Network. Shifting guidelines for myeloid growth factors: applications in cancer chemotherapy. Curr Hematol Rep. 2005;4:441-5. 39. Atallah E, Schiffer CA. Granulocyte transfusion. Curr Opin Hematol. 2006;13:45-9. 40. Turina M, Fry DE, Polk HC Jr. Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects. Crit Care Med. 2005;33:1624-33. 41. Butler SO, Btaiche IF,Alaniz C. Relationship between hyperglycemia and infection in critically ill patients. Pharmacotherapy. 2005;25:963-76. 42. Cunha BA. Infections in nonleukopenic compromised hosts (diabetes mellitus, SLE, steroids, and asplenia) in critical care. Crit Care Clin. 1998;14:263-82. 43. Gleckman RA, al-Wawi M. A review of selective infections in the adult diabetic. Compr Ther. 1999;25:109-13. 44. Senneville E. Antimicrobial interventions for the management of diabetic foot infections. Expert Opin Pharmacother. 2005;6:263-73. 45. Allon M. Dialysis catheter-related bacteremia: treatment and prophylaxis. Am J Kidney Dis. 2004;44:779-91. 46. Nissenson AR, Dylan ML, Griffiths RI,Yu HT, Dean BB, Danese MD, et al. Clinical and economic outcomes of Staphylococcus aureus septicemia in ESRD patients receiving hemodialysis. Am J Kidney Dis. 2005;46:301-8. 47. Brigden ML, Pattullo AL. Prevention and management of overwhelming postsplenectomy infection—an update. Crit Care Med. 1999;27:836-42. 48. Schutze GE, Mason EO Jr., Barson WJ, Kim KS,Wald ER, Givner LB, et al. Invasive pneumococcal infections in children with asplenia. Pediatr Infect Dis J. 2002;21:278-82. 49. Price VE, Dutta S, Blanchette VS, Butchart S, Kirby M, Langer JC, et al. The prevention and treatment of bacterial infections in children with asplenia or hyposplenia: practice considerations at the Hospital for Sick Children, Toronto. Pediatr Blood Cancer. 2006;46:597-603. 50. Gill FM, Sleeper LA,Weiner SJ, Brown AK, Bellevue R, Grover R, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood. 1995;86:776-83. 51. Overturf GD. Infections and immunizations of children with sickle cell disease. Adv Pediatr Infect Dis. 1999;14:191-218. 52. Wong WY. Prevention and management of infection in children with sickle cell anaemia. Paediatr Drugs. 2001;3:793-801. 53. Adamkiewicz TV, Sarnaik S, Buchanan GR, Iyer RV, Miller ST, Pegelow CH, et al. Invasive pneumococcal infections in children with sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal polysaccharide vaccination. J Pediatr. 2003;143:438-44. 54. Riddington C, Owusu-Ofori S. Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease. Cochrane Database Syst Rev. 2002;3: CD00342. 55. Bernatoniene J, Finn A. Advances in pneumococcal vaccines: advantages for infants and children. Drugs. 2005;65:229-55. 56. Posfay-Barbe KM,Wald ER. Pneumococcal vaccines: do they prevent infection and how? Curr Opin Infect Dis. 2004;17:177-84. 57. Atkinson WL, Pickering LK, Schwartz B, et al. General recommendations on immunization. MMWR Recomm Rep. 2002;51:1-36. 58. Blade J, Rosinol L. Renal, hematologic and infectious complications in multiple myeloma. Baillieres Best Pract Res Clin Haematol. 2005;18:635-52. 59. Augustson BM, Begum G, Dunn JA, et al. Early mortality after diagnosis of multiple myeloma: Analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party. J Clin Onc. 2005;23:9219-26.

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60. Tosi P, Gamberi B, Giuliani N. Biology and treatment of multiple myeloma. Biol Blood Marrow Transplant. 2006;12:81-6. 61. Gertz MA, Lacy MQ, Dispenzieri A, Hayman SR, Kumar SK. High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with multiple myeloma. Expert Rev Anticancer Ther. 2006;6:343-60. 62. Greenberg SB. Infections in the immunocompromised rheumatologic patient. Crit Care Clin. 2002;18:931-56. 63. Juárez M, Misischia R, Alarcón GS. Infections in systemic connective tissue diseases: systemic lupus erythematosus, scleroderma, and polymyositis/dermatomyositis. Rheum Dis Clin North Am. 2003;29:163-84. 64. Raj R, Murin S, Matthay RA,Wiedemann HP. Systemic lupus erythematosus in the intensive care unit. Crit Care Clin. 2002;18:781-803. 65. Cunha BA. Central nervous system infections in the compromised host: a diagnostic approach. Infect Dis Clin North Am. 2001;15:567-90. 66. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet. 2003;362:1828-38. 67. Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis. 2002;21: 523-31. 68. Thomas CF Jr., Limper AH. Pneumocystis pneumonia. N Engl J Med. 2004;350:2487-98. 69. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc. 1996;71:5-13. 70. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore). 2005;84:291-302. 71. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275-85.

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Chapter 42

Herpes Virus Infections MICHELLE V. LISGARIS, MD GARY I. SINCLAIR, MD

Key Learning Points 1. Human herpes viruses infections are ubiquitous 2. Severe disease occurs primarily in immunocompromised individuals.

Herpes Simplex Virus Types 1 and 2 HSV-2 is the etiologic agent of the most common genital ulcer disease caused by sexual contact. This chapter will focus on the nongenital infections caused by HSV-1 and HSV-2, although the genital infection caused by HSV-2 is discussed in detail in Chapter 15. Table 42-1 lists the clinical characteristics of the herpesviruses family.

Epidemiology Herpes simplex virus infections are ubiquitous. Globally, by the fifth decade of life more than 90% of individuals will be serologically positive for HSV-1. Seroprevalence surveys conducted since the post–World War II era have revealed an inverse correlation between HSV-1 seroprevalence and socioeconomic status. Type-specific serologic assays exist that allow delineation of HSV serotype for epidemiologic and clinical purposes. Globally, the seroprevalence of HSV-2 is rising. Presence of antibodies to HSV-2 correlates with sexual activity and generally appears routinely in the pubertal period in adolescence. Rates in the United States are highest in 800

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New Developments in the Management of Herpes Virus Infections ●

●

A newly licensed vaccine for prevention of Varicella Zoster infection (shingles) was newly licensed in the United States. It shows promise in reducing the frequency of shingles outbreaks in at risk adults, and may lessen the morbidity associated with post-herpetic neuralgia. Varicella Immuneglobulin is no longer maufactured within the United States. A new product, VariZIG, is available under an FDA approved investigational new drug (IND) protocol for use in postexposure prophylaxis of acute varicella exposure.

Table 42-1 Clinical Characteristics of Herpesviruses Family

Virus

Seroprevalence among young US adults (%)

HSV-1

50

HSV-2

25

VZV

100

EBV

75

CMV

50

HHV-6

100

HHV-7

100

HHV-8

<10

Common infections

Site of persistence

Mode of transmission

Herpes libialis, Neuronal cells Contact with herpetic whitlow, especially secretions, keratitis, trigeminal especially oral encephalitis ganglia Herpes genitalis, Neuronal cells Contact with proctitis, neonatal especially sacral secretions, herpes ganglia especially genital Chickenpox, herpes Dorsal root ganglia Contact with zoster (shingles) of the CNS infected skin lesions; respiratory route for chickenpox Infectious mononu- B lymphocytes Contact with oral cleosis secretions, blood, or transplanted organs Infectious mononu- Monocytes, Contact with oral cleosis-like macrophages or genital syndrome secretions, urine, breast milk, blood, or transplanted organs Infantile fever, T lymphocytes Contact with oral roseola secretions Unknown possible T lymphocytes Contact with oral Febrile illness, secretions or roseola breast milk Kaposi’ sarcoma Not established Contact with bodily secretions

Adapted from Prober C. Sixth disease and the ubiquity of human herpesviruses. N Engl J Med. 2005; 352:753–55.

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women and African Americans, with highest rates in black women and lowest in white men. HSV-2 antibody levels are closely related to number of sexual partners, age at onset of sexual activity, and history of other sexually transmitted diseases (STDs). Estimating incidence rates for HSV is made difficult by subclinical disease during acute seroconversion, which occurs in 30% to 70% of individuals. Virus can be excreted from mucosal surfaces and in genital and oral secretions; shedding can occur during periods when infected individuals are asymptomatic. Transmission of infection occurs when virus from an infected individual is inoculated into mucosal surfaces of uninfected individuals. Any mucosal site can be infected when exposed to excreted virus. The incubation period for HSV infection occurring beyond the neonatal period ranges from 2 days to 2 weeks.

Pathophysiology Mucosal surfaces or abraded skin sites that are exposed to HSV allow viral entry into cells where viral replication occurs. With sufficient viral replication, infection of sensory or autonomic nerve endings occurs. Virus particles are transported to the ganglia by intra-axonal flow, and within the ganglia, the virus remains dormant. HSV-1 remains latent primarily in the trigeminal ganglia and inferior and superior cervical ganglia. HSV-2 maintains dormancy in the sacral nerve root ganglia. Virus then migrates centrifugally to skin surfaces by way of peripheral sensory nerves, manifesting the symptoms of primary HSV infection. After resolution of infection, infectious virus particles cannot be found in the involved ganglia although viral DNA can be isolated in up to 25% of ganglia. Viral factors are believed to influence the anatomic location of viral reactivation. For example, when HSV-1 infects both oral and genital sites, reactivation occurs more frequently in the orolabial region than in genital sites. The opposite is true for HSV-2. Reactivation of disease depends on many host factors, the most significant of which seems to be T-cell function because intact T-cell immunity is required for viral containment. It is not surprising then that recurrent, often severe infections are seen in persons with altered T-cell immunity (1).

Clinical Manifestations Mucocutaneous Infections Gingivostomatitis Symptomatic primary HSV-1 infection involving the oropharynx, is a disease typically of childhood, and occurs in only 10% to 30% of primarily infected children. Vesicular lesions involving the buccal and gingival mucosa, palate, pharynx, and/or tongue present after an incubation period of 2 to 12 days

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(mean 4 days) and can spread to the lips and face. Lesions are often accompanied by fever, malaise, and submandibular lymphadenopathy. Vesicular ulceration, oropharyngeal edema, and pain often make oral intake difficult. The duration of viral excretion from the oropharynx averages 7 to 10 days. Illness typically lasts for 2 weeks but can persist for 3 weeks. In children, systemic therapy reduced the duration of oral lesions, fever, eating and drinking difficulties, and viral shedding when administered within 72 hours of symptom onset (2). In this age group, differential diagnosis includes herpangina (coxsackie A and B virus), varicella, herpes zoster, and hand, foot, and mouth disease (coxsackie A); concomitant skin eruptions are distinguishing features of these infections. When primary infection occurs in the adolescent or adult, involvement of HSV-2 is possible. In this population HSV pharyngitis can be misdiagnosed as strep throat and thus is likely under-recognized; a mononucleosis-like syndrome can also occur.

Orolabial Infection (Cold Sores) Reactivation of latent infection manifests as cold sores. A prodrome of pain, burning, itching, or tingling heralds the appearance of vesicles by several hours. Vesicles progress to ulceration and crusting within 3 to 4 days. Pain and complete healing resolve completely within 8 to 10 days. Systemic symptoms are typically not problematic with recurrent episodes, which vary in frequency between individuals. Lesions caused by HSV-1 recur more frequently than those caused by HSV-2. Reactivation is often precipitated by fever, stress, sun/UV light exposure, and declines cell-mediated immunity. Antiviral therapy, if administered with the onset of prodromal symptoms, can decrease the duration of symptoms. Although topical agents are available, the need for frequent application, although decreasing symptoms by less 24 hours or less, makes these agents less desirable than systemic therapy. Herpetic Whitlow Herpetic whitlow is the term used for HSV infection of the finger and is typically an occupationally acquired infection. Autoinoculation of the digit can also occur during primary infections with either HSV-1 or HSV-2. Characteristically this infection presents with the abrupt onset of erythema, edema, and localized tenderness; fever with epitrochlear and axillary lymphadenitis is common. Whitlow can be clinically confused with paronychial infections. Care providers of children or hospitalized patients with active herpetic whitlow should not have direct care responsibilities for patients with immunocompromising illnesses or neonates. Systemic treatment is recommended to speed the healing process (Table 42-2). Herpes Gladiatorum and Herpes Rugbiorum Herpes gladiatorum and herpes rugbiorum are often used to describe HSV dermatitis that occurs in participants of close-contact sports such as wrestling or rugby. It affects 2.6% and 7.6% of high school and college

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Table 42-2 Antiviral therapy for non-genital HSV infections Syndrome

Antiviral Agent

HSV gingivostomatitis Acyclovir suspension Orolabial HSV Acyclovir “cold sores” (7,8) Famciclovir Valacyclovir Penciclovir 1% cream Docosanol 10% cream Acyclovir 5% cream Prophylaxis for sun exposure Herpetic whitlow Acyclovir Famciclovir Valacyclovir Herpes gladiatorum Acyclovir Valacyclover Eczema herpeticum

Acyclovir

Herpes keratitis

Trifluridine 1% soln Vidaribine ointment Acyclovir

Dose and Duration

15 mg/kg taken 5 times daily (3) 400mg po 5 times daily for 7 days (decrease symptoms by 1/2 day) 500mg po bid for 7 days (dec. symptoms by 2 days) 2gm po bid for one day (dec. symptoms by 1 day) Apply every 2 hours for 4 days (dec. symptoms by 1 day) Apply 5 times daily until healed (dec. symptoms by 1/2 day Apply 6 times daily for 7 days (dec. symptoms by 1/2 day) 400mg po tid for 10 days 250mg po tid 7-10 days 1000mg po bid for 10 days 400mg po tid for 7-10 days / 500 – 1000mg daily during season for prevention (4) Severe disease: 5mg/kg IV every 8 hours for minimum of 5 days Mild disease: 400mg po 5 times daily for 5-10 days One drop every 2 hours (max. 9 gtts/day) for 21 days Used for children: Apply to eyes 5 times daily for up to 21 days 400mg po bid for 12 months reduces the rate of recurrence of ocular HSV (9)

Data from Centers for Disease Control and Previon. Decline in annual incidence of varicella-selected states 1990-2001. MMWR Morb Mortal Wkly Rep. 2003;42:884-5; Plotkin SA. Clinical and pathogenetic aspects of varicella-zoster. Postgrad Med J. 1985;61(Suppl 4):7-14; Choo PW, Donahue JG, Manson JE, Platt R. The epidemiology of avricella and its complications J Infect Dis. 1995;172:706-12; Barnes DW, Whitley RJ. CNS diseases associated with varicella zoster virus and herpes simplex virus infection: pathogenesis and current therapy. Neurol Clin. 1986;4:265-83.

wrestlers respectively. Infections involve hands, arms, shoulders, ears, eyes, and thorax. Transmission results from direct inoculation of virus into traumatized skin. Control methods include education of athletes and trainers about the transmissibility of herpes infection, routine skin examinations before participation in events with exclusion of athletes with suspicious skin lesions, and sanitizing of wrestling mats with 1% bleach solution between wrestling matches (3,4).

Eczema Herpeticum Eczema herpeticum is also referred to as Kaposi varicelliform eruption. This form of disseminated HSV occurs as a superinfection of preexisting dermatitic

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or atopic skin disorders, second degree burns, or postdermabrasion and is a dermatologic emergency. The onset is marked by many clusters of vesicles in the areas of preexisting skin disease. Vesicles spread, becoming hemorrhagic and crusted and soon become painful punched-out erosions. These will often coalesce to form large bleeding erosions. Most patients will have fever and malaise. If disease is severe, intravenous antiviral agents are indicated as dissemination occurs; mild disease can be treated with oral agents (Table 42-2). Antibacterials are indicated when bacterial superinfection is present or suspected.

Ophthalmic Infections HSV-1 is one of the most common causes of corneal blindness. Keratoconjunctivitis caused by HSV-1 or HSV-2 presents as unilateral eye pain, lacrimation, conjunctivitis, and blurred vision. Fluorescein staining reveals topical dendritic figures on the corneal surface. It is crucial to exclude HSV in cases of keratoconjunctivitis because topical agents with corticosteroids can worsen the condition. Thirty to fifty percent of individuals will develop recurrent infection within 2 years of initial presentation. Evidence suggests oral suppressive therapy in addition to topical agents can decrease recurrence rates. Recurrent or severe disease can result in significant corneal scarring resulting in permanent visual damage. HSV can cause serious eye infections in immunocompromised individuals.

Central Nervous System Infection This topic is discussed in Chapters 3 through 5.

Diagnosis The time-honored Tzanck preparation is the quickest method of diagnosis but is not always readily available. A #15 surgical blade should be used to open the top of a vesicle, scraping the underside of the vesicle as well as the base. The blade is then wiped across a glass slide, heat-fixed, and stained with toluidine blue. The presence of multinucleated giant cells with molded, jigsaw-puzzle nuclei and acantholytic balloon cells will confirm viral infection, but is not virus-specific. Direct fluorescent antibody testing enables rapid identification of the virus, as results are available within several hours. Viral culture from a fresh vesicle can require at least 48 hours for final results. If the culture is taken from a crusted site, as often seen in older lesions, results can be negative.

Treatment Acyclovir, famciclovir, valacyclovir, ganciclovir, foscarnet, and cidofovir are antiviral agents available for the treatment of herpes virus infections. With the

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exception of foscarnet and cidofovir, all available agents are guanosine analogs. These analogs require HSV tyrosine kinase for phosphorylation. After activation, they compete with deoxyguanosine triphosphate and inhibit herpes virus DNA polymerase. Valacyclovir is the prodrug of acyclovir; both incorporate directly into viral DNA and become chain terminators, thus halting viral DNA synthesis. Famciclovir is the prodrug of penciclovir. Although they inhibit viral DNA polymerase as well, they are not obligate chain terminators. Differences in pharmacokinetic properties are the essential differences between these agents clinically. Resistance develops to these agents when tyrosine kinase activity is altered. The most commonly seen mechanism is absent or deficient enzyme activity. Ganciclovir is not considered first-line therapy for HSV infections as it is far more potent for CMV infection. CMV is not useful in the treatment of acyclovir-resistant HSV. Foscarnet and cidofovir are used when resistant HSV is suspected or confirmed. If acyclovir resistance is suspected, consultation with an infectious diseases specialist should be sought because of the toxicities of available antiviral therapeutics for resistant herpes simplex virus. (5) For specific recommendations on antiviral agents, dosing, and therapy duration, see Table 42-2.

Varicella Zoster Virus Infection Two distinct clinical syndromes are associated with VZV infection: chickenpox (primary varicella) and herpes zoster (shingles).

Epidemiology Chickenpox Chickenpox (primary varicella) is a highly contagious disease caused by primary infection with VZV and is manifested by a febrile illness with a diffuse vesicular rash. Humans are the only known reservoir of VZV. Spread of the virus occurs through respiratory droplets as well as through the inhalation of particles aerosolized from new crops of chickenpox or zoster lesions. Early viral replication occurs in the nasopharynx and upper respiratory tract, and is followed by viremia and subsequent skin and neural infection. Although the disease is ubiquitous, clusters or epidemics of chickenpox occur in late winter and early spring. Before the introduction of routine childhood immunization with the varicella vaccine, the annual incidence of chickenpox in the United States was 3 to 4 million cases per year—a figure approximately the same as the national birth rate (6). After implementation, the incidence of chickenpox declined by 71% to 84% and 67% to 82% in areas with active and passive surveillance respectively (7,8). The median age of onset of chickenpox is less than 3 years, but 5% to 10% of patients will escape infection and will still be susceptible to VZV when

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they reach adulthood (6). More than half a million visits to physician offices each year are related to chickenpox infection, and 250 people die each year because of chickenpox (6). The risk of dying from chickenpox is 2 in 100,000 for healthy children, but increases by a factor of 15 for adults (6). The long-term effect of routine immunization in the United States can alter these statistics.

Herpes Zoster After resolution of primary varicella infection, VZV persists in latent form in the dorsal root ganglia of the central nervous system. Later, localized viral activation and replication can occur if the balance between viral factors and host immunity is altered. Disease caused by reactivation of the virus occurs in 20% of infected individuals at some point in life (6). The annual incidence of herpes zoster ranges from 0.4 to 1.6 cases per 1000 people among healthy people younger than 20 years of age, and as high as 4.5 to 11 cases per 1000 people among those 80 years of age and older (9). Most commonly, patients with herpes zoster are older than 55 years of age (30% in one study of a managed care population, in which patients older than 55 years of age constituted only 8% of all patients) (10). The risk of a second attack is as high as the risk of a first (9), however, three or more episodes should raise concern about occult immunosuppression. Notably, nonimmune individuals can contract primary varicella by exposure to the lesions of herpes zoster. Because these lesions can be aerosolized, patients with disseminated herpes zoster in medical facilities should be placed in private rooms to avoid risking exposure to nonimmune healthcare workers and immunocompromised patients.

Pathophysiology The pathophysiology of the pox in both chickenpox and herpes zoster is similar. Vesicles involve the corium and the dermis. The vesicular fluid is initially clear and centered on an erythematous base, thus giving the classic dewdrop on a rose petal appearance. The fluid becomes cloudy as polymorphonuclear leukocytes infiltrate, local cells degenerate, and fibrin collects in the vesicle. The pustule then breaks down, crusts over with scab, and eventually heals (11).

Clinical Manifestations Chickenpox The typical course of chickenpox involves rash, low-grade fever, listlessness, pruritus, and malaise. Body temperature ranges from 37.7°C to 39.4°C (100°F-103°F), and the fever lasts for 3 to 5 days (6). It takes approximately 14 days to develop the rash of chickenpox after exposure, with a range of 10 to 20 days (6). The infectious period starts approximately 48 hours

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before the appearance of lesions and lasts until approximately 4 or 5 days thereafter, when the lesions have crusted over (6). The initial rash is usually localized to the trunk and face. Successive crops of pox appear for 2 to 4 days, spreading to the periphery and scalp, and can be found anywhere, including the oropharynx and the vagina (6). Crusts generally fall off after 1 to 2 weeks, leaving slight depressions in the skin (6,9). Secondary bacterial infection of pox lesions can lead to local scarring. Many unusual and serious complications can result from chickenpox, and the primary-care physician should be aware of these. A study done in the early 1990s estimated that the 30-day rate of reported complications ranged from 167 to 249 cases for every 10,000 cases of primary varicella—a rate much higher than reported in similar previous studies done in the 1970s (12). In the recent study, complications included central nervous system (CNS) disease, varicella pneumonia, skin superinfection, and Reye syndrome. Fetal and neonatal infection also represent complicated cases of varicella. Central nervous system complications of chickenpox include acute cerebellar ataxia, varicella encephalitis, transverse myelitis, and aseptic meningitis. Acute cerebellar ataxia occurs in approximately 1 in every 4000 children younger than 15 years of age (6). Symptoms appear from several days before to 2 weeks after the appearance of rash, and usually resolve within 2 to 4 weeks without additional treatment (13). Death rates have been estimated to be between 0% and 5%, and are usually associated with the development of other complications of varicella, such as pneumonia (13). Varicella encephalitis occurs with an incidence of 0.1% to 0.2% (6). It is characterized by depressed consciousness, headache, vomiting, altered thought patterns, high fever, and seizures. Symptoms can occur from 11 days before to several weeks after the onset of the rash (13). Death rate estimates for varicella encephalitis range from 0% to 35% (6,13). Rare cases of both transverse myelitis and aseptic meningitis caused by VZV have been reported, usually with complete recovery as the outcome (13). CNS complications in the course of chickenpox usually merit expert consultation, because patients can benefit from treatment with antiviral medications and/or corticosteroids, although the data on this remain somewhat ambiguous (13). Varicella pneumonia is another serious complication of chickenpox. It is more common in adults, with clinical pneumonia developing in 0.3% to 1.8% of cases, and radiologic changes occurring even more frequently (14). Varicella pneumonia is probably the most common severe complication of chickenpox, accounting for 27.6% of varicella-related deaths (14). Cigarette smoking is a risk factor for such pneumonia; rates of 42% to 47% have been reported for varicella pneumonia among smokers (14). Tachypnea, cough, and dyspnea are prominent presenting features, beginning 3 to 5 days into the illness (6). Nodular or interstitial patterns can be seen on chest radiography. The death rate of untreated varicella pneumonia is estimated at 11% in otherwise healthy adults (14), and from 35% to 44% in pregnant women (14,15). Expert consultation is warranted for such pneumonia, because

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aggressive treatment, including antiviral medication, has been proven to decrease illness and death resulting from it (15). Varicella infection during pregnancy is a complex management problem. In addition to an increased severity of the disease and its complications for the mother owing to her suppressed immunity, two distinct risks are posed to the baby. First, when primary varicella occurs early in pregnancy, there is an increased risk of congenital abnormalities (occurring in 1% to 2% of infants of infected mothers), including skin scarring, hypoplastic extremities, eye abnormalities, and mental retardation (6). Second, a high perinatal infant death rate (30% for infants of untreated mothers) is noted when pregnant women develop chickenpox during the period from 5 days before to 48 hours after delivery (16). This period of fetal/neonatal vulnerability is most likely related to the absence of protective transplacental antibodies from the mother, who at this time is in an early stage of infection and has not yet developed protective anti-VZV antibodies. Many systemic complications can occur in the affected infant, and expert consultation is mandatory. Because of these significant risks of chickenpox in pregnancy, a pregnant woman exposed to chickenpox who has no history of previous infection or immunization should be given passive immunization (see discussion of varicella zoster immunoglobulin in the Passive Immunization section). Acyclovir should be given when chickenpox develops during pregnancy (see the Treatment section). Reye syndrome is a hepatic and systemic disorder that occurs in some patients with chickenpox who take aspirin for symptom relief. The syndrome is characterized by vomiting, restlessness, increased blood ammonia levels, hyperglycemia, and increased aminotransferase activity (6). Other potential complications of chickenpox include skin superinfections, necrotizing fasciitis (particularly with group A streptococci) (17), myocarditis, nephritis, a bleeding diathesis, and hepatitis (6).

Herpes Zoster The lesions of varicella zoster or shingles most commonly occur in the thoracic or lumbar dermatomal distributions but can occur in any dermatome (6). Pain in the dermatomes precedes the appearance of lesions by 48 to 72 hours. The lesions are vesicular on an erythematous base, much like those of primary varicella. New lesions appear for 3 to 7 days, and pain usually lasts for approximately 2 weeks. Complete healing of the skin can take as long as a month (6). In addition to the effects just discussed, isolated involvement of divisions of the fifth cranial nerve can be seen in cases of zoster. When the ophthalmic branch of the trigeminal nerve (V1) is involved, eyelid involvement, keratitis, iridocyclitis, secondary glaucoma, and zoster ophthalmicus can occur (6). Ocular involvement mandates ophthalmologic consultation. When any of the branches of the fifth cranial nerve are involved, mucous membrane and tonsillar lesions also can be seen. Involvement of the geniculate ganglion leads to the Ramsay-Hunt syndrome, with pain and vesicles occurring in the

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external auditory meatus; additionally, loss of taste can occur in the anterior two thirds of the tongue, and ipsilateral facial palsy can occur (6). Extracutaneous manifestations of zoster are rare. Meningoencephalitis, a painful motor paralysis (which is distinctive, because most paralysis syndromes are associated with anesthesia), Guillain-Barré syndrome, transverse myelitis, and myositis have all been reported. In the immunosuppressed patient, dissemination of VZV, with pneumonitis, hepatitis, and encephalitis, is more common, and the syndrome can affect many dermatomes for a prolonged period (6). Perhaps the most significant complication of herpes zoster is postherpetic neuralgia. Although rare in children, it occurs in 27%, 47%, and 73% of zoster patients who are older than 55, 60, and 70 years of age, respectively (9). The neuralgia is generally defined as pain in a dermatome previously affected by zoster and which lasts longer than 1 month. Early treatment with antiviral agents and corticosteroids can play a role in reducing this feared complication (see the following Treatment section) (9).

Diagnosis The diagnoses of both chickenpox and varicella zoster are largely clinical and are based on the appearance of the rash and the usual natural history of the disease as outlined previously. Disseminated HSV infection can be mistaken for varicella. Viral culture is more sensitive for HSV than for VZV, which grows slowly and unreliably in vitro (18). Late pustules and crusted lesions can be confused with impetigo, and individual pox lesions can actually be superinfected with Staphylococcus aureus and/or group A betahemolytic streptococci (17). A Gram stain can be helpful in distinguishing VZV from bacterial pustules or impetigo. A Tzanck preparation can also be done, but is only helpful when classic multinucleated giant cells are identified. Serum titers of anti-VZV IgG antibody are of little benefit in acute disease, but are helpful in determining the immune status of exposed people without a clear history of clinical varicella (18). The most sensitive confirmatory test for herpes zoster or chickenpox is the VZV-specific direct fluorescence monoclonal antibody test (DFA) done on scrapings taken from the base of an unroofed pox lesion during an episode of either condition. In one study in which clinical diagnoses of chickenpox and herpes zoster were used as the gold standard, sensitivity and negative predictive value were estimated at 97%, and specificity was 100%. By contrast, the sensitivity and negative predictive value of VZV culture were estimated at 49% and 60%, respectively. Discordance between results of the DFA test and culture was associated with acyclovir treatment, with testing of lesions more than 5 days old, and with testing of lesions less than 1 day old. Notably, only two cases were found in which the culture was positive, and the DFA test was negative. Both of these cases involved pox lesions less than 1 day old. Had the DFA test been repeated later in

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these cases, more cells have expressed viral antigen, and the discordance in diagnostic results could have been eliminated (19). Using the DFA test for diagnostic confirmation whenever there is clinical doubt is recommended. Coxsackie virus, enterovirus, and HSV infections can all present with vesicular rashes, and each of these entities requires a different therapeutic approach.

Chickenpox For chickenpox in small children, the traditional approach to care has been to control symptoms and maintain hygiene by bathing, astringent soaks, and aluminum acetate soaks (6). Pruritus is eased by the use of topical lotions or oral antihistamines. Acetaminophen should be used instead of aspirin because of aspirin’s association with Reye syndrome. The American Academy of Pediatrics recommends treatment with acyclovir for all adults and adolescents, and for children with other underlying disease, especially those with immunosuppression, because of their increased risk of developing severe disease (6,18). For chickenpox, the oral pediatric dose of acyclovir is 20 mg/kg given four times per day for 5 days. The oral adult dose is 800 mg given five times per day for 5 to 7 days (6,18). Ideally, the first dose should be given within 24 hours of the onset of symptoms. Oral acyclovir is not recommended for healthy children with uncomplicated chickenpox. We recommend acyclovir for all women who contract varicella during pregnancy. Acyclovir is listed as a Class B teratogen. Studies have shown decreased maternal and fetal illness and death with acyclovir (14,15). Most experts agree that the potential benefits of acyclovir outweigh the risks of using it. Valacyclovir and famciclovir are also Class B teratogens, but are less well studied than acyclovir. Intravenous acyclovir (500 mg/m2 every 8 hours or 10-12 mg/kg every 8 hours) and aggressive supportive care should be given to anyone exhibiting severe local or systemic complications of chickenpox (such as pneumonitis or CNS disease). Intravenous acyclovir should also be used for anyone whose illness is severe enough to require hospitalization. Herpes Zoster Treatment of herpes zoster is a problem more common to the primary care physician than to other practitioners. Corticosteroid therapy has been recommended both for alleviating symptoms of acute neuritis and for decreasing the incidence of postherpetic neuralgia, but the data for its efficacy are somewhat controversial (6,9). Oral acyclovir, as well as the newer anti-herpes agents valacyclovir and famciclovir, has clearly been proven to accelerate healing and to decrease symptoms if given within 72 hours of the onset of rash (20-23). The efficacy of the three drugs seems to be equivalent. Meta-analyses demonstrate a decreased incidence of postherpetic neuralgia in patients who have received antiviral medications (20-23). It is recommended that an oral antiviral

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agent be routinely given to all patients presenting within 72 hours of the onset of symptoms of zoster if they have no contraindications to such drugs. Decisions about which of the three drugs to use should be based on cost and ease of administration for the individual patient. The dosage for acyclovir is the same as would be used for chickenpox (800 mg given five times per day for 7 days). The dosage of famciclovir for zoster is 500 mg every 8 hours for 7 days, and the dosage of valacyclovir is 1 g every 8 hours for 7 days. Because of a paucity of data, the decision to use corticosteroids and/or to treat patients outside of the 72-hour framework must be individualized. Acute pain should be managed with analgesic agents, including narcotics if necessary. Chronic pain, which can occur in up to 50% of older patients, is managed with tricyclic antidepressants, anticonvulsant medications (usually carbamazepine, gabapentin, or pregabalin), and agents that deplete substance P (capsaicin cream), as in other chronic pain syndromes (9).

Prevention Isolation Hospitalized patients who contract VZV infection or exhibit zoster lesions must be isolated until all lesions have crusted over to protect the infection of nonimmune and immunocompromised individuals. Nonimmune patients and health care workers who are significantly exposed to chickenpox and/or zoster should be considered infectious from day 8 to day 21 after exposure, and should be isolated or relieved of duty as appropriate. Nonimmune is defined as having low or negative titers of anti-VZV IgG antibody (<1.0 index units by enzyme-linked immunosorbent assay), or having a negative clinical history of chickenpox if titer results are pending. Significant exposures include residence in the same household as the index patient, face-to-face indoor play with the patient, occupying an adjacent bed to the patient in a multipatient room or ward, and touching or hugging the index patient (14). Passive Immunization As of October 2004, varicella-zoster immune globulin (VZIG) production in the United States has been discontinued. Under a recent investigational new drug application, a lyophilized form of purified human varicella IgG, VariZIG (Cangene Corporation, Winnipeg, Canada), is available. VariZIG is recommended for postexposure prophylaxis for persons at high risk for severe disease and complications. These individuals include the following: neonates whose mothers developed primary varicella at any time from 5 days before delivery to 48 hours postpartum; neonates exposed postnatally; immunocompromised children, adolescents, and adults, even if receiving IVIg; all nonimmune pregnant women who sustain significant exposure to VZV; susceptible, exposed hospital personnel with significant exposure to VZV. The dose of VZIG is 125 units given intramuscularly for every 10 kg of body weight, up to a maximum of 625 units. Intramuscular injection of

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VariZIG is expected to provide maximum benefit when administered as soon as possible after exposure, although it can be effective if administered as late as 96 hours after exposure; treatment after 96 hours is of uncertain value. Availability of VariZIG is through an expanded access protocol that has received central institutional review board (IRB) approval, therefore the FDA does not require additional approval by the IRB of the treatment facility. Because of the investigational nature of this product, informed consent must be obtained and other patient protections must still be in place, before the administration of VariZIG (24).

Active Immunization Vaccination against chickenpox is currently recommended for all immunocompetent children and adolescents unless they have a clear clinical history of chickenpox and are therefore immune (25). Vaccination of nonimmune, high-risk adults is strongly encouraged. It should be given to all susceptible persons older than 13 years of age who are at high risk for exposure: health care or day care workers, persons who live and work in environments where transmission can occur (college students, employees and residents of correctional institutions, and military personnel), nonpregnant women of childbearing age, adolescents and adults living in households with children, and international travelers (25). A reliable history of having had clinical chickenpox is adequate for establishing immune status. For adults who do not recall having had chickenpox, assaying titers of anti-VZV IgG antibody is likely to be cost effective, because 71% to 93% of these people will prove to be immune (25). In 1999, varicella vaccine was also recommended for postexposure prophylaxis of persons without evidence of varicella immunity and without contraindications to vaccination. Vaccination should occur within 96 hours and possibly up to 120 hours postexposure. If illness occurs, with or without postexposure vaccination, antiviral treatment (e.g., acyclovir) can be considered for adolescents and adults (25). The vaccine for chickenpox is a cell-free preparation of live, attenuated VZV of the wild Oka strain. It contains trace quantities of Neosporin and gelatin, to which a small minority of patients can have an allergic reaction. A single dose in children 12 months to 12 years of age results in a 97% rate of seroconversion. Two doses given over an interval of 4 to 8 weeks seem to be necessary for effecting immunity in people older than 13 years of age. Studies in Japan, where the vaccine has been licensed since the 1970s, suggest that it confers protective immunity for at least 20 years. Vaccination is protective against severe VZV disease in 95% of vaccinees, and protective against all disease in 70%. Within 1 month of vaccination, 7% to 8% of vaccinees will develop a mild maculopapular or vesicular rash (25). A zoster-like syndrome has been seen in 18 cases per 100,000 person years in vaccinated children followed for 7 years. Because the estimate for zoster occurring after natural infection is 77 cases per 100,000 person years, immunization does not seem to increase the risk of zoster (25).

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Vaccination against chickenpox is contraindicated for immunocompromised individuals. This includes patients receiving systemic corticosteroid therapy (except in the case of adrenal replacement therapy), pregnant women, patients with HIV/AIDS, and patients with lymphoproliferative malignancies (except for children with acute lymphoblastic leukemia in remission, for whom ongoing studies suggest that vaccination against chickenpox is beneficial) (25). Inhaled corticosteroid therapy is not a contraindication to vaccination (25). Patients who have not received systemic corticosteroids for 3 months can also be vaccinated safely (25). Whenever possible, vaccinees should avoid contact with immunocompromised people for 3 weeks after vaccination. Plasma, whole blood, intravenous immune globulin, and VZIG can theoretically interfere with the antibody response to varicella vaccine for approximately 5 months (25). The recent availability of the live attenuated Oka/Merck VZV vaccine, Zostavax, for use in adults older than 60 years of age who have had previous varicella infection offers promise in reducing the frequency of varicella zoster attacks and severity of postherpetic neuralgia. The vaccine was approximately 55% efficacious in decreasing the frequency of zoster outbreaks; a 66.5% vaccine-associated reduction in the incidence of postherpetic neuralgia was documented. The vaccine was less efficacious in persons older than 70 years of age, however, the improvement in severity of postherpetic neuralgia was most pronounced in this age group (26).

Epstein-Barr Virus and Infectious Mononucleosis Epidemiology Infection with EBV causes a ubiquitous febrile syndrome occurring in 90% to 95% of most populations tested for serologic evidence of such infection (27,28). In Western countries, approximately 50% of seroconversions for EBV infection occur before the age of 5 years, and a second peak occurs during the second decade of life (27,28). Symptomatic infectious mononucleosis (IM) is more common when infection occurs in the second decade (27,28). Low titers of anti-EBV antibody are present in throat washings of people with IM (27). Virus persists in the oropharynx for up to 18 months after acute EBV infection. It can be cultured from the oropharynx of 10% to 20% of immunocompetent adults at any time. Susceptible college roommates of people with EBV infection experience seroconversion no more often than the general susceptible college population. For these reasons, precautions for isolating EBV-infected individuals in the community are neither advisable nor feasible (27). The primary method of transmission is through saliva transferred by various means including kissing. Transfused blood can also transmit EBV disease (27).

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Pathogenesis In tissue culture, EBV can be grown only in B cells and in epithelial tissues of the nasopharynx (27). Primary inoculation is believed to be through the nasopharynx. A 30- to 50-day incubation period ensues (28). Viral replication starts in the lymphoid tissue of the pharynx and spreads throughout the entire lymphoreticular system. Disease is almost always self-limiting, although intermittent shedding of virus occurs for the remainder of life (27).

Clinical Manifestations Although generally a benign, self-limiting illness, IM can have a clinical presentation that seems out of proportion to the true severity of illness. IM can mimic leukemia, streptococcal pharyngitis, and acute viral hepatitis. Table 42-3 provides signs and symptoms of IM. The likelihood of symptomatic infection with EBV increases with age. Pediatric infections are likely to be asymptomatic, whereas in military recruits, 90% of infections have been found to be clinically apparent (27). Signs and symptoms of infection generally last 2 to 3 weeks, although fatigue can last somewhat longer (27). Sore throat is maximal for 3 to 5 days. Fever tends to last for 10 to 14 days (27). Administration of ampicillin, which frequently

Table 42-3 Signs and Symptoms of Acute Epstein-Barr Virus (Infectious Mononucleosis) Symptoms and Signs

Sore throat Malaise Headache Anorexia Myalgias Chills Nausea Abdominal discomfort Cough Arthralgias Lymphadenopathy Pharyngitis Fever Splenomegaly Hepatomegaly Palatal exanthem Jaundice Rash

Percent of Patients with Symptom

82% 57% 51% 21% 20% 16% 12% 9% 5% 2% 94% 84% 76% 52% 12% 11% 9% 10%

Adapted from Schooley RT. Epstein-Barr virus (infectious mononucleosis). In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 4th Ed. New York: Churchill Livingstone; 1995:1364–77.

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occurs when the syndrome is mistaken for acute streptococcal pharyngitis, produces a pruritic maculopapular eruption in 90% to 100% of cases and is contraindicated (27). However, development of such a rash should not cause a patient to be labeled as penicillin-allergic (28). Initial suggestions that EBV is the causative agent of chronic fatigue syndrome are no longer supported by most reviewers (29,30).

Complications EBV infection can be attended by many hematologic complications. Autoimmune hemolytic anemia occurs in 0.5% to 3% of cases and is associated with cold agglutinins of the IgM class. Hemolysis usually starts in the second or third week of illness and can persist for 1 to 2 months. Corticosteroids can hasten recovery (27). A mild thrombocytopenia, with platelet counts below 140,000 cells/mm3, has been noted in 50% of cases of IM (27). Severe cases are rare but have been reported, and responses of such cases to corticosteroids and splenectomy have been documented (27). Mild neutropenia is frequent in IM, although severe cases of EBV infection leading to sepsis have been reported (27). Splenic rupture is a rare complication of IM, with the highest incidence occurring between the fourth and twenty-first days of illness (27,28). It is estimated to occur in 1 or 2 of every 1000 cases (28). Because abdominal pain is not a striking feature of mononucleosis, its appearance warrants investigation for splenic rupture. Occasionally, splenic rupture can be the presenting symptom of IM. The abdominal catastrophe can alter the differential blood count, and affected patients can paradoxically have an increased granulocyte count. Approximately one half of splenic ruptures are attributable to trauma, and contact sports should be avoided for at least the first 3 weeks after diagnosis of such rupture (27). Overly vigorous physical examination should also be avoided (27). Neurological syndromes occur in fewer than 1% of cases of primary EBV infection, but are occasionally the only manifestation of such infection (27,28). They include encephalitis, meningitis, myelitis, Guillain-Barré syndrome, optic neuritis, retrobulbar neuritis, cranial nerve palsies, mononeuritis multiplex, brachial plexus neuropathy, seizures, subacute sclerosing panencephalitis, transverse myelitis, psychosis, demyelination, and hemiplegia. One unusual syndrome is called metamorphopsia, or Alice in Wonderland syndrome. It involves deficits in perception of size, shape, and spatial orientation (28). Neurological complications are actually the most frequent cause of death in acute EBV infection in otherwise healthy individuals (31). However, the course of such infection is usually benign, and most patients recover completely. A 1970 review (covering the preacyclovir era) revealed only 20 documented EBV-associated deaths (27). EBV infection is associated with Burkitt lymphoma and with nasopharyngeal carcinoma (27).

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Severe upper airway obstruction occurs in 1 of every 100 to 1000 cases of EBV infection. It can occur at any age but is more common in young children for anatomic reasons. Airway obstruction is considered an indication for steroid therapy, but the clinician must remain aware of the possibility of a concurrent bacterial pharyngitis (28).

Diagnosis The diagnosis of syndromic acute EBV infection is generally straightforward and is based on typical manifestations as described earlier, the presence of atypical lymphocytosis, and a positive monospot test. Infectious agents that cause syndromes that resemble mononucleosis include adenovirus, CMV, hepatitis A, HHV-6, HIV-1 (in acute infection), rubella virus, and toxoplasma (in acute infection) (28). Medications such as phenytoin and sulfa drugs can also cause symptoms resembling those of IM, including fever and lymphadenopathy (28). Lymphoma and leukemia are sometimes initially mistaken for mononucleosis. Various processes can produce false-positive monospot tests. These include mumps, malaria, rubella, serum sickness, and lymphoma. However, these conditions tend to produce much lower titers of heterophile antibodies than does acute EBV infection (28).

Laboratory Findings In 70% of cases of IM, a 60% to 70% mononuclear lymphocytosis with a leukocyte count of approximately 15,000 will be seen, thus imparting the name infectious mononucleosis to the syndrome (27). Atypical lymphocytes are usually seen, but their numbers can range from almost none to more than 90% of the total lymphocyte count (27). It should be noted that atypical lymphocytes can also be seen in CMV and HIV infections, viral hepatitis, toxoplasmosis, rubella, mumps, roseola, and drug reactions (28). Atypical lymphocytes are large and heterogeneous and have a vacuolated cytoplasm and lobulated, eccentric nucleus. This is in contrast to the more uniform appearance of lymphoblasts as seen in acute leukemia. The classic heterophile antibody test is done by reporting the highest serum dilution capable of agglutinating sheep erythrocytes after adsorption of a test serum by guinea pig kidney. A titer of 40 or greater is strong evidence for IM (27). Classic agglutination tests, which took 24 hours to do, have been modified to create commercially available monospot tests whose sensitivity and specificity are similar to those of agglutination tests even though they can be done in 2 minutes (28). The time at which heterophile antibody tests become positive in IM is variable, with pediatric cases tending to develop heterophile antibody positivity later or not at all, whereas most adolescent and young adult cases are heterophile antibody-positive at presentation (27). As a rule of thumb, heterophile antibodies are present in 60% to 70% of patients in the first week

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of symptoms and in 80% to 90% by the third and fourth weeks. The heterophile antibody usually disappears after 3 months, but can persist for up to a year (28). Overall, rapid monospot kits are estimated to have sensitivities ranging from 63% to 84% and specificities ranging from 84% to 100% (28). A panel of Epstein-Barr virus-related antibodies is shown in Table 42-4 (32). This sort of analysis should be reserved for situations in which heterophile antibody tests are negative (suspected monospot-negative mononucleosis), a definitive diagnosis is critical, the presentation is atypical, and/or the phase of EBV infection must be known (28). The estimated 1997 cost of a monospot test was $16, whereas an EBV panel can cost more than $80 (28).

Treatment Treatment of IM is largely supportive because 95% of cases recover uneventfully (27). Corticosteroids decrease the period of febrility and hasten the resolution of constitutional symptoms in IM, but should be reserved for severe complications. Indications for their use are impending airway obstruction, severe thrombocytopenia, hemolytic anemia, CNS involvement, myocarditis, severe pneumonitis, and pericarditis (27,33). The recommended dosing schedule is 30 to 40 mg of prednisone twice daily, tapered over a period of 1 to 2 weeks (27). Controlled trials of acyclovir in EBV infection have shown decreased viral shedding but no clear-cut clinical benefit (26,34). The use of acyclovir in complicated cases of IM and in patients with malignancies associated with immunocompromise is under investigation.

Prevention Isolation is not indicated for patients with IM because the infection is ubiquitous and requires intimate contact for transmission. People with IM should consider abstaining from blood donation for 6 months after acute infection (27).

Table 42-4 Serum Epstein-Barr Virus Antibodies as a Function of Infection Status Infection Status

No previous infection Acute infection (0–3 months) Recent infection (3–12 months) Past infection (>12 months)

Anti-VCA IgG

Anti-VCA IgM

Anti-VCA EA

Anti-VCA EBNA


+ + +


+ +/




+/
+/






+

Anti-VCA IgG = IgG class antibody to viral capsid antigen; Anti-VCA IgM = IgM class antibody to viral capsid antigen; EA = early antigen; EBNA = Epstein-Barr nuclear antigen;
= <1:10 (<1:2 for EBNA); + = >1:10 (>1:2 for EBNA).

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Other Epstein-Barr Virus-related Syndromes Chronic Active EBV Infection (CAEBV) Chronic active EBV (CAEBV) infection is a rare condition that is characterized by recurrent IM-like symptoms after a well-documented primary EBV infection. Patients with CAEBV have a high incidence of hepatic failure, lymphoma, or hemophagocytic syndromes. A specific antibody pattern of high IgG anti-viral capsid antigen (VCA) and early antigen (EA), failure to produce EBNA1 and sometimes persistence of anti-VCA IgM is characteristic for CAEBV (33). The ability of EBV to immortalize cell lines during viral latency has resulted in its association with malignant conditions, many of which occur in individuals with chronic immunosuppressive conditions such as HIV or solid and bone marrow transplantation. Burkitt lymphoma in African children, nasopharyngeal carcinoma, and some histiologic types of Hodgkin lymphoma (35) have been associated with EBV infection. In HIV-infected individuals, EBV-related malignancies include primary central nervous system lymphoma and non-Hodgkin lymphoma, usually of the high-grade B cell type. EBV-related posttransplantation lymphoproliferative disorder (PTLD) ranges from a benign self-limited polyclonal proliferation to true malignancy indistinguishable from non-Hodgkin lymphoma. Overall death rates are as high as 60%. EBV genome is found in more than 90% of the B cell PTLD occurring in the first year after solid organ transplantation. The risk for developing PTLD is variable depending on the type of the organ transplanted. The highest incidence is seen in intestinal transplantation (7%-11%), followed by lung (1.8%-7.9%), heart (3.4%), liver (2.2%), and kidney (1%) (36). Avoiding unnecessary potent immunosuppressives is a key factor in reducing the incidence of PTLD (37). EBV-DNA viral load can be a useful test in monitoring patients for PTLD (38).

Cytomegalovirus Infection CMV infection in the immunocompetent host is rarely associated with significant disease. A full discussion of CMV infection in immunocompromised individuals can be found in Chapters 39 through 41.

Epidemiology The prevalence of CMV infection varies, depending on the population surveyed, from 40% to 100% (39). People in developing countries and those of lower socioeconomic background tend to have higher prevalence rates. One peak of seroconversion is noted in the perinatal period, and the second is noted in the reproductive years. The virus has been isolated from blood,

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cervical secretions, breast milk, semen, and, particularly in children, urine and respiratory tract secretions (38,40). Seroconversion after blood transfusion and/or transplantation has also been documented, presumably from latent virus stored in leukocytes and other tissues. In contrast to the case with EBV, immunocompetent adults do not routinely shed CMV in throat secretions, blood, respiratory secretions, or urine, but patients who are recovering from an acute systemic illness can shed CMV for several months (39). Women have been noted to carry CMV persistently in cervical secretions, and homosexual men have been noted to carry it persistently in their semen (40). Horizontal transmission of CMV infection is frequent. In daycare centers, excretion rates of the virus are estimated at 70% (40). Children can pass the virus to each other and to nonimmune adult providers through saliva and urine. Adolescents and young adults can pass the virus through sexual activity and kissing. Vertical transmission of CMV can occur through transplacental passage of the virus, through contact with the cervix at birth, and postnatally through ingestion of breast milk (40). One percent of live-born infants excrete CMV at birth (40). In utero infection can result either from primary maternal infection or through maternal reactivation disease, but serious sequelae are much more likely to be the result of primary maternal infection (40). From 10% to 20% of infants whose in utero infections result from primary maternal infection with CMV will have mental retardation or deafness (40). Infection in utero seems to be much more dangerous than infection in the birth canal or infection from breast milk, neither of which is likely to be associated with clinical disease (40).

Clinical Manifestations Congenitally acquired CMV occurs in infants whose mothers acquire CMV infection during pregnancy, typically during the first half. It is the most serious of neonatal infections and is often fatal. In surviving infants, fulminant cytomegalic inclusion disease develops and manifests as jaundice, hepatosplenomegaly, a petechial rash, CNS malformation, and multiple organ involvement in the affected newborn. The course of this syndrome can be devastating, but its management is beyond the scope of this chapter. Perinatal infection with CMV has been associated with subtle learning disabilities and with interstitial pneumonia (40). After infancy, CMV tends to cause a mononucleosis-like syndrome. CMV-induced mononucleosis can be clinically hard to distinguish from its EBV-associated counterpart. It is part of the differential diagnosis of monospot-negative mononucleosis. Pharyngitis, tonsillitis, and lymphadenopathy are less prominent than with EBV associated-IM, however, hepatitis and fever can take longer to resolve. Acute CMV can occur postoperatively through the transfusion of blood containing CMV, and is sometimes the

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cause of late-onset (2-4 weeks) postoperative fevers. The probability of being infected with CMV by a unit of blood is less than 3% (39). Although the syndrome of acute CMV infection is usually benign and self-limiting, many complications have been reported. These include interstitial pneumonitis, hepatitis, granulomatous hepatitis, Guillain-Barré syndrome, meningoencephalitis, myocarditis, thrombocytopenia, and hemolytic anemia (39,41).

Diagnosis Diagnosis of CMV infection can be accomplished with many different laboratory techniques, some of which are preferred in different clinical scenarios. Available diagnostic tests include histopathology, serology, viral culture, shell vial assays, polymerase chain reaction (PCR) techniques and amplification assays. Histopathologic evidence of CMV-related inclusion bodies in affected cells on tissue specimens is the gold standard for diagnosis of evidence of CMV end-organ disease. Serologic testing is useful for establishing CMV immune status and for confirming acute infection by demonstrating elevation in IgM or a fourfold increase in titers in convalescent serum testing, as in suspected congenital CMV or in cases of monospot negative mononucleosis syndrome (42). CMV culture can be done on urine, mouth swabs, tissues, blood, serum buffy coats, and other fluids; results can take weeks by standard techniques. Cytopathic effects on infected cells yields a positive result. Because of asymptomatic viral shedding, a positive culture result must be interpreted with caution. Only culture isolation from blood suggests pathogenic infection. The CMV shell vial assay is a rapid-culture technique using centrifugation of cells and immunofluorescence staining of CMV antigens with monoclonal antibodies (42). The pp65 protein is a specific marker present in early active CMV infection. The CMV antigenemia assay detects this antigen in polymorphonuclear leukocytes in venous blood using pp65 monoclonal antibodies. Its presence in blood precedes the development of clinical disease. The newest assay, CMV Hybrid Capture, is a rapid molecular hybridization technique that detects the presence of CMV nucleic acid within leukocytes. It does not require cell culture or DNA amplification processes and therefore it is more rapid and simple. It can be used for both qualitative and quantitative detection of CMV in whole blood. These tests are used in a preemptive approach for the management of CMV disease in transplant populations as a positive test precedes the development of clinical disease. In the presence of neutropenia, leukocyte-based assays are not useful (42). CMV-DNA PCR is an extremely sensitive and specific test, but does not yield clinically relevant data in all clinical scenarios. It is not cost-effective or practical enough for routine clinical use when more rapid and less labor intensive tests are available. It can detect viremia 1 to 2 weeks sooner than

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antigenemia and capture assays and in 30% of samples that test negative by the same methods. However the presence of viremia in culture negative, clinically asymptomatic patients without antigenemia is difficult to interpret. In neutropenic patients, a positive result will guide preemptive therapy (42).

Prevention Because of the ubiquitous nature of CMV infection and because of prolonged viral shedding in the urine of infected children, no specific screening or isolation precautions for the disease have proven feasible. Hand washing and routine hygienic measures are recommended when caring for all children (40). Severely immunosuppressed individuals should be isolated from known cases of CMV infection, and consideration should be given to using CMVnegative blood products (40). At present, no specific guidelines for avoiding CMV infection are available to pregnant women, other than hand washing and good hygiene (40). Intravenous CMV immune globulin has been used with some efficacy in transplant recipients, but has not yet been adequately tested in other populations (40).

Treatment No standard guidelines are available for treating immunocompetent patients with complications of CMV infection because of the rarity of such cases. Treatment of CMV and other infections in patients with AIDS and in the immunocompromised host is covered in Chapters 39 through 41. CMV is resistant to acyclovir, but ganciclovir, foscarnet, and cidofovir all have antiCMV activity. All three drugs have major associated toxicities, and any benefit in treating the immunocompetent individual, even in those rare cases in which serious CMV disease has manifested, has yet to be proven (41).

Human Herpes Virus Type 6 Originally described as human B-cell lymphotropic virus (HBLV), HHV-6 was discovered in 1986 in patients with lymphoproliferative disorders (43). The virus shares the same common characteristic of herpesviruses of being able to establish a persistent state after primary infection and is most closely related to CMV. Two variants, A and B, have been identified. Infection is ubiquitous with upwards of 80% of infants infected by the first year of age; by 2 years of age, nearly all humans are seropositive for HHV-6. The frequent detection of HHV-6 in saliva and salivary glands suggests that salivary glands are a potential site for HHV-6 persistence and that saliva is a vehicle for virus transmission. Intrauterine and perinatal transmission have been suggested, and virus has been isolated from genital secretions, saliva, breast milk, and urine. Differentiation between variants is

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based on molecular techniques, as serology cannot differentiate between the two variants. The variants share 90% sequence homology but differ in epidemiology. Variant A is primarily isolated from immunocompromised individuals and spinal fluid, whereas variant B is commonly isolated from otherwise healthy children and adults (44).

Clinical Manifestations Most primary infections in infants are subclinical. Primary infection with HHV-6 can present clinically with the following syndromes: ●

●

●

●

●

●

●

Infantile fever, the most common manifestation of primary HHV-6, occurs without rash development. Commonly associated symptoms include irritability, otitis, respiratory symptoms and/or diarrhea. Seizures occurred in up 13% of infants. Up to 10% of hospital admissions for acute febrile illness among 1653 patients were attributed to acute HHV-6. Exanthem subitum (roseola, sixth disease) is the classic disease that is described in primary HHV-6 infection. It is characterized by 3 to 5 days of high, unremarkable fevers, mild upper respiratory infection (URI) symptoms and occasional cervical lymphadenopathy. The classic macular/maculopapular eruption appears as fever resolves and is accompanied by modest atypical lymphocytosis and relative neutropenia. Febrile seizures, encephalitis, and meningitis can complicate the illness. Febrile seizures can be precipitated by HHV-6 because of both high fever and direct neural invasion by the virus. CSF is commonly PCR positive and can remain so for years. Monospot-negative mononucleosis-like syndrome of varying severity occurs at varying ages. Hepatitis is not commonly seen with roseola but can be fulminant in infants and neonates with primary HHV-6 viremia. Skin disorders other than roseola include morbilliform eruptions in children fully vaccinated against measles and rubella. Association with other skin disorders are still in question, such as pityriasis rosea and Gianotti-Crosti syndrome. Neurological diseases caused by the highly neurotrophic nature of HHV-6 can occur. Indeed, encephalitis in conjunction with exanthema subitum is known. Meningoencephalitis has been reported in immunocompetent adults and children, but the incidence is very low (45). The persistent presence of HHV-6 in neural tissue, however, complicates assigning causality to the presence of HHV6 in the setting of chronic neurologic conditions. Controversy exists about its role in the pathogenesis in multiple sclerosis for this reason.

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HHV-6 reactivation can cause life-threatening complications in immunosuppressed patients. In both bone marrow transplantation and solid organ transplantation, HHV-6 reactivation is associated with encephalomyelitis, pneumonitis, hepatitis, bone marrow suppression, fever, skin rash, and graft dysfunction. There is speculation that HHV-6 can accelerate HIV disease progression caused by synergistic effects seen in vitro, however this remains unclear and difficult to substantiate in clinical settings (46). Although HHV-6 was discovered from patients with lymphoproliferative disorders, no causal relation to neoplasms has been reported. Likewise, in careful case-control studies, an association between HHV-6 and chronic fatigue syndrome could not be established (47).

Diagnosis High seroprevalence rates in the general population make a single serologic sample meaningless; however, seroconversion or fourfold increases in antibody titers in paired convalescent are strong indicators of recent infection. IgM assays are not reliable indicators of acute infection when used alone. Antigen-specific monoclonal antibodies and in-situ hybridization can detect HHV-6 in tissues but cannot determine causality in pathogenesis. Isolation of virus from cultured peripheral blood mononuclear cells can be diagnostic in children presenting with acute exanthema-subitum–like illness, but this technique can be less helpful in immunocompromised asymptomatic patients because of reactivation of viral replication during immune suppression. PCR can detect both the presence and the viral load of HHV-6; isolation from plasma or serum versus whole blood samples seems more predictive of active disease because of viral latency in mononuclear cells.

Treatment In-vitro susceptibility testing of HHV-6 to currently available antiviral agents suggests a susceptibility profile similar to CMV, with resistance to acyclovir, variable response to ganciclovir, and inhibition by foscarnet and cidofovir. Controlled trials have yet to be done but available data in transplant recipients suggests that foscarnet or ganciclovir are effective for both prophylaxis and treatment of HHV-6. Data from case reports have been inconclusive on whether the administration of antiviral drugs results in clinical improvement (48).

Human Herpes Virus Type 7 In 1990, HHV-7, a novel herpesvirus, was isolated from the peripheral blood mononuclear cells of a healthy individual. HHV-7 infects nearly all humans by 5 years of age. It is believed to cause an illness closely resembling HHV-6.

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A causal relation between HHV-7 and distinct clinical illnesses have been confirmed. Isolated reports of encephalitis, hepatitis, and pityriasis rosea have been reported. HHV-7 serology, antigen detection, and PCR detection are available. Ganciclovir and foscarnet inhibit HHV-7 growth in vitro (44).

Human Herpes Virus Type 8 Epidemiology HHV-8 or Kaposi sarcoma-associated herpesvirus (KSHV) is the eighth and most recently discovered human herpesvirus. It was not until 1994 that Chang and Moore, using PCR techniques, isolated HHV-8 from lesions of Kaposi sarcoma, establishing its role in the disease (49). HHV-8 infection, unlike other herpesviruses, is not ubiquitous. Seroprevalence of HHV-8 is the highest in sub-Saharan Africa reaching up to 50%. Seroprevalence in the Mediterranean region approaches 10% but shows geographical variation between countries. Five percent of North Americans and Northern Europeans are infected. The lowest rates (0.2%) are in Japan. Men are more commonly affected than women. Methods of transmission of HHV-8 also vary geographically. In the United States, transmission is primarily through sexual contact among men who have sex with men (50,51). In regions where seroprevalence is higher, nonsexual transmission also occurs. High viral titers in saliva, compared to other body fluids, suggests oral contact as a unifying vehicle for sexual and nonsexual HHV-8 transmission; in highprevalence countries infection seems to be widespread among children even before they are sexually active. Vertical transmission between mother and child as well as transmission from infected transplanted organs has been reported (52).

Clinical Manifestations HHV-8, like other herpesviruses, causes both latent and lytic infections in cells, with latent infection predominating. Genes expressed during latency promote cell survival and are believed to play a role in tumorigenesis. Clinical data on primary HHV-8 infection is limited. Of 86 Egyptian children 1 to 4 years of age, evaluated prospectively after presenting with a febrile syndrome of undetermined origin, by a increase in convalescent antibody titers as well as high salivary HHV-8 levels in the setting of initial seronegativity, 6 were found to have acute HHV-8 infection. Associated symptoms included fever, maculopapular rash progressing from head to trunk to extremities, and UTI symptoms (53). Reported symptoms in high-risk adult men included mild diarrhea, fatigue, localized rash, and cervical and submental lymphadenopathy (54). More serious illness and death in HHV-8 infection arise from the oncogenic nature of the latent viral infection. Three disorders are closely associated

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with HHV-8 infection; Kaposi sarcoma (KS), multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL) also called body cavity B-cell lymphoma. HHV-8 DNA has been found in association with various other clinical conditions, but the causative role of the virus in these diseases is unclear. Among these conditions are non-KS skin lesions in transplant recipients, reactive lymphadenopathy, Bowen disease, pemphigus vulgaris (with or without HIV infection), salivary gland tumor (bilateral parotid mucosa-associated lymphoid tissue [MALT] lymphoma of the parotid gland), hemophagocytic syndrome, noncleaved cell lymphoma, many lymphomas, sarcoidosis, and others (55).

Kaposi Sarcoma Kaposi sarcoma (KS) is a rare angioproliferative disorder that occurs predominantly in HIV-infected patients and transplant recipients. KS is the most common HIV-associated malignancy. KS is much more common in transplant recipients of Mediterranean, Jewish, Arabic, Caribbean, or African descent. The reported incidence ranges from 0.5% in most Western countries to 5.3% in Saudi Arabia (56). The diagnosis of KS can often be made solely by clinical examination. Typically, KS involves the skin. Lesions are initially in patches but progress to plaques and then nodular lesions. Because of the vascular nature of the lesions, initial lesions seem violaceous, but older lesions take a brown coloration because of hemosiderin deposition into tissues. Four variants of KS exist and differ clinically. Classic KS is an indolent disease occurring in elderly men of Mediterranean and Eastern European descent. Lesions are localized primarily in the lower extremities. Endemic KS is seen in certain sub-Saharan African countries. In adults, endemic KS resembles classic disease, with disease in men being 20 times more frequent than in women. In children, KS is often fatal, presenting as an aggressive multifocal, lymphadenopathic disease without associated skin disease. Epidemic KS, seen in HIV-infected individuals, is typically aggressive, with involvement of the skin, gastrointestinal tract, and the lungs. The face and oral mucosa are often involved. Because of the vascular nature of these lesions, KS should be considered in the differential diagnosis of hemoptysis and gastrointestinal bleeding in an AIDSs patient. Lesion biopsy reveals angioproliferative lesions, spindle cells, and extravasation of blood. The first goal in the treatment of KS is to restore immunological function in immunocompromised individuals, if possible. Local therapy can be effective for individual lesions but will have no effect on the prevention of new lesions or disseminated disease. Local therapies include intralesional vinblastine, cryotherapy, radiotherapy, and retinoids. Extensive disease requires systemic therapy. Systemic modalities include α-interferon and liposomal anthracyclines, paclitaxel, and sirolimus (57). In HIV-infected patients, effective antiretroviral therapy is widely considered to be a crucial part of treatment.

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Primary Effusion Lymphoma or Body Cavity B-cell Lymphoma PEL is a rare form of large B-cell non-Hodgkin lymphoma (NHL) first described in 1989 in an HIV-infected patient. Cases in elderly men and organ transplant recipients have been described. It is characterized by pleural, pericardial, or peritoneal lymphomatous effusion. PEL accounts for roughly 3% of AIDS-related NHL and carries a median survival of only months. Successful treatment using cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (CHOP)-like chemotherapy with or without antiretroviral therapy has been reported (58).

Multicentric Castleman Disease HHV-8-associated MCD is a poorly understood malignant lymphoproliferative disorder occurring in HIV-infected individuals. Its pathogenesis can be related to immune dysregulation of interleukins (IL) 6 and 10 (59,60). Hallmark features of MCD include diffuse lymphadenopathy, which can wax and wane over time and is almost always associated with prominent B symptoms and massive splenomegaly. Hepatomegaly, respiratory symptoms, edema, and hypoalbuminemia affect most sufferers. Diagnosis can be made by fine-needle aspiration of involved lymph nodes; communication between clinician and pathologist about the suspected diagnosis is essential. MCD is usually rapidly fatal in absence of therapy, which can include corticosteroids, systemic chemotherapy, and monoclonal antibodies to IL-6 and or anti-CD20. Immune restoration with highly active antiretroviral therapy (HAART) plays an important role in improvement of survival (61).

Diagnosis Laboratory diagnosis of HHV-8 is based on serology and PCR. There is no culture available for HHV-8. Serology can be useful in documenting previous infection. PCR is a useful technique for viral load detection and documenting primary infection or lytic phase reactivation. Histopathology is usually the diagnostic study used to document HHV-8 related disorders. Histopathology has the highest effect clinically as diagnosis of HHV-8 infection can be meaningless clinically, but diagnosis and staging of Kaposi sarcoma or other serious manifestations of HHV-8 infection is of a great clinical importance.

Treatment There is no data on the use of antiviral therapy for primary HHV-8 infection. Restoration of immune function is an important aspect in treatment of HHV-8 related disorders. Decreasing immunosuppressive therapy for transplant recipients or starting HAART for HIV-infected persons can lead to regression of

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HHV-8 related disorders. Antiviral therapy did not affect the progression of HHV-8 related disorders. REFERENCES 1. Whitley RJ. Varicella-zoster virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1780-6. 2. Centers for Disease Control and Prevention. Decline in annual incidence of varicella-selected states 1990-2001. MMWR Morb Mortal Wkly Rep. 2003;52:884-5. 3. Seward JF,Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX, et al. Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA. 2002;287:606-11. 4. Kost RG, Straus SE. Postherpetic neuralgia—pathogenesis, treatment, and prevention. N Engl J Med. 1996;335:32-42. 5. Donahue JG, Choo PW, Manson JE, Platt R. The incidence of herpes zoster. Arch Intern Med. 1995;155:1605-9. 6. Haake DA, Zakowski PC, Haake DL, Bryson YJ. Early treatment with acyclovir for varicella pneumonia in otherwise healthy adults: Retrospective controlled study and review. Rev Infect Dis. 1990;12:788-98. 7. Broussard RC, Payne DK, George RB. Treatment with acyclovir of varicella pneumonia in pregnancy. Chest. 1991;99:1045-7. 8. American Academy of Pediatrics. Varicella-zoster infections. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:711-25. 9. Wilson GJ,Talkington DF, Gruber W, Edwards K, Dermody TS. Group A streptococcal necrotizing fasciitis following varicella in children: case reports and review. Clin Infect Dis. 1995;20:1333-8. 10. Erlich KS. Management of herpes simplex and varicella-zoster virus infections. West J Med. 1997;166:211-5. 11. Coffin SE, Hodinka RL. Utility of direct immunofluorescence and virus culture for detection of varicella-zoster virus in skin lesions. J Clin Microbiol. 1995;33:2792-5. 12. Wood MJ, Kay R, Dworkin RH, Soong SJ,Whitley RJ. Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trials. Clin Infect Dis. 1996;22:341-7. 13. Tyring S, Barbarash RA, Nahlik JE, Cunningham A, Marley J, Heng M, et al. Famciclovir for the treatment of acute herpes zoster: effects on acute disease and postherpetic neuralgia. A randomized, double-blind, placebo-controlled trial. Collaborative Famciclovir Herpes Zoster Study Group. Ann Intern Med. 1995;123:89-96. 14. Perry CM, Faulds D. Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996;52:754-72. 15. Jackson JL, Gibbons R, Meyer G, Inouye L. The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia. A meta-analysis. Arch Intern Med. 1997;157: 909-12. 16. Centers for Disease Control and Prevention. A new product (VariZIG) for postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol. MMWR Morb Mortal Wkly Rep. 2006;55(early release):1-2. 17. Centers for Disease Control and Prevention. Prevention of varicella: Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1999;48(RR-6):1-5. 18. Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005;352:2271-84. 19. Johannsen EC, Schooley RT, Kaye KM. Epstein-Barr virus (infectious mononucleosis). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. New York: Churchill Livingstone; 2005:1801-21. 20. Hickey SM, Strasburger VC. What every pediatrician should know about infectious mononucleosis in adolescents. Pediatr Clin North Am. 1997;44:1541-56. 21. Ablashi DV. Viral studies of chronic fatigue syndrome. Clin Infect Dis. 1994;18 Suppl 1:S130-3. 22. Bell DS. Chronic fatigue syndrome update. Findings now point to CNS involvement. Postgrad Med. 1994;96:73-6, 79-81. 23. Penman HG. Fatal infectious mononucleosis: a critical review. J Clin Pathol. 1970;23:765-71.

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25. American Academy of Pediatrics. Epstein-Barr virus infections (infectious mononucleosis). In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:286-8. 25. Haller A, von Segesser L, Baumann PC, Krause M. Severe respiratory insufficiency complicating Epstein-Barr virus infection: case report and review. Clin Infect Dis. 1995;21: 206-9. 26. Andersson J, Ernberg I. Management of Epstein-Barr virus infections. Am J Med. 1988;85:107-15. 27. Macsween KF, Crawford DH. Epstein-Barr virus-recent advances. Lancet Infect Dis. 2003;3:131-40. 28. Hjalgrim H,Askling J, Rostgaard K, Hamilton-Dutoit S, Frisch M, Zhang JS, et al. Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med. 2003;349:1324-32. 29. Preiksaitis JK. New development in the diagnosis and management of post-transplant lymphoproliferative disorders in solid organ transplant (SOT) recipients. CID. 2004;39:1016-23. 30. Green M. Management of Epstein-Barr virus-induced post-transplant lymphoproliferative disease in recipients of solid organ transplantation. Am J Transpl. 2001;1:103-8. 31. Gartner BC, Fischinger J. Schafer H Epstein-Barr viral load as a tool to diagnose and monitor post-transplant lymphoproliferative disease. Recent Results Cancer Res. 2002;159;49-54. 32. Crumpacker CS,Wadhwa S. Cytomegalovirus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1786-801 33. Straus SE. Cytomegalovirus. In: Aberg JA, Goldman MP, Gray LD, Long JK, eds. Infectious Diseases Handbook. 6th ed. Ohio: Lexi-Comp; 2006:107-12. 34. Eddleston M, Peacock S, Juniper M, Warrell DA. Severe cytomegalovirus infection in immunocompetent patients. Clin Infect Dis. 1997;24:52-6. 35. Salahuddin SZ,Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science. 1986;234:596-601. 36. Straus SE. Human herpes virus 6 and 7. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1821-5. 37. Isaacson E, Glaser CA, Forghani B,Amad Z,Wallace M,Armstrong RW, et al. Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis. 2005;40:890-3. 38. Bolle LD, Naesens L, Clercq ED. Update on human herpesvirus 6 biology, clinical features, and therapy. Clin Micro Rev. 2005;18:217-45. 39. Reeves WC, Stamey FR, Black JB, Mawle AC, Stewart JA, Pellett PE. Human herpesviruses 6 and 7 in chronic fatigue syndrome: a case-control study. Clin Infect Dis. 2000;31: 48-52. 40. Whitley RJ, Lakeman FD. Human herpesvirus 6 infection of the central nervous system: is it just a case of mistaken association? [Editorial]. Clin Infect Dis. 2005;40:894-5. 41. Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science. 1994;266:1865-9. 42. Pauk J, Huang ML, Brodie SJ,Wald A, Koelle DM, Schacker T, et al. Mucosal shedding of human herpesvirus 8 in men. N Engl J Med. 2000;343:1369-77. 43. Martin JN, Ganem DE, Osmond DH, Page-Shafer KA, Macrae D, Kedes DH. Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med. 1998;338:948-54. 44. Dedicoat M, Newton R,Alkharsah KR, et al. Mother-to-child transmission of human herpesvirus 8 in South Africa. Clin Infect Dis. 2004;190:1068-75. 45. Andreoni M, Sarmati L, Nicastri E, El Sawaf G, El Zalabani M, Uccella I, et al. Primary human herpesvirus 8 infection in immunocompetent children. JAMA. 2002;287:1295-300. 46. Kaye KM. Kaposi’s Sarcoma-Associated herpesvirus (human herpesvirus type 8). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1827-32. 47. Ablashi DV, Chatlynne LG, Whitman JE, et al. Spectrum of Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8, diseases. Clin Micro Rev. 2002 July;15:439-64. 48. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681-91. 49. Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med. 2005;352:1317-23. 50. Simonelli C, Spina M, Cinelli R,Talamini R,Tedeschi R, Gloghini A, et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol. 2003;21:3948-54. 51. Oksenhendler E, Duarte M, Soulier J, Cacoub P, Welker Y, Cadranel J, et al. Multicentric Castleman’s disease in HIV infection: a clinical and pathological study of 20 patients. AIDS. 1996;10:61-7.

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52. Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman’s disease in HIV-infected patients. Blood. 2000;96:2069-73. 53. Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, et al. Brief report: alleviation of systemic manifestations of Castleman’s disease by monoclonal anti-interleukin-6 antibody. N Engl J Med. 1994;330:602-5. 54. Corey L. Herpes simplex virus. In Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:1762-80. 55. Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study. BMJ. 1997;314:1800-3. 56. Jensen LA, Hoehns JD, Squires CL. Oral antivirals for the acute treatment of recurrent herpes labialis. Ann Pharmacother. 2004;38:705-9. 57. Spruance SL, Hill J. Clinical significance of antiviral therapy for episodic treatment of herpes labialis: Exploratory analyses of the combined data from two valacyclovir trials. J Antimicrob Chemo. 2004;53:703-7. 58. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. Herpetic Eye Disease Study Group. N Engl J Med. 1998;339:300-6. 59. Hayden FG. Antiviral drugs (Other than antiretrovirals). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Churchill Livingstone; 2005:514-51. 60. Becker TM. Herpes gladiatorum: A growing problem in sports medicine. Cutis. 1992; 50:150. 61. Anderson BJ. The effectiveness of valacyclovir in preventing reactivation of herpes gladiatorum in wrestlers. Clin J Sport Med. 1999;9:86.

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Part X

Miscellaneous Infections

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Chapter 43

Tick-Borne Infections: Lyme Borreliosis, Ehrlichiosis and Anaplasmosis JOHAN S. BAKKEN, MD, PHD J. STEPHEN DUMLER, MD

Key Learning Points 1. The clinical manifestations of Borrelia burgdorferi infections (Lyme borreliosis) are often mild and non-specific, and signs and symptoms develop gradually over several days. 2. The diagnosis of Lyme borreliosis rests with a compatible exposure history and presence of objective physical findings (skin, joints, central nervous system, or cardiac conduction system disturbances). The clinical diagnosis should be confirmed with appropriate laboratory tests that provide indirect (serum antibodies) or direct (PCR, culture) evidence of infection. 3. Doxycycline is highly active against B. burgdorferi and is the drug of choice for treatment of early stage Lyme disease. Amoxicillin may be administered as alternative therapy to patients who are intolerant to or have contraindications to doxycycline. 4. The differential diagnosis for patients who develop rapid onset of fever and influenza-like symptoms accompanied by permutations of leukopenia, thrombocytopenia, and increased hepatic trans-aminase serum concentrations 1 to 4 weeks following exposure to ticks should include human monocytic ehrlichiosis (HME, caused by Ehrlichia chaffeensis) and human granulocytic anaplasmosis (HGA, caused by Anaplasma phagocytophilum).

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New Developments • The Infectious Diseases Society of America has published updated guidelines on

the management of Lyme disease. • Prophylactic doxycycline administration may be of value in certain situations,

after a documented Ixodes tick bite. • The IgeneX Urine antigen test for the diagnosis of Lyme disease has been

determined to lack scientific value.

5. Older individuals (especially men) and patients who have chronic illnesses or are actively immunosuppressed are at increased risk for developing serious HME or HGA and are best treated in a hospital setting initially. 6. Doxycycline is highly active against E. chaffeensis and A. phagocytophilum and is the drug of choice for the treatment of HME and HGA in adult as well as pediatric group patients.

T

he increased desire of humans to pursue outdoor recreational activities during the summer months has amplified their potential risk for exposure to pathogenic bacteria that cycle within hard-bodied ticks. Many geographical areas in North America as well as Europe have seen the rapid proliferation of tick-transmitted infections during the last 2 decades; this is a consequence of growing urbanization extending into previous wilderness areas as well as increasing populations of the mammal reservoir host animals. Lyme borreliosis (Lyme disease) was recognized as a distinctive infectious entity in 1976, and a systematic national surveillance and reporting program for Lyme borreliosis was initiated in 1982. More than 210,000 cases of Lyme borreliosis have since been reported to the Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/ncidod/ dvbid/lyme/ld_UpClimb LymeDis.htm). However, during the last 2 decades, several new tick-borne infections and their associated illnesses have been described and become increasingly recognized in the United States of America (1). These emerging illnesses include human monocytotropic ehrlichiosis (HME), human granulocytotropic anaplasmosis (HGA), and to a much lesser degree human granulocytotropic ewingii ehrlichiosis (HGEE). Furthermore, an increasing number of HGA cases has also been reported from several European countries. Although the epidemiologies of HME, HGA, and HGEE differ according to the responsible tick-vectors and their endemic distributions, seasonality, and patient demographic profiles, the clinical syndromes with each of these infections are very similar; and patients typically present with an acute onset, nonspecific febrile illness (2). This chapter will describe the cause, epidemiology, clinical presentation, diagnosis, and treatment of Lyme borreliosis, HME, HGA, and HGEE infections in the United States of America.

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Lyme Borreliosis (Lyme disease) Etiology Borrelia burgdorferi is a helical flagellated spirochete that causes a multisystem illness in humans and animals. B. burgdorferi cycles in nature between arthropod and mammalian hosts and is transmitted to humans by hard-bodied tick vectors that belong to the Ixodes persulcatus group. First cultured in vitro by Burgdorfer in 1982, the organism has complex growth requirements and grows relatively readily under microaerophilic conditions in an enriched liquid medium. B. burgdorferi measures 20 to 30 µm in length, approximately 0.3 µm in width, and may be visualized in infected tissues and fluids by using silver stains, fluorescent stains (Figure 43-1), or immunohistochemistry. After inoculation into the dermis, the spirochete spreads through cutaneous, lymphatic, and hematogenous extension; it may establish infection in skin, the nervous system, the heart, and joints (3).

Epidemiology The clinical syndrome Lyme borreliosis was first described by Steere in 1977, but a similar syndrome linked with tick bites was recognized in northern Europe almost 50 years earlier (3). Steere described a group of children who developed oligoarticular arthritis after they were bitten by ticks a few weeks before the onset of arthritis (4). The tick vectors of B. burgdorferi in the United States are the black-legged or deer tick (Ixodes scapularis or Ixodes dammini) in the Northeast and upper Midwest and the western black-legged tick (Ixodes pacificus) on the West Coast; Lyme borreliosis in the United States has been reported most commonly to occur in these geographical locations (5). Lyme borreliosis is the most commonly reported tick-borne infection in the United States and Europe (3,5). The illness has protean manifestations and may mimic other conditions of infectious and noninfectious origin. In 2002, 23,763 cases of Lyme borreliosis were reported to the CDC from 47 U.S. states and the District of Columbia, yielding a national average of 8.2 cases for every 100,000 persons. Men and women become infected with similar frequencies, and in recent years more than 80% of cases have been reported from New York, Connecticut, Pennsylvania, Delaware, Maryland, and New Jersey alone (http://www.cdc.gov/ncidod/dvbid/lyme/ld_ UpClimbLymeDis.htm). Patients are more likely to acquire Lyme borreliosis in June, July, and August, corresponding to when nymphal stage Ixodes tick populations are at peak densities, and less likely to have illness onset during December through March. The median patient age is 28 years, but patient ages are distributed in a bimodal pattern with children and middleaged adults being at greatest risk of infection (3,6).

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Clinical Manifestations The clinical manifestations of Lyme disease have been organized into categories labeled early localized (Stage 1), early disseminated (Stage 2) and late disease (Stage 3) (3,6) as shown in Table 43-1. Early localized Lyme borreliosis typically begins with erythema migrans (EM) rash, a characteristic, asymptomatic annular skin lesion (EM) that slowly develops after 10 to 14 days at the site of the bite of an infected Ixodes tick (3,6). A minority of patients (5%-20%) do not manifest the characteristic expanding rash. EM may be accompanied by minor nonspecific influenza-like symptoms and regional lymphadenopathy (Table 43-2) and, if left untreated, will spontaneously resolve within a median of 28 days. Early disseminated Lyme borreliosis may gradually appear within days to several weeks later and is commonly manifested by many EM lesions and constitutional symptoms that may include malaise, fatigue, headache, fever, chills, generalized lymphadenopathy, and migratory arthralgias and musculoskeletal pain. The manifestations of early dissemination can vary from mild musculoskeletal symptoms to a more severe presentation manifested by frank neurological abnormalities including meningitis with CSF lymphocytic pleocytosis, cranial neuritis (most commonly unilateral or bilateral facial nerve palsy), and permutations of sensory or motor radiculoneuropathy. A small

Table 43-1 Clinical stages, time to onset, target organ involvement, and possible signs and symptoms associated with Lyme borreliosis (Lyme disease). Infection stage

Time course

Infection target

Early localized 7-14 days Skin Disease after tick-bite Early disseminated Weeks to months Skin Disease after tick-bite General

Central nervous system Joints

Heart Late persistent Disease

Months to years after tick-bite

Joints Nerve tissue Skin

Possible signs and symptoms

Localized EM lesion Regional lymphadenopathy Multiple EM lesions Low grade fever Myalgias General lymphadenopathy Facial nerve palsy Headache Meningitis Arhralgias Migratory oligoarthritis A-V coduction defect Myocarditis Migratory oligoarthritis Polyneuritis Mild cognitive dysfunction Acrodermatis chronicum atrophicans

Data from Steere AC. Borrelia burgdorferi (Lyme disease, Lyme borreliosis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. Philadelphia: Elsevier Chruchill Livingstone; 2005:2798-809; Wormser GP, Dattwyler RJ, Shapiro ED et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis. Clin Infect Dis. 2006;43:1089–1134.

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Table 43-2 Frequency (%) of early signs and symptoms reported by patients who had laboratory-confirmed Lyme borreliosis*, human monocytotropic ehrlichiosis† and human granulocytotropic anaplasmosis‡. Symptom or Sign

Lyme borreliosis (%) N = 118-314

HME (%) N = 29-211

HGA (%) N = 207

Fever Headache Myalgias Malaise Rigors Anorexia Nausea Arthralgias Cough Abdominal pain Confusion Rash

31-59 28-64 35-43 2-80 59 0-23 3-17 35-48 0-5 0-9 0 60-100

95-100 60-81 40-68 30-84 61 66 38-68 30-41 24-26 10-55 20 20-36

92 70 86 97 86 47 36 32 22 4 17 3§

N indicates the number of patients evaluated. * Data from references 3 and 6. † Data from references 19-21. ‡ Data from references 29, 30, and 33. § Erythema migrans in patients coinfected with Lyme borreliosis

subset of patients with early disseminated disease can develop atrioventricular conduction defects with variable degrees of heart block or diffuse myopericarditis (3). Symptoms are often intermittent in nature and may become less severe or disappear within several weeks even in the cases of untreated infection. However, untreated infection could progress to late-stage or persistent infection. Late (persistent) infection comprised of intermittent episodes of oligoarticular arthritis may develop in untreated or inadequately treated patients, and symptoms may appear months to years after the initial tick bite. A few untreated patients can develop chronic neurological disease manifestations, which may present as subtle encephalopathy, paresthesias, or spinal radicular pain syndromes that may overlap with symptoms associated with depression, chronic fibromyalgia, or chronic fatigue syndrome (3,7).

Diagnosis The diagnosis of Lyme borreliosis should be based on objective physical findings in a person who has recently spent time in a tick-endemic area. Early localized disease is characterized by the EM rash, and serologic tests remain nonreactive for most patients during the first 2 to 3 weeks of infection. Thus, patients who have early localized disease should receive antibiotic treatment without serologic testing (6). Aspirate or punch biopsy taken from the advancing margin of the EM lesion and cultured in enriched liquid medium may yield a positive result in 60% to 80% of patients.

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By the time patients have developed active disseminated infection (3-4 weeks after tick exposure or tick bite), most patients have mounted a serologic response consisting of both IgM- and IgG-specific B. burgdorferi antibodies. The CDC recommends a 2-step serologic testing approach of patients with early disseminated or late disease, in which samples are initially tested by enzyme-linked immunosorbent assay (ELISA) or enzyme immunosorbent assay (EIA), and equivocal and positive samples are then tested by immunoblotting (3,8). However, serologic tests are poorly standardized (6) and are liable to false-positive and false-negative results; intraand interlaboratory variation in test outcomes done on identical samples has been well documented (9). Serologic tests should primarily be used to confirm the clinical diagnosis, and should not be used as the sole basis for making a diagnosis of Lyme borreliosis (3,10). Patients who present with nonspecific reports, lack objective signs of Lyme borreliosis, and have a negative ELISA or EIA screening test outcome are unlikely to have Lyme disease (strong negative predictive value) (11).

Treatment Various antimicrobial agents are active against B. burgdorferi, and most manifestations of Lyme borreliosis can be treated successfully with orally administered antibiotic drugs (Table 43-3) (3,10,12). Orally administered doxycycline for 10 to 21 days (13) or amoxicillin for 14 to 21 days (10) is recommended for treatment of early localized (Stage 1) Lyme borreliosis. Doxycycline has the advantage of being active against Anaplasma phagocytophilum, the cause of HGA, which may occur simultaneously with Lyme borreliosis; thus doxycycline should be considered the drug of choice (14). Cefuroxime axetil may be used as a treatment alternative to doxycycline for young children and pregnant women, as well as for patients who are intolerant to either doxycycline or amoxicillin (3,10). Erythromycin and macrolide derivatives are less effective than doxycycline and β-lactam agents and use should be restricted to patients who are intolerant to the preferred first- and second-line agents (3,10). Oral doxycycline given for 21 to 28 days is recommended for treatment of early disseminated (Stage 2) Lyme borreliosis in the absence of acute neurological disease (meningitis) or third-degree heart block (3,10). Amoxicillin, cefuroxime axetil, and erythromycin administered for 21 to 28 days may also be used. Facial nerve palsy and first degree or Mobitz type II heart block usually respond well to treatment with oral doxycycline or amoxicillin but therapy should be extended to 30 to 60 days (Table 43-3) (3,10). Treatment of early localized and early disseminated Lyme borreliosis with oral antibiotics is very effective, and most patients respond promptly and completely. Less than 10% of infected patients who have undergone appropriate therapy require repeated antibiotic treatment (10).

IV route

Neurological involvement

Doxycycline Amoxicillin Cefuroxime Erythromycin Not indicated

Doxycycline Amoxicillin Cefuroxime Erythromycin Doxycycline Amoxicillin Cefuroxime Doxycycline Amoxicillin Cefuroxime Erythromycin Not indicated

Oral Antibiotic choices

Not applicable

30-60

Not applicable

30-60

21-28

10-21

Duration of treatment (days)

Ceftriaxone Cefotaxime Penicillin G

Ceftriaxone Cefotaxime Penicillin G Ceftriaxone Cefotaxime Penicillin G

Ceftriaxone Cefotaxime Penicillin G

Not indicated

Not indicated

IV Antibiotic choices

14-28

14-28

14-28

14-28

Not applicable

Not applicable

Duration of treatment (days)

Oral antibiotic doses: Doxycycline hyclate. Non pregnant adults 100 mg BID. Children > 8 years old 100 mg BID. Amoxicillin. Adults 500 mg TID. Children 50 mg/kg/day, maximum dose 500 mg TID. Cefuroxime axetil. All ages 500 mg BID. Erythromycin. All ages 250 mg QID. IV antibiotic doses: Ceftriaxone. Adults 2 grams Q24 hours. Children > 8 years old 75-100 mg/kg/day, maximum dose 2 grams/day. Cefotaxime. Adults 2 grams Q8 hours. Children 150 mg/kg/day, maximum 6 grams/day. Penicillin G. Adults 5 million units Q6 hours. Children > 1 month old 250,000 units/kg/day, maximum 18 million units/day. Data from Steere AC. Borrelia burgdorferi (Lyme disease, Lyme borreliosis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 6th ed. Philadelphia: Elsevier Chruchill Livingstone; 2005:2798-809; Steere AC. Lyme disease N Engl J Med. 2001;345:115-25;Wormser GP, Nadelman RB, Dattwyler RJ, et al. Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis. 2000;31(Suppl 1):1-14.

PO or IV route

IV route

Meningitis Carditis

Arthritis Acrodermatitis

Oral or IV route

Arthritis Facial nerve palsy

Late disease

Oral route

Skin

Early disseminated disease

Oral route

Antibiotic administration

Skin

Disease manifestation(s)

Early localized Disease

Clinical Stage

Table 43-3 Recommended adult and pediatric antibiotic treatment of early and late stage Lyme borreliosis (Lyme disease)*.The oral and IV drugs are listed in order of preference. Appropriate drug doses are indicated in the footnote.

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Intravenous therapy with ceftriaxone for 14 to 28 days is recommended for treatment of patients older than age 8 years who have early disseminated Lyme borreliosis complicated by meningitis or third-degree heart block (3,10). Children younger than age 8 years old should be treated with cefotaxime rather than ceftriaxone because ceftriaxone therapy in young children has been associated with biliary sludge formation and acute cholecystitis. Thirddegree heart block usually responds quickly to parenteral therapy, but insertion of a temporary pacemaker may be necessary in some circumstances. Patients who have persistent objective arthritis with recurrent joint swelling after a recommended course of oral antibiotic therapy may benefit from treatment with another 4-week course of oral antibiotic or a 2- to 4-week course of intravenous ceftriaxone (3,10). There is no published scientific support for therapy for Lyme borreliosis extending beyond 6 to 8 weeks (10,13). Symptoms of Lyme borreliosis may persist beyond the period of antibiotic therapy. This is especially common when treatment is instituted later in the course of clinical disease; and persistence of symptoms should be managed with adjunctive medications, which may include nonsteroidal anti-inflammatory agents and antidepressants, rather than prolonged antibiotic therapy. There is currently insufficient data to recommend routine use of singledose antimicrobial prophylaxis after a tick bite (10,15). Consider a prophylactic single dose of doxycycline hyclate (200 mg adults; 4 mg children) when tick identified as Ixodes and is attached ≥36 hrs; prophylaxis started ≤72 hrs of tick removal; local rate of B. burgdorferi-infected ticks >20% and doxycycline not contraindicated (10). Persons who remove attached ticks from their skin should be monitored closely for the next 30 days for the development of EM rash at the site of the tick bite, or fever with rigors which may suggest HGA or babesiosis (another Ixodes species tick-transmitted infection caused by Babesia microti) (10).

Human Monocytotropic Ehrlichiosis Etiology Ehrlichia chaffeensis is an obligate intracellular bacterium of the order Rickettsiales, family Anaplasmataceae. This bacterium may be transmitted to humans by tick bites and can cause infections in animals and humans (16). Ehrlichia species are small (0.2-1.0 µm), obligate, intracellular gram-negative organisms (17). They infect predominantly bone marrow–derived cells in mammalian hosts, mostly mononuclear leukocytes and macrophages, where they form intracytoplasmic microcolonies named morulae from the Latin word for mulberry (Table 43-4). Ehrlichia species are easily seen in the peripheral blood smear when Wright or Giemsa stains are used and vary in appearance from highly basophilic loose or condensed aggregates to individual bacterial cells visualized within vacuoles now proven to be early endosomes.

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Table 43-4 Epidemiologic and demographic characteristics associated with Lyme disease*, human monocytotropic ehrlichiosis (HME) †, human granulocytotropic anaplasmosis (HGA)‡, and human granulocytotropic ewingii ehrlichiosis (HGEE)§. Clinical illness

Lyme borreliosis

HME

HGA

HGEE

Year first reported Tick vector americanum

1976

1987

1994

1999

I. scapularis

A. americanum I. scapularis

I. pacificus B. burgdorferi

E. chaffeensis

Causative agent Tissue Target

Skin Joints Monocyte Nerve tissue Macrophage Reported cases* > 150,000 >1,924 Endemic range North East Upper South Central (in United Midwest South East States) Pacific coast Mid-Atlantic

I. pacificus A. phagocytophilum Granulocyte

A.

E. ewingii Granulocyte

>2,497 29 North East South Central Upper Midwest Pacific coast

* Data from references 3 and 10. † Data from references 19, 20, and 45. ‡ Data from references 27, 30, 33, and 35. § Data from references 36 and 45. ¶ Personal communication A. Chapman, Centers for Disease Control and Prevention, July 13th, 2005

Epidemiology E. chaffeensis cycles in nature within Amblyomma americanum, the Lone Star tick and mammalian reservoir hosts. This tick species is found widely in the south central and south eastern United States across the region stretching from southern New York to Texas. All 3 tick stages (larva, nymph, and adult) feed on small rodents, such as the white-footed mouse (Peromyscus leucopus), and large ungulates, especially the white-tailed deer (Odocoileus virginianus) (18). Lone Star ticks are aggressive and feed willingly on humans; the endemic areas where E. chaffeensis infections occur closely overlap the endemic areas for the tick vector. The human illness that is associated with E. chaffeensis infection is called human monocytotropic ehrlichiosis or HME. The first case of HME was described in a man from Detroit, Michigan, in 1986, a few weeks after he had acquired tick bites in Arkansas (17). Since the discovery, the CDC has identified at least 3,190 cases of HME as of the end of 2006 (1,19,28). Although only infrequently diagnosed, active surveillance for cases identified has estimated incidence rates to be as high as 138 cases/100,000 population in some areas of southeastern Missouri.

Clinical Manifestations Most patients contract HME between May and August, and as many as 75% of clinically symptomatic patients may need to be admitted to a hospital for

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the initial part of their care (19,20). The median patient age is 44 years, and men become infected 3 to 4 times more frequently than women. However, elderly individuals and patients who are immunocompromised from HIV infection, organ transplantation, cancer or corticosteroid therapy are more prone to develop a serious illness or even death (20,21). The reported case fatality rate ranges between 1% to 3% (19). HME can have a wide range of clinical presentations, and the clinical illness varies from asymptomatic or clinically mild infection to severe or fatal disease (21,22). Symptoms typically develop abruptly 1 to 2 weeks after tick exposure or a documented tick bite. HME presents most frequently as undifferentiated, nonspecific fever accompanied by anorexia, headache, myalgias, and malaise (Table 43-2). Approximately one third of infected patients, especially children, have reported a nonspecific rash, ranging from erythematous maculopapules to petechiae (19,21). Significant complications of HME include a toxic or septic shock-like syndrome, respiratory distress that requires mechanical respiration, meningoencephalitis, hemorrhage, renal failure, cardiac failure, and opportunistic infections. Although these bacteria live in the blood and an incubation period of 1 week or more is typical before clinical manifestations appear, no cases of transfusion-related HME have been documented (23). Severe illness or death has been associated with delayed diagnosis or institution of antimicrobial therapy, which does not include a tetracycline drug (19). Laboratory test abnormalities are nonspecific and include various permutations of leukopenia, thrombocytopenia, or both as well as mild to significant increases in serum hepatic aminotransferase concentrations (19-21). Mild to profound thrombocytopenia occurs in approximately 50% of patients. The differential leukocyte count often reveals a marked left shift with increased proportions of neutrophil and band leukocytes owing to relative and absolute lymphopenia during the initial phase of illness. An absolute neutropenia can also be detected in some patients. Pancytopenia occurs despite bone marrow examinations that have showed normocellular or hypercellular marrow architecture. The changes in blood counts and serum aminotransferases are transient, and abnormal variables often revert back to the normal range with prolonged (untreated) illness (19). Treatment with doxycycline usually induces a rapid normalization of blood counts. A minority of infected patients will develop reactive lymphocytosis, including atypical lymphocytes, that becomes apparent during the second or third week of illness or after completion of antibiotic therapy.

Diagnosis Examination of the peripheral blood smear may demonstrate typical morulae in the cytoplasm of monocytes in between 1% and 20% of patients during the early phase of infection (19-21). However, blood smear microscopy is very insensitive, nonspecific, and rarely reveals the diagnosis even when

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Table 43-5 Case definitions and laboratory criteria for probable and confirmed cases of HME and HGA*. Case definition

Laboratory test result for HME

Laboratory test result for HGA

Probable infection

Morulae in peripheral blood Morulae in peripheral blood smear neutrophilsa smear mononuclear cella or Single titer E. chaffeensis serum or Single titer A. phagocytophilum serum IFAc ≥ IFAb ≥ 64 or Positive 64 or Positive A. phagocyE. chaffeensis PCRd of blood tophilum PCRe of blood Confirmed infection IFA seroconversion or serorever- IFA seroconversion or seroreversionf or Isolation sionf or Isolation of of A. phagocytophilum E. chaffeensis from bloodg or Single E. chaffeensis serum from bloodh or Single A. phagocytophilum serum IFAb ≥ 256 and a clinically compatible illness, or Single IFAc ≥ 64 and Morulae in peripheral blood smear E. chaffeensis serum IFAb ≥ 64 and Morulae in peripheral neutrophilsa or Positive A. phagocytophilum PCRe blood smear mononuclear cella or Positive E. chaffeensis PCRd of blood of blood

* Data from Bakken JS, Jumler JS. Ehrlichiosis and anaplasmosis. Infect Med. 2004;21:433-51; Walker DH, Bakken JS, Brouqui P, et al. Diagnosing human ehrlichioses: current status and recommendations. Am Society Micorbiol News. 2000;5:287-93. a Light microscopy of Wright stained peripheral acute phase blood; Indirect immunofluorescent antibody test with E. chaffeensis b or A. phagocytophilum c antigen; Polymerase chain reaction with specific E. chaffeensis d or A. phagocytophilum e primers; Fourfold or greater change in serum antibody titer f; Isolation of E. chaffeensis g or A. phagocytophilum h in tissue culture inoculated with acute phase blood.

done by experienced microscopists. Amplification of E. chaffeensis–specific DNA by polymerase chain reaction (PCR) done on acute phase blood is a rapid and specific diagnostic method that may permit early diagnosis in between 60% and 85% of infections (24). However, only a small number of clinical and hospital laboratories offer PCR on a routine basis. Thus, the diagnosis of HME is most often made retrospectively based on demonstration of a serologic response to E. chaffeensis (Table 43-5). Most patients have increased IgM and IgG antibodies in serum (polyclonal immunofluorescent antibody [IFA] titer ≥ 64) or seroconvert 14 to 21 days after the onset of illness (19,21,22). Current data suggest that IgM serology provides no additional benefit in the diagnosis of HME. (For information on therapy, please see the section “Treatment of Human Ehrlichiosis, and Human Anaplasmosis,” later in this chapter.)

Human Granulocytotropic Anaplasmosis Etiology A. phagocytophilum are obligate intracellular bacteria that are members of the order Rickettsiales, family Anaplasmataceae. These bacteria share simi-

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lar morphologic characteristics with E. chaffeensis, may be transmitted to humans by tick bites, and can cause infections in animals and humans (16). Anaplasma species are small (0.2-1.0 µm), obligate, intracellular gramnegative organisms (25); and they infect predominantly bone marrow– derived cells in mammalian hosts, mostly polymorphonuclear (neutrophil) leukocytes, where they grow to form characteristic intracytoplasmic microcolonies (morulae) (Table 43-4).

Epidemiology Human granulocytotropic ehrlichiosis (HGE) was described in 1990 as a nonspecific febrile illness that occurred among a group of older men who were bitten by ticks in the upper Midwest (25). The cause of HGE was initially attributed to Ehrlichia phagocytophila (also known as the HGE agent); but recent revisions in the taxonomy and nomenclature of the family Anaplasmataceae have reclassified the human granulocytic ehrlichiosis agent as A. phagocytophilum, mandating a change in the disease name to human granulocytic anaplasmosis, or HGA (26). Ixodes species ticks are the established vectors for Anaplasma phagocytophilum (18,27). The infectious cycles of A. phagocytophilum as well as B. burgdorferi are maintained in nature when Ixodes ticks feed on transiently or persistently infected animal reservoir hosts that potentially include small rodents such as Peromyscus leucopus, the white-footed mouse, and large ungulates like Odocoileus virginianus, the white-tailed deer. All 3 developmental tick stages (larva, nymph, and adult) feed willingly on humans, but only the nymphal and adult stages are infectious because there is no established transovarial passage of bacteria from the adult female to eggs. The CDC recorded more than 4276 cases of HGA in the United States between 1994 and the end of 2006, and 790 cases were reported in 2006 alone, the last year for complete data (28). Seroepidemiologic investigations have suggested that HGA is generally a mild infection; and case reports have shown that most patients recover uneventfully after 1 to 2 weeks, even in the absence of specific antibiotic therapy (29). The estimated HGA case fatality rate is low (0.5% to 1%). However, it may be difficult to prospectively identify patients likely to develop serious or fatal disease (27,30), and prompt institution of active antibiotic therapy is therefore advocated for all symptomatic patients who have been diagnosed with HGA (14). Epidemiologic studies have also provided evidence of high-risk regions and populations. Seroprevalence rates as high as 14.9% were recently reported in Wisconsin (31), and studies of at-risk B. burgdorferi–seropositive populations in New York State showed that as many as 35.6% also had antibodies to A. phagocytophilum (32). Passive surveillance studies of some highly endemic regions of Connecticut (1) and Wisconsin (30) have demon-

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strated incidence rates as high as 52 to 58 cases in 100,000 of the population. Despite high seroprevalence rates in endemic regions, only a single case of transfusion-related HGA has been documented, underscoring the rarity of this event.

Clinical Manifestations HGA is a clinical syndrome most commonly manifested by nonspecific fever, chills, headache, and myalgias (Table 43-2) (25,27,30,33). The symptoms and signs range from asymptomatic infection to fatal disease and the clinical severity of HGA varies directly with increasing patient age and/or comorbid illnesses. Most symptomatic patients have reported tick exposure or a tick bite 1 to 2 weeks before the onset of symptoms, and most symptomatic infections are acquired between May and August (16,30). The median patient age is 69 years, and men become infected 3 to 4 times more frequently than women (30). HGA can be severe with nearly half of patients requiring hospitalization and up to 17% requiring admission to an intensive care unit (30). Although the case fatality rate is low, complications can occur and include a septic or toxic shock–like syndrome, respiratory insufficiency, invasive opportunistic infections with both viral and fungal agents, rhabdomyolysis, pancarditis, acute renal failure, hemorrhage, and neurological diseases such as brachial plexopathy and demyelinating polyneuropathy. Various permutations of leukopenia, a left shift (often higher than 25% band neutrophils), thrombocytopenia, and hepatic aminotransferase elevations are present in most patients and provide suggestive clues to the diagnosis (33-35). Although both leukopenia and thrombocytopenia are present in many patients at presentation, these abnormalities are transient and usually normalize by the end of the second week. At least 20% and up to 80% of patients present with morulae in peripheral blood neutrophils that confirm the diagnosis (33,34).

Diagnosis The diagnosis can be confirmed by blood smear examination and PCR analysis during the early phase of infection, and by serologic testing (IFA) in late infection or convalescence (Table 43-5). PCR amplification of A. phagocytophilum DNA from acute phase blood (30,33) or isolation of A. phagocytophilum in HL-60 promyelocytic leukemia cell cultures inoculated with acute phase blood (30,33) can confirm the diagnosis, but these test modalities are available in only a limited number of laboratories. Patients who have a clinical illness compatible with HGA should be considered for specific antibiotic treatment (14,16,27). Blood samples should be secured before the patient begins antibiotic treatment because therapy will rapidly reduce the detectable quantities of infected cells or bacterial DNA.

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Serologic testing using a polyvalent IFA method with demonstration of 4fold antibody titer change or seroconversion has been used most commonly to confirm HGA (29). IgM tests are only reactive during the first 45 to 50 days after infection, and these tests are not more sensitive than those that detect IgG antibodies. (For information on therapy, please see the section “Treatment of Human Ehrlichiosis, and Human Anaplasmosis,” later in this chapter.)

Human Granulocytotropic Ewingii Ehrlichiosis Etiology and Epidemiology In 1999 Ehrlichia ewingii was identified in blood by PCR conducted on samples collected from several old and immunocompromised patients from Missouri and Oklahoma (36). Buller demonstrated that approximately 1% of patients believed to be infected with E. chaffeensis actually were infected with E. ewingii (36). E. ewingii was previously known only as a pathogen of dogs. Just like E. chaffeensis these organisms cycle within Amblyomma americanum ticks for part of their life cycle. The associated infectious syndrome is called human granulocytotropic ewingii ehrlichiosis (HGEE). HGEE has so far only been reported in patients living in Missouri, Oklahoma, and Arkansas. In contrast to E. chaffeensis, which infects monocytes and macrophages, E. ewingii lives predominantly in peripheral blood neutrophils. To date, less than 30 patients have been reported to the CDC, and many of the patients have had concurrent HIV infection or have received organ transplants.

Clinical Manifestations and Diagnosis Infected patients have reported a nonspecific febrile illness after tick exposure or a tick bite, but overall the severity of HGEE seems lower than for either HME or HGA, and no fatalities have been reported. The usual presentation is a mild summertime febrile illness that occurs after tick exposure. Reported symptoms include fever, myalgias, and malaise; and many patients presented with leukopenia, thrombocytopenia, and increased serum alanine aminotransferase or aspartate aminotransferase concentrations. PCR can be attempted for diagnosis early in illness, but few laboratories offer the specific assay required. E. ewingii has not been cultivated in vitro, and reliable rapid diagnostic tests do not currently exist. However, E. ewingii is closely related to E. chaffeensis, which results in serologic crossreactivity in IFA assays. It is therefore likely that some patients who are serodiagnosed with HME may actually be infected by E. ewingii (21,36).

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Treatment of Human Ehrlichiosis and Human Anaplasmosis Ehrlichia and Anaplasma species are uniformly susceptible to tetracycline antibiotics in vitro (37,38). Doxycycline hyclate has traditionally been the agent of choice because of favorable pharmacokinetic properties compared with other tetracycline derivatives. Because of the potential for serious or even fatal HME and HGA infection, all patients with suspected or documented HME or HGA should be treated with oral or intravenous doxycycline hyclate in the absence of specific contraindications to tetracycline drugs (Table 43-6) (16,1921,27). Doxycycline is also the drug of choice for children who are seriously ill regardless of age (39). Doxycycline therapy characteristically leads to clinical improvement in 24 to 48 hours (10,14,16,19-21,27). Thus, patients who fail to respond to treatment within this time frame should be reevaluated for an alternative diagnosis and treatment. The optimal duration of doxycycline therapy has not been established. Patients who have been treated for 7 to 10 days have resolved their infections completely, and relapse or chronic infection has never been reported, even for patients who were never treated with an active antibiotic. However, adult patients who are considered at risk for coinfection with B. burgdorferi should continue doxycycline therapy for a full 14 days. A shorter course of doxycycline (5-7 days) has been advocated for pediatric patients because of the potential risk for adverse effects (dental staining) seen occasionally in young children. Rifamycins have demonstrated excellent in vitro activity against Ehrlichia and Anaplasma species (37,38). A small number of pediatric patients and pregnant women with HGA have been treated successfully

Table 43-6 Recommended adult and pediatric antibiotic treatment of human monocytotropic ehrlichiosis*, human granulocytotropic anaplasmosis†, and human granulocytotropic ewingii ehrlichiosis‡. Antibiotic

Dose (adults)

Dose (children)

Doxycycline hyclate Tetracycline hydrochloride Rifampine,f

100 mg IVa or POb Q 12 hours 500 mg PO Q 6 hours 300 mg PO Q 12 hours

2.2 mg/kg IV or PO Q 12 hoursc 25-50 mg/kg/day PO in 4 divided dosesc 10 mg/kg PO Q 12 hours

a

Duration (days)

5-14d 5-14d 7

Intravenous administration Oral administration Until fever has resolved and for three additional days d 14 days recommended when co-incubating B. burgdorferi infection is suspected e Active against E. chaffeensis in-vitro. No clinical experience reported for treatment of HME f In-vitro activity against E. ewingii is unknown. No clinical experience reported for treatment of HGEE * Data from references 14, 19, 20, and 38. † Data from references 14, 27, 33, and 39. ‡ Data from references 30 and 45. b c

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with rifampin (40-42). Thus, patients who are deemed unsuited for tetracycline treatment because of a history of drug allergy or pregnancy, and children younger than 8 years of age who are not seriously ill should be considered for rifampin therapy. There are no published reports about the clinical efficacy of rifampin for the treatment of HME or HGEE. Studies with levofloxacin and trovafloxacin (no longer a registered medication) demonstrated some activity against A. phagocytophilum in vitro (37). However, there is no published information available about the usefulness of these antibiotic drugs or other fluoroquinolones as clinical agents in vivo.

Acute and Long-Term Prognosis of Lyme Borreliosis, Ehrlichiosis, and Anaplasmosis Lyme disease responds well to treatment, but the responses are best when treatment is instituted early in the clinical infection. A small percentage of appropriately treated patients continues to have lingering subjective symptoms called post-Lyme disease syndrome similar to chronic fatigue syndrome or fibromyalgia (10,43). However, most patients recover eventually over a period of months with minimal or no residual deficits (7,10). Epidemiologic studies and case report series indicate that HGA often is a mild, self-limited illness that resolves even without antibiotic treatment; and the long-term prognosis is favorable (31,35,44). HME may be a moderately severe infection evidenced by a death rate of approximately 3%, which is higher than for HGA (<1%) and HGEE (no reported deaths). Patients who have HME or HGA typically improve rapidly after starting doxycycline therapy, and failure to improve warrants a search for a different cause of fever. A small number of patients with HGA who did not receive adequate treatment (no antibiotic therapy was given or inactive antibiotic therapy was prescribed) all made a complete recovery within 60 days (30). There is currently no clinical evidence in the published literature to suggest that untreated HME or HGA may evolve into a chronic illness in humans, as has been seen with Lyme borreliosis. Persistently elevated antibody titers should therefore be interpreted as evidence of past infection rather than proof of an ongoing unresolved infectious process. The long-term prognosis after HME, HGA, and HGEE seems to be favorable, and patients should be expected to make a complete recovery.

Approach to the Patient with a Suspected Tick-Borne Illness The clinical presentation of Lyme borreliosis, HME, and HGA usually becomes apparent after an incubation period of 7 to 14 days (Table 43-7).

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Table 43-7 Comparison of epidemiological, clinical, and laboratory characteristics associated with Lyme borreliosis (Lyme disease)*, human monocytotropic ehrlichiosis (HME)†, and human granulocytotropic anaplasmosis (HGA)‡. Characteristic feature

Lyme borreliosis §

HME

HGA ¶

0.003-58.2# 7-14 1:3-4 59 Rapid None

Incidence rate Incubation period (days) Female:Male ratio Patient median age (years) Onset of infection Objective physical findings during acute phase Description of rash (%)

0.18-133.8 7-14 1:1 28 Gradual Skin rash

0.001-6.5 7-14 1:3-4 49 Rapid None

EM (60-100%)

Blood smear microscopy Typical Laboratory changes

Not helpful Variable

Helpful diagnostic tests in acute or convalescent phase

Serology (EIA) Western blot analysis PCR Culture Doxycycline Yes Rarely fatal

Nonspecific (20-30%) May be helpful Leukopenia Thrombocytopenia ↑ CRP ↑ AST/ALT Serology (IFA) PCR Culture

Nonspecific (2-16%) Often helpful Leukopenia Thrombocytopenia ↑ CRP ↑ AST/ALT Serology (IFA) PCR Culture

Doxycycline Not described 1-3%

Doxycycline Not described < 1%

Effective Antibiotic Chronic disease state Fatality rate

* Data from references 3, 6, and 10. † Data from references 19 and 21. ‡ Data from references 2, 33, 35 and 47. § Range annual rates Lyme borreliosis per 100,000 reported for US States 2002 (48). ¶ Range annual rates HME per 100,000 reported for US States 1999 (1). # Range annual rates HGA per 100,000 reported for US States 1996 (30) and 1999 (1).

Although the signs and symptoms associated with early localized Lyme borreliosis usually are mild and appear gradually over a period of days, the onset of HME and HGA usually occur rapidly; and most patients report of influenza-like symptoms that include high fever, marked headache, and muscle aches. Early, localized Lyme borreliosis may be easily recognized by the characteristic EM rash, and further laboratory testing may be unnecessary before the patient begins antibiotic treatment. However, patients who develop rapid onset of influenza-like symptoms and nonspecific fever after tickexposure should be evaluated with a clinical examination and routine laboratory testing that includes a complete blood count, inspection of the peripheral blood smear for presence of morulae, and determination of C-reactive protein (CRP) and hepatic aminotransferase-concentrations in serum. Reduced leukocyte and/or platelet-count, increased proportions of band neutrophils and lymphopenia in peripheral blood, mild increases

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in serum hepatic aminotransferase-concentrations and/or elevated CRPconcentrations warrant additional laboratory testing to confirm ehrlichiosis or anaplasmosis. Furthermore, these patients should be considered for antibiotic treatment with an agent that includes E. chaffeensis, E. ewingii, and A. phagocytophilum in the therapeutic spectrum. However, confirmatory laboratory tests for ehrlichiosis or anaplasmosis are generally unavailable in the acute care setting. Thus, patients who are suspected of having HME, HGA, or HGEE should begin empiric antibiotic treatment as soon as appropriate blood samples have been collected for confirmatory laboratory testing. The relative sensitivities of confirmatory laboratory tests for ehrlichiosis and anaplasmosis vary with the duration of clinical signs and symptoms, which must be taken into consideration when additional tests are ordered for diagnosis confirmation (Table 43-8). Serologic testing has historically been the most sensitive testing method, and whenever possible acute phase serum should be paired with a convalescent serum sample to demonstrate seroconversion in those instances where blood smear microscopy, PCR, or cell culture testing were either unavailable or the results were inconclusive (19,29). HGEE may be particularly difficult to diagnose because the results of blood smear evaluation and serologic testing may confuse the diagnosis with HGA and HME, respectively (45). Thus, the laboratory diagnosis of HGEE can currently only be confirmed by PCR (36). Lyme borreliosis, HME, HGA, and HGEE are reportable illnesses and all confirmed cases should be reported to the local state health department in the state where the diagnosis was made or to the CDC. The tabular list of International Classification of Diseases (ICD-9) categorizes ehrlichiosis and anaplasmosis under the subheading tick-borne rickettsioses (numerical codes for HME and HGA are 082.41 and 082.49, respectively) and Lyme borreliosis under the subheading other specified arthropod-borne infections (numerical code 088.81).

Table 43-8 Relative sensitivity of diagnostic tests used for laboratory diagnosis confirmation of HME and HGA. Duration of illness (days)

Blood smear microscopy*

Cell culture †

PCR§

0-7 8-14 15-30 31-60 >60

Medium Low

Medium Low

High Low Low

Serologic test (IFA)

Low Medium High High High

Republished with permission from Dumler JS, Walker DH. Tick-borne ehrlichioses. Lancet Infect Dis. 2001:1:21-28. Note:* Wright or Giemsa stained peripheral blood smear examination. †DH82 cells for Ehrlichia chaffeensis, HL-60 cells for Anaplasma phagocytophilum. §Different specific primers required for Ehrlichia chaffeensis and Anaplasma phagocytophilum

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Acknowledgements This work was supported in part by grant R01 AI44102 from the National Institutes of Allergy and Infectious Diseases. REFERENCES 1. McQuiston JH, Paddock CD, Holman RC, Childs JE. The human ehrlichioses in the United States. Emerg Infect Dis. 1999;5:635-42. 2. Bakken JS, Dumler JS. Ehrlichiosis and anaplasmosis. Infections in Medicine. 2004;21:433-51. 3. Steere AC. Borrelia burgdorferi (Lyme disease, Lyme borreliosis). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia, Pa: Elsevier Churchill-Livingstone; 2005:2798-809. 4. Steere AC, Malawista SE, Snydman DR, Shope RE,Andiman WA, Ross MR, et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis Rheum. 1977;20:7-17. 5. Spielman A, Hodgson JC. The natural history of ticks: A human health perspective. In: Cunha BA, ed. Tickborne Infectious Diseases: Diagnosis and Management. New York, NY: Marcel Decker; 2000:1-14. 6. Steere AC. Lyme disease. N Engl J Med. 2001;345:115-25. 7. Shadick NA, Lew RA, Liang MH. Outcomes of Lyme Disease. Ann Intern Med. 2000;133:746-747. 8. Anonymous. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep. 1995;44:590-1. 9. Bakken LL, Case KL, Callister SM, Bourdeau NJ, Schell RF. Performance of 45 laboratories participating in a proficiency testing program for Lyme disease serology. JAMA. 1992;268:891-5. 10. Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, et al. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis and babesiosis: Clinical practice guidelines by the Infectious Disease Society of America. Clin Infect Dis 2006;43:1089–1134. 11. Johnson BJ, Robbins KE, Bailey RE, Cao BL, Sviat SL, Craven RB, et al. Serodiagnosis of Lyme disease: accuracy of a two-step approach using a flagella-based ELISA and immunoblotting. J Infect Dis. 1996;174:346-53. 12. Wormser GP, Nowakowski J, Nadelman RB. Duration of treatment for Lyme borreliosis: time for a critical reappraisal. Wien Klin Wochenschr. 2002;114:613-5. 13. Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebocontrolled trial. Ann Intern Med. 2003;138:697-704. 14. Bakken JS, Dumler JS. Ehrlichia and anaplasma species. In: Yu V, Weber R, Raoult D, eds. Antimicrobial Therapy and Vaccine. 2nd ed. New York, NY: Apple Trees Productions; 2002:875-82. 15. Tick Bite Study Group. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001;345:79-84. 16. Dumler JS,Walker DH. Tick-borne ehrlichioses. Lancet Infect Dis. 2001;1:21-8. 17. Maeda K, Markowitz N, Hawley RC, Ristic M, Cox D, McDade JE. Human infection with Ehrlichia canis, a leukocytic rickettsia. N Engl J Med. 1987;316:853-6. 18. Anderson JF. The natural history of ticks. Med Clin North Am. 2002;86:205-18. 19. Fishbein DB, Dawson JE, Robinson LE. Human ehrlichiosis in the United States, 1985 to 1990. Ann Intern Med. 1994;120:736-43. 20. Olano JP,Walker DH. Human ehrlichioses. Med Clin North Am. 2002;86:375-92. 21. Paddock CD, Childs JE. Ehrlichia chaffeensis: a prototypical emerging pathogen. Clin Microbiol Rev. 2003;16:37-64. 22. Standaert SM, Dawson JE, Schaffner W, Childs JE, Biggie KL, Singleton J Jr., et al. Ehrlichiosis in a golf-oriented retirement community. N Engl J Med. 1995;333:420-5. 23. McQuiston JH, Childs JE, Chamberland ME,Tabor E. Transmission of tick-borne agents of disease by blood transfusion: a review of known and potential risks in the United States. Transfusion. 2000;40:274-84. 24. Standaert SM, Yu T, Scott MA, Childs JE, Paddock CD, Nicholson WL, et al. Primary isolation of Ehrlichia chaffeensis from patients with febrile illnesses: clinical and molecular characteristics. J Infect Dis. 2000;181:1082-8. 25. Bakken JS, Dumler JS, Chen SM, Eckman MR,Van Etta LL,Walker DH. Human granulocytic ehrlichiosis in the upper Midwest United States. A new species emerging? JAMA. 1994;272:212-8.

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26. Dumler JS, Barbet AF, Bekker CP, Dasch GA, Palmer GH, Ray SC, et al. Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and ‘HGE agent’ as subjective synonyms of Ehrlichia phagocytophila. Int J Syst Evol Microbiol. 2001;51:2145-65. 27. Bakken JS, Dumler JS. Human granulocytic ehrlichiosis. Clin Infect Dis. 2000;31:554-60. 28. Anonymous. Summary of provisional cases of selected notifiable diseases, United States, cumulative week ending Dec. 30, 2006. 29. Bakken JS, Haller I, Riddell D,Walls JJ, Dumler JS. The serological response of patients infected with the agent of human granulocytic ehrlichiosis. Clin Infect Dis. 2002;34: 22-7. 30. Bakken JS, Krueth J,Wilson-Nordskog C,Tilden RL,Asanovich K, Dumler JS. Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA. 1996;275:199-205. 31. Bakken JS, Goellner P, Van Etten M, Boyle DZ, Swonger OL, Mattson S, et al. Seroprevalence of human granulocytic ehrlichiosis among permanent residents of northwestern Wisconsin. Clin Infect Dis. 1998;27:1491-6. 32. Aguero-Rosenfeld ME, Donnarumma L, Zentmaier L, Jacob J, Frey M, Noto R, et al. Seroprevalence of antibodies that react with Anaplasma phagocytophila, the agent of human granulocytic ehrlichiosis, in different populations in Westchester County, New York. J Clin Microbiol. 2002;40:2612-5. 33. Aguero-Rosenfeld ME, Horowitz HW, Wormser GP, McKenna DF, Nowakowski J, Muñoz J, et al. Human granulocytic ehrlichiosis: a case series from a medical center in New York State. Ann Intern Med. 1996;125:904-8. 34. Bakken JS, Aguero-Rosenfeld ME, Tilden RL, Wormser GP, Horowitz HW, Raffalli JT, et al. Serial measurements of hematologic counts during the active phase of human granulocytic ehrlichiosis. Clin Infect Dis. 2001;32:862-70. 35. Wallace BJ, Brady G,Ackman DM,Wong SJ, Jacquette G, Lloyd EE, et al. Human granulocytic ehrlichiosis in New York. Arch Intern Med. 1998;158:769-73. 36. Buller RS,Arens M, Hmiel SP, Paddock CD, Sumner JW, Rikhisa Y, et al. Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis. N Engl J Med. 1999;341:148-55. 37. Maurin M, Bakken JS, Dumler JS. Antibiotic susceptibilities of Anaplasma (Ehrlichia) phagocytophilum strains from various geographic areas in the United States. Antimicrob Agents Chemother. 2003;47:413-5. 38. Brouqui P, Raoult D. In vitro antibiotic susceptibility of the newly recognized agent of ehrlichiosis in humans, Ehrlichia chaffeensis. Antimicrob Agents Chemother. 1992;36:2799-803. 39. Anonymous. Ehrlichia infections (human ehrlichioses). In: Pickering LK, ed. Red Book: 2003, Report of the Committee of Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:266-9. 40. Buitrago MI, Ijdo JW, Rinaudo P, Simon H, Copel J, Gadbaw J, et al. Human granulocytic ehrlichiosis during pregnancy treated successfully with rifampin. Clin Infect Dis. 1998;27:213-5. 41. Elston DM. Perinatal transmission of human granulocytic ehrlichiosis [Letter]. N Engl J Med. 1998;339:1941-2; author reply 1942-3. 42. Krause PJ, Corrow CL, Bakken JS. Successful treatment of human granulocytic ehrlichiosis in children using rifampin. Pediatrics. 2003;112:e252-3. 43. Shadick NA, Phillips CB, Sangha O, Logigian EL, Kaplan RF,Wright EA, et al. Musculoskeletal and neurologic outcomes in patients with previously treated Lyme disease. Ann Intern Med. 1999;131:919-26. 44. Belongia EA, Reed KD, Mitchell PD, Mueller-Rizner N,Vandermause M, Finkel MF, et al. Tickborne infections as a cause of nonspecific febrile illness in Wisconsin. Clin Infect Dis. 2001;32:1434-9. 45. Paddock CD, Folk SM, Shore GM, Machado LJ, Huycke MM, Slater LN, et al. Infections with Ehrlichia chaffeensis and Ehrlichia ewingii in persons coinfected with human immunodeficiency virus. Clin Infect Dis. 2001;33:1586-94. 46. Walker DH, Bakken JS, Brouqui P, et al. Diagnosing human ehrlichioses: Current status and recommendations. Am Society Microbiol News. 2000;5:287-93. 47. Bakken JS, Dumler JS. Ehrlichiosis In: Cunha BA, ed. Tickborne Infectious Diseases. Diagnosis and Management. New York, NY: Marcel Decker; 2000:139-68. 48. Bacon RM, Mead PS, Kool JL, Postema AS, Staples JE. Lyme disease: United States 2001-2002. MMWR Morb Mortal Wkly Rep. 2004;53:365-9.

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Chapter 44

Malaria KEITH B. ARMITAGE, MD CHARLES H. KING, MD

Key Learning Points 1. Malaria continues to be major cause of morbidity and mortality in many parts of the developing world. 2. With Plasmodium infection, travelers from developed contries are highly likely to develop clinically severe malaria because they lack any prior immunity. 3. Optimal strategies for prevention and treatment of malaria continue to evolve rapidly due to the emergence of resistant organisms and the consequent introduction of many classes of anti-malarial drugs. 4. The clinical presentation of malaria is heterogeneous, with fever being the only sign or symptom that is reliably present. 5. Malaria should always be suspected and tested for in any traveler who presents with fever after returning from malarial areas.

A

mong parasitic infections, malaria is the leading cause of death worldwide. An estimated 500 million cases occur in the world per year, with one to two million deaths (1,2). Among immigrants and travelers returning from malarious areas, malaria should be considered as a possible diagnosis in any individual with fever, and diagnostic steps should be promptly undertaken to exclude infection with the Plasmodium parasites that cause malaria (3). The four species of Plasmodium that cause malaria (i.e., P. falciparum, P. vivax, P. ovale, and P. malariae) are widely distributed throughout the world in tropical and subtropical areas where the insect vector of malaria, the anopheline mosquito, thrives (Table 44-1). Malaria is common in Africa, India, Pakistan, Southeast Asia, Papua New Guinea, the southwestern Pacific 853

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New Developments in the Management of Malaria ●

●

●

Changing patterns of drug resistance make it essential to review the latest prescribing information when giving drugs for treatment or prevention of malaria. The CDC web site is reliable and up-to-date. Malarone (atovaquone/proguanil) is a useful alternative to mefloquine for prevention of chloroquine-resistant P. falciparum malaria, and can be used in patients who have experienced neuropsychiatric side effects from mefloquine. Artemesinin compounds, traditionally used to treat fever in China, have strong antimalarial activity, and produce rapid clinical improvement in infected patients. However, when used alone, they are associated with a high risk for relapse, and they should always be used in combination with other anti-malarial drugs. Artemesinins are currently not available in the United States.

States, Haiti, and parts of South America. In the United States, it is often the primary care provider who plays a crucial role in recognizing risk for malaria among immigrants and travelers, and in implementing a diagnostic evaluation to rule out malaria at the earliest signs of possible symptomatic infection. The post-World War II optimism about eliminating malaria by controlling its mosquito vectors or through mass treatment of human cases has given way to the reality of a world in which Plasmodium species are re-expanding their territory and are now multiply drug-resistant (1,4). Today, there is an increasing resurgence of malaria in many parts of the world (2,5). Nonetheless, except for rare instances of secondary transmission of the disease from imported cases, malaria transmission has been eliminated from the United States, Puerto Rico, Jamaica, Chile, Israel, Lebanon, North Korea, and Europe. However, malaria is still found in varying degrees in all other areas of the world in which the climate is tropical or subtropical. In some parts of the world, notably sub-Saharan Africa, transmission occurs in both urban and rural settings. In most of Central and South America, malaria is found primarily in rural areas.

Etiology Malaria is transmitted by the bite of the female anopheline mosquito during the taking of a blood meal. The infectious sporozoite form of the Plasmodium parasite leaves the salivary glands of the mosquito and enters the host’s skin. Sporozoites quickly enter the circulation to reach the liver. There, they invade hepatocytes and reproduce asexually for 10 to 14 days. After this asymptomatic incubation phase, Plasmodium merozoites emerge from the liver to infect host erythrocytes within the circulation. From this point forward, growth and reproduction of malaria parasites take place within the erythrocyte. Two to three days after an erythrocyte is infected,

No 8–25 days (average 12 days) Multiple infected RBCs, predominate rings, double nuclei, banana-shaped gametocytes

Central and South America, Haiti, Dominican Republic, SubSaharan Africa, India Pakistan, Southeast Asia High parasitemia, severe anemia, (often) daily spiking fevers, cerebral malaria, renal failure, , jaundice pulmonary edema, death Yes

P. vivax

Yes, in Southeast Asia Yes 8–27 days (average 14 days) Enlarged RBCs with Schuffner’s dots; trophozoite cytoplasm may be ameboid

Anemia, splenic rupture

Sub-Saharan Africa, Central and South America Asia

P. ovale

Yes 8–17 days (average 15 days Oval RBCs with fringed edges, compact cytoplasm

No

Anemia, splenic rupture

Sub-Saharan Africa, Southeast Asia, New Guinea

P. malaria

No 15–30 days (average 15 days) RBCs unchanged

No

Persistent infection nephritis

Sub-Saharan Africa,

Malaria

RBC = red blood cells.

Appearance on thin film

Chloroquine resistance Relapse Incubation period

Clinical features

Geographic distribution

Plasmodium falciparum

Table 44- 1 Summary of Plasmodium Species

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the parasite completes its growth and asexual division. A new generation of merozoites then matures and emerges into the plasma by rupturing the erythrocyte wall. Each merozoite is then capable of infecting a new erythrocyte. In this cyclic manner, the level of infected erythrocytes increases in geometric fashion. The process of parasite development within the erythrocyte cytoplasm takes 48 hours in the case of P. falciparum, P. vivax, and P. ovale, and 72 hours in the case of P. malariae. Typically, cyclic systemic inflammation occurs in conjunction with the synchronous rupture of several infected erythrocytes, accounting for the periodicity of fever in malaria (6). In the case of P. falciparum, the merozoite is capable of infecting erythrocytes of all ages and stages of development, with the potential for massive hemolysis, severe anemia, and renal failure (7). Other Plasmodium species are not capable of infecting erythrocytes in all stages of development, and so, generally do not cause such severe complications. Malaria caused by P. vivax and P. ovale is, therefore, not so potentially lethal as malaria caused by P. falciparum. The life cycle of malaria parasites is completed when a subpopulation of merozoites develops into male and female gametocytes. When these are taken in a blood meal by a female anopheline mosquito, they mate (in sexual reproduction) within the insect abdomen and ultimately produce new sporozoites. These sporozoites migrate to the mosquito’s salivary glands to initiate infection of a new host during the next blood meal (1). Without the continued presence of mosquitoes of the right vector species, endemic transmission of malaria cannot occur. In temperate areas such as the United States, brief epidemics can occur rarely in the summer months if anopheline mosquitoes flourish in a region where chronically infected humans are harboring asymptomatic malaria (8). This is extremely uncommon, and the great majority of malaria in the United States is seen in immigrants from or travelers to endemic areas (9). Other North American cases have been caused by blood-borne transmission of malaria parasites (i.e., by transfusion or by needle sharing among injection-drug abusers). This is because merozoites in donor erythrocytes can directly infect new erythrocytes in the recipient’s circulation. In transfusion-transmitted malaria, there is no initial liver stage of infection. Because of this, late recrudescence of malaria from dormant liver hypnozoites will not occur with transfusion-associated malaria, although this often happens after initial treatment of mosquitotransmitted P. vivax and P. ovale malaria.

Clinical Manifestations Infection with malaria parasites leads to hemolysis, anemia, tissue hypoxia, and secondary immunopathologic processes caused by the release of inflammatory cytokines (6). Together, these processes account for the clinical signs and symptoms of malaria, which in the case of P. falciparum malaria can be

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severe or fatal. The symptoms of acute malaria can be variable, depending on both parasite and host factors. High fevers and rigors are the hallmark of acute malaria, and malaria should be considered in any individual with an exposure history and any type of fever (3). In addition, malaise, headaches (often severe), myalgias, and fatigue frequently occur. Other symptoms, such as nausea, diarrhea, and cough can mimic abdominal disease or pneumonia. Patients may not have a synchronous infection, and the classic periodicity of fever (quartan or tertian fever) does not have to be present. In particular, patients with P. falciparum infection often present with daily spiking fevers. Patients can also have double infection with two or more species of malaria parasite (10). This frequently results in an inconstant pattern of fever spikes. Hepatosplenomegaly, pallor, and mild jaundice are common clinical signs in patients with acute malaria. Highly immune adults from endemic areas can be infected but minimally symptomatic or asymptomatic. Such infection is often documented among recent immigrants and refugees. In this setting, if anopheline mosquitoes are also locally present, then there is the potential for personto-person transmission of malaria in the immediate neighborhood, even within nontropical climates (8). Cerebral malaria is the most severe form of malaria, causing more than 80% of fatalities from malaria (11,12). It is caused only by P. falciparum infection and occurs in 0.5% to 1% of cases, with a death rate of approximately 50%. Patients with cerebral malaria often present with seizures, stupor, and focal neurological symptoms (1). The other severe complications of falciparum malaria include acute renal failure, pulmonary edema, hypoglycemia, and shock. Partly-treated patients, or those with partial immunity, can have continued subclinical P. falciparum infection, and symptomatic relapse with falciparum malaria can occur for up to 1 year. Late relapses caused by a latent phase of infection in the liver are seen in P. vivax and P. ovale infection, but unlike P. vivax and P. ovale, P. falciparum does not have a latent liver phase, and will be eradicated if the erythrocyte stage of disease is eliminated (4).

Diagnosis The clinical gold-standard diagnosis of malaria rests on microscopy, with the demonstration of the parasites on Giemsa-stained blood smears. Thick blood smears are used as a sensitive screening test, whereas thin blood smears are necessary for species identification and estimation of the percentage of erythrocytes infected (3). This latter number gauges the severity of infection. The presence of the parasites in the blood can fluctuate, and many smears (separated by approximately 12 hours) should be done during the 24 to 48 hour fever cycle—many negative smears are required before the diagnosis of malaria can be ruled out. Even if blood smears are

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initially negative, treatment should not be delayed if the clinical suspicion of severe malaria is high (3). Detection of circulating antigen is an alternative approach to diagnosis of falciparum malaria. Sensitivity and specificity are good, but does not exceed the performance characteristics of expert microscopy. Polymerase chain reaction (PCR)-based diagnosis is an emerging tool for diagnosis in research settings, with a much greater sensitivity for mixed Plasmodium species infections than with microscopy (10,13).

Treatment Antimalarial drugs are used for both the prophylaxis and treatment of infection caused by Plasmodium species. Decisions on the choice of therapy are based on: (a) the clinical suspicion of P. falciparum as the causative organism, (b) the severity of the infection, and (c) the known drug-resistance patterns for the areas in which the patient has traveled. Given the complexity of treatment regimens, consultation with an infectious disease specialist or other highly experienced clinician is appropriate when contemplating treatment of possible cases of symptomatic malaria. The selection of a specific drug or drug combination depends on the malaria species involved, local drug availability, and whether the patient is treated as an inpatient or outpatient. Resistance patterns of malaria parasites continue to evolve, and new therapeutic agents, such as the artemether compounds, are becoming more generally available. It is imperative to have up-to-date information when treating malaria. The Centers for Disease Control and Prevention (CDC) Malaria Hotline (770-488-7788, M-F 8 a.m.-4:30 p.m.; 770-488-7100 other times) and the CDC Internet site (www.cdc.gov) are good sources for up-to-date information.

Chloroquine Phosphate Chloroquine phosphate is a 4-aminoquinoline used primarily for the treatment and prevention of infection by P. vivax, P. malariae, P. ovale, and sensitive strains of P. falciparum. Chloroquine-sensitive strains of P. falciparum are now rare, and are found in only a few geographic areas. Chloroquine can be given orally with food or injected parenterally. Parenteral dosing can be associated with respiratory depression, hypotension, cardiac arrest, and seizures, particularly after rapid administration of chloroquine. Parenteral therapy should be used only for patients unable to take oral medicine, and patients should be switched to the oral route as soon as possible. Oral doses of chloroquine are absorbed to an extent exceeding 90%, and intramuscular and subcutaneous doses are also rapidly absorbed. Because of the large volume of distribution of chloroquine, a loading dose is required. The drug undergoes extensive metabolism, and the kidney

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excretes approximately 50%. Renal failure does not change the therapeutic dose of chloroquine, but prophylactic doses should be reduced. The precise mechanism of action of chloroquine is unknown; it is known that chloroquine raises the pH of lysosomal vesicles of Plasmodium, and inhibits the proteolysis of hemoglobin. In treating malaria, chloroquine is active against the asexual erythrocytic stages of sensitive strains of the causative parasites, and its administration leads to rapid clinical improvement. Chloroquine is therefore indicated for the erythrocytic stage of development of sensitive strains of Plasmodium species. Unfortunately, in most areas of the world P. falciparum is chloroquine-resistant, and can be resistant to second-line drugs as well (4); in addition, there have been reports of P. vivax chloroquine resistance in Papua New Guinea and Indonesia (3). Chloroquine has no exoerythrocytic activity and therefore is of no use against tissue stages of the life cycle of malarial parasites. When used to treat the erythrocytic stages of P. vivax and P. ovale, it must be followed with an agent such as primaquine that is active against the tissue hepatic phase, to completely eradicate infection (i.e., effect a radical cure). Chloroquine phosphate (Aralen) is supplied as 250- and 500-mg tablets (containing 150- and 300-mg base). Hydroxychloroquine sulfate (Plaquenil) is supplied in 200-mg tablets, and for dosing purposes, 400 mg of hydroxychloroquine sulfate is equal to 500 mg of chloroquine phosphate. Chloroquine hydrochloride for injection is supplied at a concentration of 50 mg/mL. For malaria prophylaxis against sensitive strains, 500 mg of chloroquine is given once a week. Prophylactic dosing is started 1 to 2 weeks before exposure and is continued for 4 weeks after exposure (Table 44-2). The dose of chloroquine for treatment of acute infection is 1 g, followed by 500 mg 6 to 8 hours later, with subsequent dosing at 500 mg/day for 2 days, for a total dose of 2.5 g. Parenteral dosing schedules are not as well established, but chloroquine can be given in a dose of 3.5 mg/kg every 6 hours to a total dose of 2.5 g. Children should not be given more than 10 mg/kg of chloroquine base per day regardless of the route of administration (Table 44-3), and their usual prophylactic dosage of chloroquine base is 5 mg/kg/wk (see Table 44-2). Common side effects of the treatment dose of chloroquine (used in acute malaria attacks) include gastrointestinal upset, pruritus, headache, and visual disturbance. As noted earlier, intravenous preparations are available, but should be used cautiously, because rapid infusion of chloroquine can lead to cardiovascular collapse. The prophylactic dose is usually well tolerated, although prolonged use can lead to skin eruptions and changes in the fingernails. Prolonged use of chloroquine in high daily doses has been associated with more serious side effects such as myopathy and neuropathy. Chloroquine is contraindicated in severe hepatic disease, psoriasis, and porphyria.

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Table 44-2 Prophylaxis of Malaria Organism

Drug

Adult Dosage

Pediatric Dosage

Chloroquineresistant Plasmodium falciparum*

Mefloquine (Lariam)

250 mg/wk PO Begin 1 week before exposure Continue 4 weeks after exposure 100 mg/d PO Begin 2 days before exposure Continue 28 days after exposure Proguanil 200 mg/d PO plus chloroquine as below

5–9 kg: 1/8 tablet 10–19 kg: 1/4 tablet 20–30 kg: 1/2 tablet 31–45 kg: 3/4 tablet >45 kg: adult dosage Contraindicated in children <8 years of age

Doxycycline (Vibramycin)

Chloroquine + proguanil

Atavaquone + proguanil (Malarone)

Chloroquine-sensi Chloroquine tive P. falciparum (Aralen) and P. vivax, P. ovale,

1 tablet daily Begin 2 days before exposure Continue 7 days after exposure

500 mg/wk chloroquine phosphate PO (300-mg base) Begin 2 weeks before exposure Continue 6 weeks after exposure

<2 years: 50 mg/d 2–6 years: 100 mg/d 7–10 years: 150 mg/d >10 years: adult dose plus chloroquine as below 11–20 kg: 1 pediatric tablet 21–30 kg: 2 pediatric tablets 31–40 kg: 3 pediatric tablets >40 kg: adult dosage 8.3 mg/kg/wk (5-mg base)

PO = orally. * Chloroquine-resistant Plasmodium falciparum prophylaxis is also effective for Chloroquine-sensitive P. falciparum.

Mefloquine Mefloquine is a quinoline-carbinolamine compound active against chloroquine-resistant P. falciparum in most parts of the world, and is used for the prophylaxis and treatment of malaria where chloroquine resistance is likely. It is available only in oral form. Mefloquine has a long half-life, with an elimination time of 2 to 3 weeks. It is excreted in the feces, and dose adjustments do not need to be made in renal failure. The mechanism of action of mefloquine is unknown, but is probably similar to that of chloroquine. Like chloroquine, mefloquine is active only against the erythrocytic forms of P. falciparum. In the United States, mefloquine is sold under the trade name Lariam and is supplied as 250-mg tablets.

Quinine dihydrochloride++

10 mg/kg loading dose (maximum 600 mg) infused in NS over 1-2 hours, then 0.02 mg/kg/min for 72 hours+ 20 mg salt/kg loading dose in D5W over 4 hours, then 10 mg salt/kg over 2-4 hours every 8 hours (maximum

900 mg tid for 7 days 750 mg PO initial dose followed by 500 mg PO 6-12 h later 4 mg/kg/d PO for 3 days 750 mg PO initial dose followed by 500 mg PO 6-12 h later

250 mg qid for 7 days

Same as adult dosage

Same as adult dosage

Continued

650 mg PO tid for 3-7 days 100 mg bid for 7 days

a

Quinine sulfate plus one of the following: Doxycycline OR Tetracycline OR Clindamycin Mefloquine (Lariam) also effective for chloroquineresistant P.vivax Artesunate++ plus Mefloquine Parenteral Therapy Quinidine gluconate

5 - 8 kg: 0.5 adult tablet per day 11-20 kg: 1 adult tablet per day 21-30 kg: 2 adult tablets per day 31-40 kg: 3 adult tablets per day 25 mg/kg/d divided in three doses for 3-7 days 4 mg/kg/d divided in 2 doses for 7 days* 25 mg/kg/d divided in 4 doses* for 7 days 20-40 mg/kg/d divided in 3 doses for 7 days 15 mg/kg PO as initial dose, followed by 10 mg/kg PO 6-12 h later 4 mg/kg/d PO for 3 days 15 mg/kg PO as initial dose, followed by 10 mg/kg PO 6-12 h later

4 tablets PO per day for 3 days

Atovaquone/ proguanil (Malarone)

Chloroquineresistant Plasmodium falciparum

Pediatric Dosage

Adult Dosage

Drug Options

Organism

Table 44-3 Treatment of Malaria

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Atovaquone/ proguanil (Malarone)

and (as needed) Primaquine phosphate# 30 mg/d base PO (52 mg phosphate salt) for 14 days, or 45 mg/week base PO for 8 weeks for more resistant strains 4 tablets PO per day for 3 days

.

5-8 kg: 0.5 adult tablet per day 11-20 kg: 1 adult tablet per day 21-30 kg: 2 adult tablets per day 31-40 kg: 3 adult tablets per day for 3 days

0.6 mg/kg/d base (1 mg/kg salt) for 14 days

15 mg/kg PO, followed by 7.5 mg/kg six hours later, then 7.5 mg/kg on days 2 and 3

Artemether++

Chloroquine phosphate (Aralen)

Same as adult dosage

1800 mg/d) for 72 hours+ or until patient is able to take oral medication 3.2 mg/kg IM, then 1.6 mg/kg daily for 5-7 days 1000 mg PO, then 500 mg six hours later, then 500 mg on days 2 and 3

Footnotes: Abbreviations– PO = orally, NS = normal saline, D5W = 5% dextrose in water * not recommended for children less than 8 years old + cardiac, blood pressure, and glucose monitoring is required. Loading dose should be decreased in those who have previously received quinine or mefloquine. Switch to oral therapy when patient is stable. If prolonged parenteral therapy beyond 72h is required, quinine or quinidine dose should be reduced 30-50% after this initial period. ++ not available in the United States # for the prevention of relapse due to P. vivax and P. ovale

Alternative:

Chloroquinesensitive P. falciparum and P. vivax, P. ovale, and P. malariae

Pediatric Dosage

Adult Dosage

Drug Options

862

Organism

Table 44-3 Continued

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The most common prophylactic dosing schedule with mefloquine is 250 mg/week, beginning 1 week before travel. The drug should be continued for 4 weeks after the last exposure (see Table 44-2). A single dose of 1000 to 1500 mg of mefloquine is used for treating chloroquine-resistant falciparum malaria. Side effects are uncommon at doses of less than 1000 mg; nausea, vomiting, abdominal pain, and dizziness have been reported. Serious side effects of the central nervous system, such as seizures, hallucinations, psychosis, and depression, occur rarely at prophylactic doses (<0.5%) (14). Use of mefloquine in patients with cardiac conduction abnormalities or those taking beta-blockers for anti-arrhythmic indications has, in rare cases, been associated with sudden death, and its use should be avoided in these circumstances. Mefloquine is teratogenic in some animals, and although controlled data are not currently available about its safety in human pregnancy, it has been used in both prophylaxis and treatment of pregnant women in high-risk situations (15). The therapeutic dose for children is 25 mg/kg. Emergence of resistance to antimalarial drugs can occur rapidly, and the most recent information about this can be obtained from the CDC Malaria Branch (770-488-7788). As of 2005, resistance to mefloquine was most often reported in parts of Thailand, Cambodia, and Myanmar (Burma).

Quinine Quinine is an alkaloid extracted from the bark of the cinchona tree, and is highly active against blood forms of all malarial parasites. It is more toxic and less efficacious than chloroquine, and its primary clinical use is in treatment of resistant falciparum malaria. Quinine can be given by the oral, intravenous, rectal, or intramuscular route; it is metabolized in the liver and excreted by the kidney. The exact mechanism of action of quinine is unknown. The most commonly used preparation is quinine sulfate, the oral dose of which is 650 mg thrice daily, taken after meals, for 7 to 10 days; outside Southeast Asia, the duration of treatment with quinine can be decreased from 7 to 3 days if other antimalarial drugs such as tetracycline, doxycycline or clindamycin, are used concurrently (see Table 44-3). Parenterally administered quinine is more toxic than the orally administered drug, and should be reserved for the more severe cases of malaria (3,4); the intravenous dose of quinine is 20 mg of the salt/kg in 500 mL of 5% dextrose-in-water (D5W) infused over a 4-hour period, with subsequent infusion at 10 mg/kg for 2 to 4 hours in every 8-hour period (see Table 44-3). Patients severely ill with falciparum malaria who have high levels of parasitemia (>5% to 10%) or massive hemolysis should be treated with exchange transfusion in combination with drug therapy (3). Parenteral quinine is not available in the United States. Quinidine, a stereoisomer of quinine, can be used in its place for patients who need parenteral therapy for malaria. Quinidine is given by continuous intravenous infusion. The most commonly used dosing schedule is 10 mg/kg in

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a loading dose over 1 to 2 hours, followed by continuous infusion of 0.02 mg/kg/min until oral quinine therapy can be safely substituted (see Table 44-3). Quinidine undergoes hepatic metabolism and is excreted in the urine. Blood levels of this drug should be followed closely in patients with hepatic or renal failure. Because it has been for the most part supplanted as an anti-arrhythmic by newer drugs, parenteral quinidine gluconate can be difficult to obtain. If local hospital pharmacies or distributors do not have it in stock, the manufacturer, Eli Lilly Co, can be contacted directly (800-821-0538) to expedite shipment (3). Pending the availability intravenous therapy for severe malaria, intrarectal or intramuscular quinine therapy is an effective alternative (16). As for oral therapy, parenteral quinine or quinidine therapy should be combined with a second antimalarial, such as doxycycline (100 mg every 12 h) or clindamycin (5 mg base/kg every 8 hours), both of which can be given by infusion. Intravenous quinine and quinidine can cause hypotension and serious cardiac arrhythmias, particularly when given in bolus doses, and cardiac monitoring should be used during the entire period of their administration. The fatal oral dose of quinine for adults is 2 to 8 g, and care should be taken to keep this drug safe from children, who might accidentally overdose. Oral quinine is associated with various side effects including nausea, vomiting, diarrhea, and hypoglycemia, and can prove ineffective in pediatric cases because of patient refusal (17). Dosing with meals decreases gastrointestinal side effects. Dose-related side effects include tinnitus, headache, changes in vision, and vertigo. Tinnitus, optic neuritis, and hypersensitivity reactions are contraindications to the use of quinine.

Pyrimethamine Pyrimethamine is a dihydrofolate-reductase inhibitor that is highly active against this enzyme in malaria parasites. It is used in the prophylaxis and treatment of resistant falciparum malaria. Pyrimethamine is well absorbed orally and has an extremely long tissue half-life (80-95 hours). It is particularly effective when used in combination with other folic acid antagonists, and such combination therapy delays the emergence of resistance. A common pyrimethamine/sulfa drug combination used for malaria is Fansidar, which consists of pyrimethamine 25 mg and sulfadoxine 500 mg. In other countries, pyrimethamine in a dose of 12.5 mg is also available in combination with dapsone in a dose of 100 mg as Maloprim, but this formulation is not available in the United States. Pyrimethamine in a single dose of 75 mg in combination with a sulfa drug is used for treating acute attacks of falciparum malaria. However, increasing resistance of P. falciparum to the pyrimethamine/sulfa combination has been encountered in Asia and East Africa, and in these areas, antifolate drug therapy is no longer recommended as first-line treatment (4). In treating acute malaria, quinine is frequently used in combination with pyrimethamine,

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because pyrimethamine acts slowly in clearing parasitemia (see Table 44-3). The pediatric therapeutic dose of pyrimethamine is one fourth of a 25-mg tablet for children 2 to 11 months of age, one half of a tablet for children 1 to 3 years of age, one tablet for children 4 to 8 years of age, and two tablets for children 9 to 14 years of age. Children older than 14 years of age take the adult dose (three tablets). Long-term prophylactic use of pyrimethamine/sulfa combinations (Fansidar) has been associated with severe cutaneous skin reactions, and is no longer recommended. Mefloquine, atovaquone/proguanil, and doxycycline have largely supplanted the use of pyrimethamine/sulfa combinations (4,18). There have been no reports of fatal cutaneous reactions to Fansidar when the drug is used only for acute febrile episodes of malaria. High doses of pyrimethamine lead to megaloblastic anemia, which can be prevented with concurrent use of folinic acid (leucovorin).

Proguanil (Chloroguanide) Like pyrimethamine, proguanil (chloroguanide) is an inhibitor of protozoan dihydrofolate reductase. The drug is well absorbed orally, is readily excreted, and does not accumulate in the body. To be effective for prophylaxis of malaria it must be taken daily. Proguanil is used in the prophylaxis of resistant falciparum malaria (see Table 44-2), particularly as an alternative to pyrimethamine/sulfa in East Africa. For reasons that are not clear, proguanil is less effective in West Africa. The prophylactic dosage is 200 mg/day, and is associated with few side effects (occasional mouth ulcers, nausea, and diarrhea). In areas where P. falciparum is resistant to chloroquine, the combination of daily proguanil and weekly chloroquine is only approximately 75% effective in preventing falciparum malaria, as opposed to an efficacy of more than 95% for mefloquine. In addition, the need for a daily dose of proguanil (vs. weekly dosing with mefloquine) can lead to diminished compliance with its use. The more effective combination of proguanil/ atovaquone is described next.

Proguanil/Atovaquone (Malarone) In April 2000, the combination of proguanil and the hydroxynaphthoquinone antimalarial agent, atovaquone, was approved by the FDA for prophylaxis and therapy for malaria, including strains of P. falciparum that are resistant to chloroquine. The trade name for this combination of atovaquone 250 mg and proguanil 100 mg is Malarone. The pediatric-strength tablet contains 62.5 mg of atovaquone and 25 mg of proguanil. Malarone is generally well tolerated and should be taken with food. For prophylaxis, Malarone is given once daily, beginning 2 days before exposure and continuing for 7 days after exposure. Malarone prophylaxis is often used as an alternative

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to mefloquine if there are concerns about neuropsychiatric side effects. Malarone also can be used in the therapy for uncomplicated chloroquineresistant P. falciparum (and other strains of malaria) at a dosage of four pills per day for 3 consecutive days.

Primaquine Primaquine, an 8-aminoquinoline, is the prototype antimalarial drug for tissue stages of malarial infection. The drug is well absorbed orally and is extensively metabolized. Primaquine interferes with the mitochondrial function of Plasmodium species. It is primarily used to treat the liver phase of malaria caused by P. vivax and P. ovale. Patients treated for the blood phase of P. vivax or P. ovale malaria must receive treatment of the tissue phase to prevent relapse of their infection. By contrast, infection with P. falciparum does not have a long-term hepatic stage, and primaquine is not needed when the erythrocytic phase of falciparum malaria is successfully treated. However, patients who acquire P. falciparum malaria, and who are not taking chloroquine or other prophylaxis, should be treated with primaquine, because coinfection with another species of malarial parasite is quite common (10), and relapses of this latter P. vivax or P. ovale infection can occur if no treatment is given for the hepatic stage of those diseases. The dose of primaquine is expressed in terms of its base compound. Primaquine is supplied in tablets containing 26.3 mg of the salt, which is equal to 15 mg of free primaquine base. Primaquine at 30 mg/day in combination with chloroquine cures malaria caused by sensitive strains of P. vivax. For more resistant strains, 45 mg of primaquine is given with chloroquine weekly for 8 weeks (see Table 44-3). Primaquine should always be given with a schizonticidal agent (preferably chloroquine) in acute vivax or ovale malaria to prevent the development of resistance. At higher doses, primaquine can cause gastrointestinal distress; however, the major toxicity is related to the drug’s redox potential. In high doses primaquine can cause methemoglobinemia. In glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, primaquine at its usual doses provokes hemolysis, and patients should be screened for G6PD deficiency before any primaquine prophylaxis or treatment. With higher doses of primaquine or in susceptible patients, the erythrocyte count should be followed. Primaquine can rarely cause central nervous system toxicity. Agranulocytosis has also been reported, and primaquine is contraindicated in patients with neutropenia. Primaquine should also not be used during pregnancy (3).

Artemisinin (Qinghaosu) The artemisinins (qinghaosu) are members of a group of related compounds, traditionally used to treat fever in China, that have recently been demonstrated to have strong antimalarial activity (19). Artemether and artesunate

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compounds are emerging as an alternative therapy for resistant falciparum malaria, and have been used extensively in Southeast Asia. These compounds (see next paragraph) are among the most rapidly schizonticidal drugs available. The mechanism of their action is not well understood, but is thought to be mediated by free radical damage to parasite membranes. Artesunate is commonly given orally or as a suppository for nonsevere malaria. The oral dose is 4 mg/kg/day given over a period of 3 days. Intramuscular administration of artemether is used in cases of severe malaria where other parenteral therapy is not available. For this route of administration, 3.2 mg/kg is given intramuscularly (IM) as a loading dose, followed by 1.6 mg/kg daily for 5 to 7 days. Recently, experts have suggested the use of combination therapy, that is, artemisinin (short-acting) along with a longacting agent such as mefloquine or lumefantrine, for optimal treatment of P. falciparum malaria, to effect rapid clearance and limit the risk of rebound recrudescence of infection (1,4). Severe toxicities with artemisinin and its related compounds are rare. Transient first-degree heart block, abdominal pain, diarrhea, fever, and cytopenias have been reported, but are uncommon, and artemisinin compounds described here are generally well tolerated. Although, their safety in pregnancy has not been formally established, risk-benefit evaluation in individual cases can favor their use in high-risk pregnant patients (15).

Halofantrine Halofantrine is a 9-phenathrenemethanol effective against chloroquinesensitive and chloroquine-resistant falciparum malaria. The drug is available only in oral form; it is best absorbed when taken with a fatty meal. Halofantrine is excreted in the feces. The mechanism of action of this drug is not known. Like chloroquine and mefloquine, it is active only against the intraerythrocytic stages of Plasmodium species. Halofantrine is used in areas where there is resistance to chloroquine and mefloquine. There is some evidence of cross-resistance with mefloquine, which can limit the future usefulness of halofantrine. Administration consists of three 500-mg doses given at 6-hour intervals for adults and children weighing more than 40 kg, and 8 mg/kg given at the same 6-hour intervals for children weighing less than 40 kg. A second course of treatment after 7 days is recommended for nonimmune patients who were not previously exposed to malaria. The most common side effects of halofantrine are headache, nausea, abdominal pain, diarrhea, and rash. The use of halofantrine is contraindicated in pregnancy and for lactating women.

Tetracycline Members of the tetracycline family can be used to treat multiply-drug–resistant falciparum malaria. They are slow to act and should be used with quinine. Tetracycline is given orally at a dosage of 250 mg four times daily. The

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equivalent dosage of doxycycline is 100 mg twice daily (see Table 44-3). Doxycycline can also be used for short-term prophylaxis of malaria at a dosage of 100 mg/day (see Table 44-2). Tetracyclines are associated with sun sensitization, and should not be used in children younger than 8 years of age, or during pregnancy (3,4,15).

Choice of Therapy In mild cases of malaria, oral quinine or proguanil/atovaquone should be used for treatment if falciparum malaria is suspected and is likely to be chloroquineresistant. Severe infections, especially those marked by infection of more than 5% of erythrocytes, as measured on a thin blood smear, require parenteral treatment with quinidine or quinine (if available) and close monitoring (3). Chloroquine-sensitive falciparum malaria and malaria caused by other Plasmodium species can be treated with oral or parenteral chloroquine, bearing in mind that rare chloroquine-resistant P. vivax have been reported in Papua New Guinea, Indonesia, and Oceania. Patients with P. vivax and P. ovale should also be treated with primaquine for the latent liver phase of disease and to prevent relapse (see Table 44-3).

Prevention Prevention of malaria is based on reducing mosquito exposure in endemic areas, and on the use of low-dose antimalarial therapy to inhibit the progression of early, subclinical infection. Among people residing in endemic areas, research data indicate that reduction in the overall number of mosquito bites per annum will significantly alter the risk of death from malaria. The same is true for reducing the exposure of travelers in malaria-endemic zones. Mosquito control can be achieved through the widespread or focused use of insecticides, by screening, and by the use of insect repellents. In the 1950s, many nations were able to significantly reduce their malaria prevalence through peridomestic spraying with dichlorodiphenyltrichloroethane (DDT). This approach proved to be environmentally toxic, however, and spraying programs have been significantly curtailed (1). In recent years, focused use of permethrin insecticide-impregnated bed nets has proven effective in reducing transmission of malaria in endemic populations. Personal use of insect repellent has also been shown to reduce the risk of infection in travelers (20). In addition to vector avoidance, drug prophylaxis with chloroquine, mefloquine, or proguanil/atovaquone, as described earlier in the section on treatment of malaria, further reduces the risk of acquiring symptomatic malaria (21). Antimalaria vaccines are under development, but are strictly investigational, and their usefulness is not yet proven.

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Summary In the first decade of the new millennia, malaria remains a threat to residents and visitors in most tropical and subtropical areas of the world. Changing epidemiology, evolving drug resistance, and the development of new drugs will continue to challenge internists and other providers in managing patients with malaria and advising appropriate prophylaxis. Providers should continue to seek the latest information when presented with these challenges. But despite these changes, the key management principle for physicians remains—malaria should always be suspected and looked for in travelers returning from malaria areas who present with fever.

REFERENCES 1. Greenwood BM, Bojang K,Whitty CJ,Targett GA. Malaria. Lancet. 2005;365:1487-98. 2. Krogstad DJ. Malaria as a reemerging disease. Epidemiol Rev. 1996;18:77-89. 3. Center for Disease Control and Prevention. Treatment of malaria (guidelines for clinicians). Available at: http://www.cdc.gov/malaria/pdf/clinicalguidance.pdf. 4. Baird JK. Effectiveness of antimalarial drugs. N Engl J Med. 2005;352:1565-77. 5. Olliaro P, Cattani J,Wirth D. Malaria, the submerged disease. JAMA. 1996;275:230-3. 6. Schofield L, Grau GE. Immunological processes in malaria pathogenesis. Nat Rev Immunol. 2005;5:722-35. 7. Chotivanich K, Udomsangpetch R, Simpson JA, Newton P, Pukrittayakamee S, Looareesuwan S, et al. Parasite multiplication potential and the severity of Falciparum malaria. J Infect Dis. 2000;181:1206-9. 8. Zucker JR. Changing patterns of autochthonous malaria transmission in the United States: a review of recent outbreaks. Emerg Infect Dis. 1996;2:37-43. 9. Angell SY, Cetron MS. Health disparities among travelers visiting friends and relatives abroad. Ann Intern Med. 2005;142:67-72. 10. Mehlotra RK, Lorry K, Kastens W, Miller SM,Alpers MP, Bockarie M, et al. Random distribution of mixed species malaria infections in Papua New Guinea. Am J Trop Med Hyg. 2000;62:225-31. 11. Engwerda CR, Good MF. Interactions between malaria parasites and the host immune system. Curr Opin Immunol. 2005;17:381-7. 12. Severe and complicated malaria. World Health Organization, Division of Control of Tropical Diseases. Trans R Soc Trop Med Hyg. 1990;84 Suppl 2:1-65. 13. Blossom DB, King CH, Armitage KB. Occult Plasmodium vivax infection diagnosed by a polymerase chain reaction-based detection system: a case report. Am J Trop Med Hyg. 2005;73:188-90. 14. Croft AMJ, Garner P. Mefloquine for preventing malaria in non-immune adult travelers. Cochrane Database Syst Rev. 2005;CD:000138. 15. Whitty CJ, Edmonds S, Mutabingwa TK. Malaria in pregnancy. BJOG. 2005;112:1189-95. 16. Eisenhut M, Omari A, MacLehose HG. Intrarectal quinine for treating Plasmodium falciparum malaria: a systematic review. Malar J. 2005;4:24. 17. Maitland K, Nadel S, Pollard AJ,Williams TN, Newton CR, Levin M. Management of severe malaria in children: proposed guidelines for the United Kingdom. BMJ. 2005;331: 337-43. 18. White NJ. The treatment of malaria. N Engl J Med. 1996;335:800-6. 19. Woodrow CJ, Haynes RK, Krishna S. Artemisinins. Postgrad Med J. 2005;81:71-8. 20. Fradin MS. Mosquitoes and mosquito repellents: a clinician’s guide. Ann Intern Med. 1998;128:931-40. 21. Chen LH, Keystone JS. New strategies for the prevention of malaria in travelers. Infect Dis Clin North Am. 2005;19:185-210.

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Appendix

Recommended Antimicrobial Regimens in Adults for Specific Infections JAMES S. TAN, MD TIMOTHY R. PASQUALE, PHARMD

Disease

BONE INFECTIONS Joint Infections Septic arthritis

Recommended Antimicrobial Therapy*†

Etiology

Staphylococcus aureus (methicillin sensitive)

S. aureus (methicillinresistant)

Staphylococcus epidermidis

Group A, B, C, G streptococci

Enterococcus faecalis

Nafcillin 2 g IV q4-6h for 2 wk Alternatives: Cefazolin 2 g IV q8h or clindamycin 900 mg IV q8h or vancomycin 15 mg/kg IV q12h for 2 wk Vancomycin 15 mg/kg IV q12h for 2 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q6-8h or doxycycline 100 mg IV q12h or linezolid 600 mg IV/PO q12h for 2 wk Vancomycin 15 mg/kg IV q12h for 2 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q6-8h or linezolid 600 mg IV/PO q12h for 2 wk Penicillin G 2 MU IV q4h for 2 wk Alternatives: Vancomycin 15 mg/kg IV q12h or cefazolin 2 g IV q8h for 2 wk Penicillin G 2 MU IV q4h or ampicillin 2 g IV q6h for 2 wk plus gentamicin 1 mg/kg IM/IV q8h for 2 wk Continued

871

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Appendix

Appendix Continued Disease

Etiology

Neisseria gonorrhoeae

Neisseria meningitidis

Haemophilus influenzae (betalactamase negative)

H. influenzae (betalactamase positive)

Pseudomonas aeruginosa

Osteomyelitis

S. aureus (methicillin sensitive)

S. Aureus (methicillin resistant) and S. epidermidis (methicillin resistant)

Streptococcus pyogenes, Streptococcus agalactiae, and other penicillin sensitive streptococci

Recommended Antimicrobial Therapy*†

Alternatives: Vancomycin 15 mg/kg IV q12h for 2 wk plus gentamicin 1 mg/kg IM/IV q8h for 2 wk or linezolid 600 mg IV/PO q12h monotherapy for 2 wk Ceftriaxone 2 g IV q24h for 2 wk Alternatives: Ciprofloxacin 400 mg IV q12h or 500 mg PO bid or other fluoroquinolone for 2 wk|| Penicillin G 2 MU IV q4h for 2 wk Alternatives: Ceftriaxone 2 g IV q24h for 2 wk Ampicillin 2 g IV q6h for 2 wk Alternatives: Cefuroxime 1.5 g IV q6-8h or SXT ‡ 15-20 mg/kg/d IV divided q6-8h for 2 wk Ceftriaxone 2 g IV q24h for 2 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q 6 to 8 h for 2 wk Piperacillin 4 g IV q6h for 2 wk +/− tobramycin 5-7 mg/kg IV daily for 2 wk Alternatives: Cefepime 2 g IV q12h or ceftazidime 1-2 g IV q8h for 2 wk plus aminoglycoside or ciprofloxacin 400 mg IV q8h or 750 mg PO bid for 2 wk Nafcillin 2 g IV q4-6h for 4-6 wk Alternatives: Cefazolin 2 g IV q8h or clindamycin 900 mg IV q8h or vancomycin 15 mg/kg IV q12h for 4-6 wk Vancomycin 15 mg/kg IV q12h for 4-6 wk Alternatives: SXT ‡ 15-20 mg/kg/d IV divided q6-8h plus rifampin 300 mg IV/PO q12h for 4-6 wk or linezolid 600 mg IV/PO q12h monotherapy for 6 wk Penicillin G 2 MU IV q4h or ampicillin 2 g IV q4h for 4-6 wk Alternatives: Cefazolin 2 g IV q8h or ceftriaxone 2 g IV q24h for 4-6 wk

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Penicillin allergy: Vancomycin 15 mg/kg IV q12h or clindamycin 900 mg IV q8h for 4-6 wk Enterococcus species Ampicillin 2 g IV q4h for 4-6 wk and Streptococcus plus gentamicin 1 mg/kg IV/IM species with MIC q8h for 1-2 wk > 0.5 mcg/mL Alternatives: Vancomycin 15 mg/kg IV q12h for 4-6 wk plus (optional) gentamicin 1 mg/kg IV/IM q8h for 1-2 wk Escherichia coli, Proteus Ceftriaxone 2 g IV q24h for 4-6 wk mirabilis, Klebsiella Alternatives: species Ciprofloxacin 750 mg PO q12h or levofloxacin 750 mg PO q24h for 4-6 wk E. coli and Klebsiella Imipenem/cilastatin 500 mg IV q6h species (ESBLor meropenem 1 g IV q8h for producing bacteria) 4-6 wk or ertapenem 1 g IV q24h Alternatives: Based on susceptibility results Serratia marcescens Cefotaxime 2 g IV q6h +/− gentamicin 5 mg/kg/d divided up q8h or levofloxacin 500 mg IV/PO daily Alternatives: Ciprofloxacin 400 mg IV q12h or 500 mg PO q12h Pseudomonas Cefepime 2 g IV q12h for 4-6 wk aeruginosa Alternatives: Piperacillin 4 g IV q6h or imipenem/cilastatin 500 mg IV q6h or meropenem 1 g IV q8h or ciprofloxacin 400 mg IV q8h or 750 mg PO q12h for 4-6 wk Bacteroides fragilis Metronidazole 500 mg IV q6h for 4-6 wk Alternatives: Clindamycin 900 mg IV q8h for 4-6 wk; if a mixed infection, beta-lactam/beta-lactamase inhibitor§ combination or imipenem/cilastatin 500 mg IV q6h or meropenem 1 g IV q8h or ertapenem 1 g IV q24h (no Pseudomonas coverage) Peptostreptococcus Clindamycin 900 mg IV q8h species Alternatives: Penicillin G 2 MU IV q4h or metronidazole 500 mg IV q6h or beta-lactam/beta-lactamase inhibitors combination§ Continued

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Appendix Continued Disease

Etiology

CENTRAL NERVOUS SYSTEM Brain Abscess Paranasal sinuses (frontal lobe)

Streptococci species, Haemophilus species, anaerobes (Bacteroides species, Fusobacterium, anaerobic streptococci) Inner ear (otitis Streptococci species, media) and mastoid Haemophilus species, sinus Enterobacteriaceae, Bacteroides species, anaerobic streptococci Metastatic from a Staphylococci species, distant focus Streptococcus species, (endocarditis, enteric gram-negative urinary tract bacilli, P. aeruginosa, infection, intraanaerobes abdominal infection, lung infection)

Post-traumatic/postoperative

Staphylococci species, Streptococci species, enteric gram-negative bacilli, P. aeruginosa, Clostridium species

Acute Viral Encephalitis Common viral Arboviruses, causes enteroviruses, HSV-1, mumps

Less common and rare viral causes

Recommended Antimicrobial Therapy*†

Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h; 6-8 wk of parenteral antibiotic therapy has traditionally been recommended Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h

If source is: Endocarditis: Nafcillin 2 g IV q4h or vancomycin (15 mg/kg) q12h plus gentamicin 3-5 mg/kg IV q8-12h Pulmonary lesion: Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h. For Actinomycetes, add penicillin G 2-4 MU IV q4h. For Nocardia, add SXT ‡ 2-5 mg/kg PO q6h. Intra-abdominal infection: Metronidazole 500 mg IV q6h plus cefotaxime 1-2 g IV q4-8h or ceftriaxone 2 g IV q12h. For Enterococci species, add ampicillin 2 g IV q4h or vancomycin 15 mg/kg IV q12 h. Post-traumatic: Nafcillin 2 g IV q4h plus ceftriaxone 2 g IV q24h. For anaerobes, add metronidazole 500 mg IV q6h. Post-operative: Vancomycin 15 mg/kg IV q12h plus ceftazidime 1-2 g IV q8h.

For HSV encephalitis, start acyclovir 10 mg/kg IV q8h. For other causes of viral encephalitis, treatment is usually supportive care. CMV, EBV, HIV, measles, Treatment is usually supportive VZV, adenovirus, care. Colorado tick fever

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virus, influenza A, parainfluenza, LCMV, rabies, rubella Acute Bacterial Meningitis Age 7-50 years

Cefotaxime 75 mg/kg IV q4-8h (not to exceed 2 g q4-6h) or ceftriaxone 100 mg/kg IV q1224h (not to exceed 2 g q12h) plus vancomycin 15 mg/kg IV q6-12h plus dexamethasone 0.15 mg/kg IV q6h to be given 10-20 min before antibiotics. Age >50 years S. pneumoniae, Listeria Vancomycin 15 mg/kg IV q8-12h monocytogenes, gramplus ampicillin 2 g IV q4h plus negative rods (rare) cefotaxime 2 g IV q4-6h or ceftriaxone 2 g IV q12h Impaired cellular L. monocytogenes, gram- Ampicillin 2 g IV q4h plus immunity suspected negative rods ceftazidime 2 g IV q8h or (e.g., alcoholics, including cefepime 2 g IV q8h high-dose P. aeruginosa corticosteroid treatment) Head trauma, postS. Aureus, coagulaseVancomycin 15 mg/kg IV q6-12h neurosurgery, or negative staphylococci, (depending on the renal function; cerebrospinal fluid gram-negative bacilli children and young adults require shunt including more frequent dosing) plus P. aeruginosa, ceftazidime 2 g IV q8h S. pneumoniae Recurrent episodes S. pneumoniae (most Cefotaxime 75 mg/kg IV q4-8h (not common) to exceed 2 g q4-6h) or ceftriaxone 100 mg/kg IV q12-24h (not to exceed 2 g q12h) plus vancomycin 15 mg/kg IV q6-12h Acute Viral Meningitis Common viral causes Enteroviruses, Supportive care arboviruses, HIV, (Acyclovir for HSV-2) HSV-2 Less common and HSV-1, HSV-6, LCMV, Supportive care rare viral causes mumps, adenoviruses, (Acyclovir for HSV) CMV, EBV, influenza virus, parainfluenza type 3, measles, rubella, VZV Chronic Meningitis Tuberculous Mycobacterium See Chapter 25 for treatment tuberculosis recommendations. Fungal Cryptococcus Treatment depends on etiology; no neoformans, urgent need for empiric treatment Coccidioides immitis, (see Chapters 28 and 40). Histoplasma capsulatum S. pneumoniae, N. meningitidis

Continued

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876

Appendix

Appendix Continued Disease

Etiology

GASTROINTESTINAL SYSTEM Infectious Diarrhea and Gastroenteritis Shigellosis

Shigella species

Salmonellosis

Salmonella enteritidis

Campylobacteriosis

Campylobacter jejuni

E. coli: enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroinvasive (EIEC)

E. coli

E. coli: enterohemorrhagic (EHEC)

E. coli O157:H7, other enteric bacteria that produce Shiga-like toxin

Aeromonas/ Plesiomonas diarrhea

Aeromonas, Plesiomonas shigelloides

Antibiotic-associated diarrhea

Clostridium difficile

Recommended Antimicrobial Therapy*†

SXT ‡ 160/800 mg PO q12h for 3 d or a fluoroquinolone: ofloxacin 300 mg PO q12h for 3 d, norfloxacin 400 mg PO q12h for 3 d, or ciprofloxacin 500 mg PO q12h × 3 d Treatment is recommended for severe cases, for patients <6 months or >50 years of age, and for patient with prosthesis, valvular heart disease, severe atherosclerosis, malignancy, or uremia. Adults: SXT ‡ 160/800 mg PO q12h for 3 d (if susceptible) or a fluoroquinolone: norfloxacin 400 mg PO q12h for 5-7 d, ciprofloxacin 500 mg PO q12h for 5-7 d, or ofloxacin 200 mg PO q12h for 5-7 d Azithromycin 500 mg PO daily for 5 d or erythromycin stearate 500 mg PO qid for 5 d or a fluoroquinolone as above. SXT ‡ 160/800 mg PO q12h for 3 d or a fluoroquinolone: ciprofloxacin 500 mg PO q12h × 3 d, ofloxacin 300 mg PO q12h × 3 d, or norfloxacin 400 mg PO q12h × 3 d Antibiotic therapy has no established effect on duration of acute diarrhea, and certain antibiotics can increase the release of toxin. SXT‡ 160/800 mg PO q12h for 3 d or a fluoroquinolone: ciprofloxacin 500 mg PO q12h × 3 d, ofloxacin 300 mg PO q12h × 3 d, or norfloxacin 400 mg PO q12h × 3 d. Discontinue the offending agent. Metronidazole 500 mg/PO 98º; 500 mg IV q 6º for 10-14 d or vancomycin 125 mg PO qid for 10-14 d. Bacitracin has also been used.

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Yersiniosis

Cholera

Giardiasis

Amebiasis

Cryptosporidiosis

Isosporiasis

Microsporidiosis Cyclosporiasis

877

Antimicrobial therapy is not usually required except for severe infections or associated bacteremia. For severe cases, use combination of doxycycline, aminoglycoside, SXT ‡, or fluoroquinolone. Vibrio cholerae Doxycycline 300 mg PO as a single dose or tetracycline 500 mg PO qid for 3 d or SXT ‡ 160/800 PO bid for 3 d or fluoroquinolone PO as a single dose Giardia lamblia Metronidazole 250-750 mg PO q8h for 7-10 d or tinidazole 2 g PO as a single dose or nitazoxanide 500 mg PO q12h for 3 d Entamoeba histolytica • Metronidazole 750 mg PO q8h for 5-10 d plus diiodohydroxyquin 650 mg q8h for 20 d. • Paromomycin 500 mg PO tid for 10 d or tinidazole 2 g PO daily for 3 d Cryptosporidium species None in most cases. Consider paromomycin 500 mg PO q8h for 7 d for severe cases; in patients with AIDS give 14-28 d, then q12h indefinitely or nitazoxanide 500 mg PO q12h for 3 d. Isospora species SXT ‡ 160-800 mg PO q12h for 7-10 d; in patients with AIDS give 320-1600 mg PO q12h for 2-4 wk, then 160-800 mg PO once daily indefinitely. Microsporidium species Albendazole 400 mg PO q12h for 3 wk Cyclospora species SXT ‡ 160-800 mg PO q6h for 10 d; in patients with AIDS give 3201600 mg PO q12h for 2-4 wk, then 160-800 mg PO once daily indefinitely. Yersinia enterocolitica

Biliary Tract Infections Cholecystitis, cholangitis

Enterobacteriaceae, Enterococcus species, anaerobes (Bacteroides, Clostridium)

Single agents: Ampicillin/sulbactam 3 g IV q6h or piperacillin/ tazobactam 3.375 g IV q6h or cefoxitin 2 g IV q 6-8 h. Combination therapy: (1) Ciprofloxacin 400 mg IV q12h or cefotaxime 1-2 g IV q8h plus metronidazole 500 mg IV q8h (2) Aztreonam 2 g IV q8h plus clindamycin 900 mg IV q8h Continued

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Appendix

Appendix Continued Disease

Etiology

Recommended Antimicrobial Therapy*†

If severe or life-threatening: Imipenem/cilastatin 500 mg IV q6h or piperacillin/tazobactam 3.375 g IV q6h

Viral Hepatitis Hepatitis A

No specific therapy has been shown to be of benefit. If within 2 wk of exposure, gamma-globulin 0.02 mL/kg IM one time is protective. Entecavir 0.5-1.0 mg PO daily, lamivudine 100 mg PO daily, adefovir 10 mg PO daily, or pegylated interferon alpha-2a (Pegasys) 180 mcg SQ q wk or interferon alpha-2b (Peg-Intron) 1.5 mcg/kg SQ q wk for 1 year. If genotype 1: Ribavirin (if <75 kg: 400 mg PO q morning and 600 mg PO q evening, if >75 kg: 600 mg PO bid) plus pegylated interferon alpha-2a (Pegasys) 180 mcg SQ q wk or pegylated interferon alpha2b (PEG-Intron) 1.5 mcg/kg SQ q wk for 48 wk If genotype 2 or 3: Ribavirin 400 mg PO bid for 24 wk plus pegylated interferon alpha2a (Pegasys) 180 mcg SQ q wk or pegylated interferon alpha-2b (PEG-Intron) 1.5 mcg/kg SQ q wk for 24 wk. or ribavirin (if <75 kg: 400 mg PO q morning and 600 mg PO q evening, if >75 kg: 600 mg PO bid) plus standard interferon alpha-3 MU SQ three times a wk for 24 wk. No specific therapy has been shown to be of benefit. No specific therapy has been shown to be of benefit.

Hepatitis B

Hepatitis C

Hepatitis D Hepatitis E

Peritonitis Primary peritonitis

Secondary peritonitis

Enterobacteriaceae, S. pneumoniae, Enterococcus species, anaerobes Enterobacteriaceae, Bacteroides species,

Cefotaxime 2 g IV q8h or piperacillin-tazobactam 3.375 g IV q6h (if Enterococcus and/or anaerobes are suspected). Single agents: Ampicillin-sulbactam 3 g IV q6h (no

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Appendix

P. aeruginosa, Enterococcus species

Tertiary peritonitis

S. epidermidis, P. aeruginosa, Stenotrophomonas maltophilia, Candida species

879

Pseudomonas coverage) or piperacillin-tazobactam 3.375 g IV q6h IV Combination therapy: (1) Ertapenem 1 g q24h IV ± gentamicin 1.7 mg/kg IV q8h IV (2) Ciprofloxacin 400 mg IV q12h plus metronidazole 500 mg IV q8h Single agents: Imipenem-cilastatin 500 mg IV q6h or meropenem 1 g IV q8h (carbapenems have no activity against Stenotrophomonas maltophilia) Combination therapy: Cefepime 2 g IV q12h or ciprofloxacin 400 mg q12h IV plus vancomycin 15 mg/kg IV q12h

Intra-abdominal Abscess Liver abscess (pyogenic)

Anaerobes, Enterococcus Single agents: species, E. coli, Imipenem-cilastatin 500 mg IV q6h Klebsiella or meropenem 1 g IV q8h or pneumoniae, ertapenem 1 g IV d q24h (no Pseudomonas species, Pseudomonas coverage) or S. aureus, piperacillin-tazobactam 3.375 g IV Streptococcus viridans q6h or tigecycline 100 mg IV then 50 mg IV q12h (no Pseudomonas coverage) Combination therapy: (1) Ampicillin 1-2 g IV q6h plus gentamicin 1.5 mg/kg IV q8h plus metronidazole 500 mg IV q6h (2) Ceftazidime 2 g IV q8h or cefepime 2 g IV q12h plus metronidazole 500 mg IV q6h Penicillin allergy: Metronidazole 500 mg IV q6h plus ciprofloxacin 400 mg IV q12h (this combination lacks Streptococcus and Enterococcus coverage). Liver abscess (amebic) Entamoeba histolytica Metronidazole 750 mg PO tid for 7-14 d Splenic abscess E. coli, Salmonella Single agents: species, Ceftriaxone 2 g IV q24h or Staphylococcus levofloxacin 500 mg IV q24h species, Streptococcus Penicillin allergy: species Vancomycin 1 g IV q12h plus gentamicin 1.5 mg/kg IV q8h or Continued

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Appendix

Appendix Continued Disease

Pancreatic abscess

Appendiceal abscess

Diverticular abscess

Etiology

Recommended Antimicrobial Therapy*†

aztreonam 2 g IV q8h plus clindamycin 600-900 mg IV q8h Same as pyogenic liver abscess.

Bacteroides fragilis, Enterobacteriaceae, Enterococcus species, E. coli, K pneumoniae, P aeruginosa, S. aureus Bacteroides fragilis, Same as pyogenic liver E. coli, Peptostreptococcus species, P. aeruginosa Bacteroides fragilis, Single agents: E. coli Same as pyogenic liver cefoxitin 2 g IV q6h. Combination therapy: Same as pyogenic liver Penicillin-allergy: Same as pyogenic liver

abscess.

abscess or

abscess. abscess.

GENITOURINARY SYSTEM Common Sexually Transmitted Diseases Genital ulcers Chancroid

Haemophilus ducreyi

Herpes genitalis

Herpes simplex

Episodic recurrent herpes

Suppressive treatment

Granuloma inguinale (donovanosis)

Lymphogranuloma venereum

Chlamydia trachomatis

Azithromycin 1 g PO single dose or ceftriaxone 250 mg IM single dose or ciprofloxacin 500 mg PO bid for 3 d or erythromycin base 500 mg PO qid for 7 d Acyclovir 400 mg PO tid for 7-10 d or acyclovir 200 mg PO 5× daily for 7-10 d or famciclovir 250 mg PO tid for 7-10 d or valacyclovir 1 g PO bid for 7-10 d Acyclovir 400 mg PO bid for 5d or famciclovir 125 mg PO bid for 5d or valacyclovir 500 mg PO daily for 3d Acyclovir 400 mg PO bid or famciclovir 250 mg PO bid or valacyclovir 500 mg PO daily or 1000 mg PO daily (if > 9 recurrences/year) SXT ‡ 160/800 mg PO bid for a minimum of 3 wk or doxycycline 100 mg PO bid for a minimum of 3 wk Doxycycline 100 mg PO bid for 21 d

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Syphilis Primary/secondary

881

Treponema pallidum Penicillin G benzathine 2.4 MU IM single dose Alternative treatment: Doxycycline 100 mg PO bid for 2 wk or tetracycline 500 mg PO qid for 2 wk Penicillin G benzathine 2.4 MU IM single dose; consider giving another dose after 1 wk If patient is penicillin-allergic, treat with penicillin after desensitization. Do not give tetracyclines in pregnant patients. Same as primary syphilis. Penicillin G benzathine 2.4 MU IM weekly × 3 doses Alternative treatment: Doxycycline 100 mg PO bid for 4 wk or tetracycline 500 mg PO qid for 4 wk Penicillin G 18-24 MU IV (in 4-6 divided doses) daily for 10-14 d monotherapy or penicillin G procaine 2.4 MU IM daily plus probenecid 500 mg PO qid for 10-14 d. Penicillin G 100,000-150,000 U/kg/d (two divided doses for the first 7 d, three divided doses thereafter) for 10-14 d or penicillin G procaine 50,000 U/kg/d IM daily for 10-14 d If patient is penicillin allergic, treat with penicillin after desensitization.

Primary/secondary syphilis in pregnancy

Early latent Late latent, or latent of unknown duration, and late syphilis

Neurosyphilis

Congenital syphilis

Syphilis in HIV Primary, secondary, and latent

Penicillin G benzathine 2.4 MU IM weekly times three doses If patient is penicillin allergic, treat with penicillin after desensitization.

Urethritis and cervicitis Nongonococcal Chlamydia, ureaplasma urethritis Chlamydia

Chlamydia trachomatis

Chlamydia in pregnancy

C. trachomatis

Recurrent and persistent urethritis

Trichomonas, ureaplasma

Azithromycin 1 g PO as a single dose or doxycycline 100 mg PO bid for 7 d Azithromycin 1 g PO as a single dose or doxycycline 100 mg PO bid for 7 d Erythromycin base 500 mg PO qid for 7 d or azithromycin 1 g PO as a single dose Metronidazole 2 g PO in a single dose plus erythromycin base Continued

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Appendix

Appendix Continued Disease

Etiology

Gonococcal infections Neisseria gonorrhoeae (uncomplicated; when urethritis is present, it is reasonable to presume that the patient is infected with both gonococcal and nongonococcal agents) GC conjunctivitis Disseminated GC

GC meningitis or endocarditis Pelvic inflammatory disease

Recommended Antimicrobial Therapy*†

500 mg PO qid for 7 d or erythromycin ethylsuccinate 800 mg PO qid for 7 d (Single dose preferred) Cefixime 400 mg PO single dose or ceftriaxone 125 mg IM single dose If Chlamydia infection is not ruled out, add azithromycin 1 g PO single dose or doxycycline 100 mg PO bid for 7 d.

Ceftriaxone 1 g IM single dose Intravenous regimen: Ceftriaxone 1 g IM/IV q24h or cefotaxime 1 g IV q8h Penicillin-allergic patients: Ciprofloxacin 400 mg IV q12h⎢⎢ or ofloxacin 400 mg IV q12h⎢⎢ or levofloxacin 250 mg IV daily or Then complete at least 7 d of therapy with cefixime 400 mg PO bid or ciprofloxacin 500 mg PO bid⎢⎢ or ofloxacin 400 mg PO bid⎢⎢ or levofloxacin 500 mg PO daily ⎢⎢. Ceftriaxone 1-2 g IV q12h ● Meningitis: 10-14 d ● Endocarditis at least 4 wk Inpatient regimen A: Cefoxitin 2 g IV q6h plus doxycycline 100 mg IV or PO q12h Inpatient regimen B: Clindamycin 900 mg IV q8h plus gentamicin 1.5 mg/kg IV/IM q8h plus doxycycline Alternative regimen: Ofloxacin 400 mg IV q12h or levofloxacin 500 mg IV daily plus metronidazole 500 mg IV q8h or ampicillin/sulbactam 3 g IV q6h plus doxycycline 100 mg IV or PO q12h. Outpatient regimen A: Metronidazole 500 mg PO bid for 14 d plus ofloxacin 400 mg PO

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883

bid for 14 d or levofloxacin 500 mg PO daily for 14 d Outpatient regimen B: Cefoxitin 2 g IM single dose plus probenecid 1 g PO single dose or Ceftriaxone 250 mg IM in a single dose or other third-generation cephalosporin plus doxycycline 100 mg PO bid for 14 d with or without metronidazole 500 mg PO bid for 14 d Urinary Tract Infection Acute bacterial cystitis E. coli, (consider local resistance to SXT or fluoroquinolones) other gram-negative enteric bacteria, Staphylococcus saprophyticus

Acute pyelonephritis

Prostatitis Acute bacterial prostatitis

Chronic bacterial prostatitis

E. coli, (consider local resistance to SXT or fluoroquinolones) other gram-negative enteric bacteria

SXT ‡ 160/800 mg PO bid for 3 d (use with caution in pregnancy) or ciprofloxacin 500 mg PO q12h for 3 d (not recommended in pregnancy) or levofloxacin 250 mg PO q24h for 3 d (not recommended in pregnancy) or nitrofurantoin 100 mg PO qid for 7 d or cephalexin 500 mg PO qid for 7 d (ineffective for enterococci) SXT ‡ DS 160/800 mg PO q12h for 14 d or ciprofloxacin 500 mg PO q12h for 7 d or levofloxacin 500 mg PO q24h for 7 d or cephalexin 500 mg PO qid for 14 d Hospitalized patients (empiric therapy): Ampicillin 2 g IV q6h plus gentamicin 5 mg/kg IV q24h or ceftriaxone 1 g IV q24h or imipenem/cilastatin 500 mg IV q6h or piperacillin/ tazobactam 3.375 g IV q6h Each of the above regimens is given for 2-4 days; switch to oral therapy when susceptibility results are available.

Enterobacteriaceae Parenteral antibiotic: Ciprofloxacin (E. coli most common) or levofloxacin or SXT ‡ or doxycycline or penicillin plus aminoglycoside followed by oral antimicrobial for a total of 3-6 wk Enterobacteriaceae Ciprofloxacin 500 mg PO bid or (including Klebsiella, levofloxacin 500 mg PO q24h for Serratia, 4-6 wk or SXT ‡ 160/800 mg PO Pseudomonas, and bid for 1-3 months Proteus species), Enterococcus species Continued

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884

Appendix

Appendix Continued Disease

Etiology

Chronic abacterial prostatitis

Unknown; Chlamydia and ureaplasma are possible

Epididymitis Epididymo-orchitis Gonococci, Chlamydia (sexually transmit(heterosexual) ted, age <35 years) Epididymo-orchitis Enteric organisms, (nonsexually urinary pathogens transmitted, age >35 years) Vaginitis and Vaginosis Bacterial vaginosis

Trichomononiasis

Moniliasis

Recommended Antimicrobial Therapy*†

Doxycycline 100 mg PO bid for 2 wk or erythromycin for 2 wk

Ceftriaxone 250 mg IM in a single dose plus doxycycline 100 mg PO bid for 10 d Ofloxacin 300 mg PO bid for 10-14 d or ciprofloxacin 500 mg PO bid for 10-14 d

Metronidazole 800 to 1200 mg/d PO for 1 wk or metronidazole 2 g PO single dose Topical therapy: Metronidazole gel 0.75% for 5 d or clindamycin 2% once daily for 7 d Trichomonas vaginalis Metronidazole 500 mg PO bid for 7 d or metronidazole 2 g PO single dose Candida albicans, Fluconazole 150 mg PO single dose non-albicans Candida or ketoconazole 400 mg PO bid for 5 d or itraconazole 200 mg PO daily for 3 d (or bid for 1 d) Topical therapy: See Chapter 17.

HEART AND VASCULAR INFECTIONS Endocarditis Streptococcus viridans Streptococcus viridans, and Streptococcus Streptococcus bovis bovis with MIC ≤ 0.12 µg/mL

Native valve: Preferred: Penicillin G 12-18 MU IV/24 h either continuously or in 4-6 equally divided doses for 4 wk or ceftriaxone 2 g IV/IM q24h for 4 wk Alternative: Penicillin G 12-18 MU/24 h either continuously or in 6 equally divided doses for 2 wk plus gentamicin 3 mg/kg IV/IM q24h for 2 wk or ceftriaxone 2 g IV/IM q24h for 2 wk plus gentamicin 3 mg/kg IV/IM q24h for 2 wk For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 4 wk

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885

Prosthetic valve: Preferred: Penicillin G 24 MU/24 h IV either continuously or in 4-6 equally divided doses for 6 wk with or without gentamicin 3 mg/kg IV/IM q24h for 2 wk or ceftriaxone 2 g IV/IM q24h for 6 wk with or without gentamicin 3 mg/kg IV/IM q24h for 2 wk For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 6 wk Streptococcus viridans Streptococcus viridans, Native valve: and Streptococcus Streptococcus bovis Preferred: bovis with MIC Penicillin G 24 MU/24 h IV either continuously or in 4-6 equally ≥ 0.12 µg/mL to divided doses for 4 wk plus < 0.5 µg/mL gentamicin 3 mg/kg IV/IM q24h for 2 wk Or ceftriaxone 2 g IV/IM q24h for 4 wk plus gentamicin 3 mg/kg IV/IM q24h for 2 wk. For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 4 wk Prosthetic valve: Preferred: Penicillin G 24 MU/24 h IV either continuously or in 4-6 equally divided doses for 6 wk plus gentamicin 3 mg/kg IV/IM q24h for 6 wk Or ceftriaxone 2 g IV/IM q24h for 6 wk plus gentamicin 3 mg/kg IV/IM q24h for 6 wk. For patients intolerant of penicillins and cephalosporins: Vancomycin 15 mg/kg IV q12h for 6 wk Enterococci, E. faecalis, Enterococcus Native valve: streptococci with faecium Ampicillin 2 g IV q4h for 4-6 wk MIC > 0.5 µg/mL or penicillin G 24 MU/24 h IV continuously or in 6 equally divided doses plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 4-6 wk Penicillin-resistant organism, or penicillin allergy: Vancomycin 15 mg/kg IV q12h plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 6 wk. Continued

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Appendix

Appendix Continued Disease

Etiology

Other streptococci

Group A, B, C, G streptococci or S. pneumoniae

Staphylococci

S. aureus, coagulasenegative Staphylococcus

Recommended Antimicrobial Therapy*†

Prosthetic valve: Ampicillin 2 g IV q4h for 6 wk or penicillin G 24 MU/24 h IV continuously or in 6 equally divided doses plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 6 wk Penicillin-resistant organism, or penicillin allergy: Vancomycin 15 mg/kg IV q12h plus gentamicin 1 mg/kg IV q8h or streptomycin 7.5 mg/kg (not to exceed 500 mg) q12h for 6 wk Preferred: Penicillin G 2-3 MU IV q4h for 4 wk or ceftriaxone 2 g IV q24h for 4 wk Penicillin allergy: Vancomycin 15 mg/kg IV q12h for 4 wk (adjust dose in renal dysfunction) Staphylococcal (methicillinsensitive) native valve endocarditis: Preferred: Nafcillin or oxacillin 2 g IV q4h for 6 wk (optional, add gentamicin 1 mg/kg IV q8h for 3-5 d in seriously ill patients) For non-IgE mediated penicillin allergic patients: Cefazolin 2 g IV q8h for 6 wk For IV drug users with uncomplicated righ-sided endocarditis: Nafcillin or oxacillin 2 g IV q4h plus gentamicin 1 mg/kg IV q8h for 2 wk Staphylococcal (methicillin-resistant) native valve endocarditis or penicillin allergy: Vancomycin 15 mg/kg IV q12h for 6 wk Staphylococcal (methicillinsensitive) prosthetic valve endocarditis: Nafcillin or oxacillin 2 g IV q4h for ≥ 6 wk plus rifampin 900 mg/ 24 h in 3 divided doses for ≥6 wk

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Appendix

HACEK microorganisms

Culture-negative endocarditis

Vascular Infections Mycotic aneurysm (infective endocarditis associated aneurysm)

Mycotic aneurysm (atherosclerotic vessel associated aneurysm and trauma-related false aneurysm) Vascular graft infection

Intravenous-line infection

887

plus gentamicin 1 mg/kg IV/IM q8h for 2 wk Staphylococcal (methicillin-resistant) prosthetic valve endocarditis or penicillin allergy: Vancomycin 15 mg/kg IV q12h for ≥6 wk plus rifampin 900 mg/24 h in 3 divided doses for ≥6 wk plus gentamicin 1 mg/kg IV/IM q8h for 2 wk. Haemophilus Native valve: aphrophilus/ Ceftriaxone 2 g IV/IM q24h for paraphrophilus, 4 wk or ampicillin/sulbactam 3 g Actinobacillus IV q6h for 4 wk or ciprofloxacin actinomycetemcomi400 mg IV q12h or 500 mg PO tans, Cardiobacterium q12h for 4 wk hominis, Eikenella Prosthetic valve: corrodens, Kingella Ceftriaxone 2 g IV/IM q24h for kingii 6 wk or ampicillin/sulbactam 3 g IV q6h for 6 wk or ciprofloxacin 400 mg IV q12h or 500 mg PO q12h for 6 wk Rule out other agents Treatment recommendation same as by culture or serology enterococcal endocarditis. for fungi, Chlamydia, Bartonella, Brucella, Coxiella Usually Staphylococcus species or Streptococcus species

Salmonella, Staphylococcus species, others

Staphylococcus species

Staphylococcus species

Based on culture and susceptibility testing, antimicrobial therapy for at least 4-6 wk. Surgical excision with extensive local debridement. Duration of antimicrobial therapy is similar to infective endocarditis. Based on culture and susceptibility testing, antimicrobial therapy for at least 4-6 wk. Surgical excision with extensive local debridement.

Based on culture and susceptibility testing, antimicrobial therapy for at least 4-6 wk. Surgical excision with extensive local debridement when abscess and necrotic areas are found. Based on culture and susceptibility testing, antimicrobial therapy for at least 2-6 wk. Remove catheter if due to S. aureus. Start vancomycin 15 mg/kg IV q12h before susceptibility results are available. Continued

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Appendix

Appendix Continued Disease

Septic Phlebitis Cavernous sinus

Lateral sinus

Sagittal sinus Cortical

Internal jugular vein

Great vein Pelvic veins, pylephlebitis

Peripheral

Etiology

S. aureus (70%), group A streptococci, Streptococcus pneumoniae, gramnegative bacilli, anaerobes Group A streptococci, S. aureus, Bacteroides, Proteus mirabilis, E. coli S. aureus, group A streptococci S. pneumoniae, Haemophilus influenzae, Neisseria meningitis S. aureus, gram-negative bacilli, Candida species

Recommended Antimicrobial Therapy*†

Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h (or cefotaxime 2 g IV q4-6h) plus metronidazole 500 mg IV q6h.

Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h (or cefotaxime 2 g IV q4-6h) plus metronidazole 500 mg IV q6h. Vancomycin 15 mg/kg IV q12h.

Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h. If brain abscess or sinus source, add metronidazole 500 mg IV q6h. Vancomycin 15 mg/kg IV q12h plus ceftriaxone 2 g IV q12h. If Candida suspected, add amphotericin B 0.6-1.0 mg IV q24h. S. aureus, gram-negative Vancomycin 15 mg/kg IV q12h plus bacilli ceftriaxone 2 g IV q12h. S. aureus, gram-negative • Ampicillin/sulbactam 3 g IV q6h aerobic rods, or ticarcillin/clavulanate 3.1 g IV anaerobes q6h or (Bacteroides fragilis), • Piperacillin/tazobactam 3.375 g microaerophilic IV q6h or imipenem/cilastatin streptococci 500 mg IV q6h or meropenem 1 g IV q8h plus an optional aminoglycoside (gentamicin or tobramycin 3-5 mg/kg IV in single or divided doses) or • Metronidazole 500 mg IV q6h plus gentamicin or tobramycin 1.5 mg/kg IV q8h S. aureus, group A Vancomycin 15 mg/kg IV q12h. Add streptococci an aminoglycoside if patient had prolonged hospitalization or prior antimicrobial agents.

IMMUNOCOMPROMISERELATED INFECTIONS HIV Infection

Preferred regimens (as recommended by Department of Health and Human Services guidelines, 4 May 2006): • Efavirenz 600 mg PO q h plus lamivudine 150 mg PO bid or

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889

emtricitabine 200 mg PO daily plus zidovudine 300 mg PO bid or tenofovir 300 mg PO daily or • Lopinavir/ritonavir 400/100 mg PO bid plus lamivudine 150 mg PO bid or emtricitabine 200 mg PO daily plus zidovudine 300 mg PO bid AIDS and Opportunistic Infections Pneumocystis jiroveci pneumonia (PCP) Acute therapy

Chronic maintenance

Preferred: SXT ‡ 15-20 mg/kg/d IV or PO q6-8h for 21 d. Alternative therapy for mild-tomoderate PCP: Dapsone 100 mg PO daily and TMP 15-20 mg/kg/d in 3 divided doses for 21 d or primaquine 15-30 mg (base) PO daily and clindamycin 300-450 mg orally q6-8h for 21 d or atovaquone 750 mg PO bid with food for 21 d Alternative therapy for severe PCP: Pentamidine 4 mg/kg IV daily infused over at least 60 min for 21 d or clindamycin 600-900 mg IV q8h and primaquine base 1530 mg/d orally for 21 d or trimetrexate 45 mg/m2 or 1.2 mg/kg IV daily with leucovorin 20 mg/m2 or 0.5 mg/kg IV or PO q6h (leucovorin must be administered for 3 d after the last dose of trimetrexate) for 21 d Preferred: SXT ‡ 160/800 mg PO daily or 80/400 mg PO daily Alternatives: SXT ‡ 160/800 mg PO three times a wk or dapsone 50 mg PO bid or 100 mg PO daily or dapsone 50 mg PO daily plus pyrimethamine 50 mg PO weekly plus leucovorin 25 mg PO weekly or dapsone 200 mg PO weekly plus pyrimethamine 75 mg PO weekly plus leucovorin 25 mg PO weekly or aerosolized pentamidine 300 mg nebulized monthly or atovaquone 1500 mg PO daily Continued

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890

Appendix

Appendix Continued Disease

Cerebral toxoplasmosis Acute therapy

Chronic maintenance

Cryptococcal meningitis

Etiology

Recommended Antimicrobial Therapy*†

First-line therapy: Pyrimethamine 200 mg PO × 1 dose, then 50-100 mg PO daily and sulfadiazine 1-2 g PO q6h plus leucovorin 10 mg PO daily for at least 6 wk Alternative therapy: Pyrimethamine 200 mg PO × 1 dose, then 50-100 mg PO daily plus leucovorin 10 mg PO daily plus one of the following: clindamycin 600 mg IV q6h or 300-450 mg PO q6h or azithromycin 1200-1500 mg/d PO or clarithromycin 1 g PO bid or atovaquone 750 mg q 6 h. First-line therapy: Pyrimethamine 25-75 mg/d PO plus leucovorin 10-25 mg/d PO plus sulfadiazine 500-1000 mg PO qid Alternative therapy: Pyrimethamine 25-75 mg/d PO plus leucovorin 10-25 mg/d PO plus clindamycin 300-450 mg PO q6-8h Induction and consolidation: • Amphotericin B 0.7-1.0 mg/kg/d IV plus flucytosine 100 mg/kg/d for 2 wk, then fluconazole 400 mg/d for a minimum of 8 wk or • Amphotericin B 0.7-1.0 mg/kg/d IV plus flucytosine 100 mg/kg/d for 6-10 wk or • Amphotericin B 0.7-1.0 mg/kg/d for 14 d, then fluconazole 400 mg/d for 8-10 wk or • Amphotericin 0.7-1.0 mg/kg/d IV for 6-10 wk or If CSF cryptococcal antigen <1:1024 and normal mental status, consider: • Fluconazole 400-800 mg/d for 10-12 wk or • Itraconazole 400 mg/d for 10-12 wk or • Fluconazole 400-800 mg/d plus flucytosine 100-150 mg/kg/d for 6 wk or

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Appendix

Cytomegalovirus retinitis

Mycobacterium-avium complex (MAC)

891

• AmBisome 3-6 mg/kg/d IV for 6-10 wk Maintenance: • Fluconazole 200-400 mg PO daily for life or • Itraconazole 200 mg PO bid for life or • Amphotericin B 1 mg/kg IV 1-3 times per wk for life Induction therapy: • Ganciclovir 5 mg/kg IV q12h for 14-21 d or • Valganciclovir 900 mg PO bid for 21 d or • Foscarnet 90 mg/kg IV q12h for 14-21 d Maintenance: • Ganciclovir 5 mg/kg IV daily or • Valganciclovir 900 mg PO daily or • Foscarnet 90-120 mg/kg/d IV daily Preferred (at least 2 drugs as initial therapy): • Clarithromycin 500 mg PO bid plus ethambutol 15 mg/kg PO daily • Consider adding rifabutin 300 mg PO daily for patients with advanced immunosuppression, high mycobacterial load, or in the absence of effective antiretroviral therapy: Alternative agent to clarithromycin: • Azithromycin 500-600 mg PO daily Alternative 3rd or 4th drug for severe disease: • Ciprofloxacin 500-750 mg PO bid or • Levofloxacin 500 mg PO daily or • Amikacin 10-15 mg/kg IV daily

RESPIRATORY TRACT INFECTIONS Acute Bronchitis and Acute Exacerbations of Chronic Bronchitis Acute tracheobronUsually viral chitis Acute exacerbation of H. influenzae, chronic bronchitis M. catarrhalis, without risk factors S. pneumoniae

No antibiotic therapy indicated Preferred: Azithromycin 500 mg PO d 1, then 250 mg PO daily for 4 d or azithromycin 500 mg PO daily for Continued

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892

Appendix

Appendix Continued Disease

Etiology

Acute exacerbation of H. influenzae, chronic bronchitis M. catarrhalis, with risk factors S. pneumoniae, (cardiac disease, ≥4 Klebsiella species and exacerbations per other gram-negative pathogens year, FEV1 < 50% predicted, home oxygen, chronic oral steroids, antibiotic use in previous 3 months) Chronic suppurative H. influenzae, bronchitis M. catarrhalis, S. pneumoniae, Klebsiella species, P. aeruginosa, and Enterobacteriaceae

Recommended Antimicrobial Therapy*†

3 d or clarithromycin 250-500 mg PO bid or telithromycin 800 mg PO daily or second- or thirdgeneration cephalosporin or amoxicillin 875 mg PO bid or doxycycline 100 mg PO bid or SXT ‡ 160/800 mg PO q12h Alternative: Levofloxacin 500 mg PO daily or gatifloxacin 400 mg PO daily or gemifloxacin 320 mg PO daily or moxifloxacin 400 mg PO daily Preferred: Levofloxacin 500 mg PO daily or gatifloxacin 400 mg PO daily or gemifloxacin 320 mg PO daily or moxifloxacin 400 mg PO daily or augmentin 875/125 mg PO bid Alternative: Patient may require parenteral therapy. Consider referral to specialist or hospital. Ambulatory patient: Levofloxacin 750 mg PO daily or ciprofloxacin 750 mg PO bid Hospital patient: Parenteral therapy usually required (antibiotic therapy should include activity against gram-negative pathogens including Pseudomonas).

Pharyngitis, Epiglottitis, and Other Upper Respiratory Infections Pharyngitis/tonsillitis Group A, C, G Penicillin VK 250 mg PO q6h for streptococci, “viral” 10 d, amoxicillin 250 mg PO q8h infectious mononuclefor 10 d, amoxicillin/clavulanate osis, Corynebacterium 875 mg PO q12h for 5 d, diphtheriae, cephalexin 250 mg q6-8 h for Arcanobacterium 10 d, cefuroxime axetil 250 mg haemolyticum, bid for 10 d, cefpodoxime Mycoplasma proxetil 100 mg bid for 10 d, pneumoniae azithromycin 500 mg PO × 1 dose, then 250 mg q24h for 3 d, clarithromycin 250 mg bid for 10 d, erythromycin base 500 mg PO qid for 10 d.

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Appendix

Epiglottitis

Sinusitis and Otitis Acute sinusitis

Chronic sinusitis

Otitis media

Otitis externa

Malignant otitis externa

Community-Acquired Pneumonia Outpatient treatment

893

Group A streptococci, H. influenzae

Ceftriaxone 2 g IV q24h or cefotaxime 2 g IV q4-8h or ampicillin/sulbactam 3 g IV q6h or piperacillin/tazobactam 3.375 g IV q6h or ticarcillin/clavulanate 3.1 g IV q4-6h or SXT‡ 8-10 mg/kg/d divided in q6-12h

S. pneumoniae, H. influenzae, S. aureus

Amoxicillin 1000 mg PO tid or amoxicillin-clavulanate XR 2000 mg PO bid or cefuroxime 250 mg PO bid or cefpodoxime 200-400 mg PO bid or clarithromycin 250500 mg PO bid or azithromycin 500 mg PO d 1, then 250 mg PO daily for 4 d or levofloxacin 750 mg PO daily or moxifloxacin 400 mg PO daily See Chapter 20 for treatment options.

S. pneumoniae, H. influenzae, S. aureus, anaerobes S. pneumoniae, Amoxicillin 1000 mg PO tid or H. influenzae, amoxicillin-clavulanate XR M. catarrhalis, 2000 mg PO bid or cefuroxime S. pyogenes, S. aureus, 250 mg PO bid or cefpodoxime P. aeruginosa 200-400 mg PO bid or clarithromycin 250-500 mg PO bid or azithromycin 500 mg PO d 1, then 250 mg PO daily for 4 d or levofloxacin 750 mg PO daily or moxifloxacin 400 mg PO daily S. epidermidis, S. aureus, Treatment usually local care. Use Corynebacterium systemic antibiotics if there are species, anaerobes signs of significant tissue involvement. P. aeruginosa Imipenem 500 mg IV q6h or meropenem 1 g IV q8h or ciprofloxacin 400 mg IV q12h or ceftazidime 2 g IV q8h or cefepime 2 g IV q12h or tobramycin plus piperacillin 4-6 g IV q 4-6 h or ticarcillin 3 g IV q4h

S. pneumoniae, M. pneumoniae, H. influenzae, C. pneumoniae, respiratory viruses

Clarithromycin 500 mg PO bid or clarithromycin XL 1000 mg QD QD PO bid or azithromycin 500 mg one time, then 250 mg PO daily for 4 d or doxycycline 100 mg PO bid or telithromycin 800 mg PO daily Continued

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894

Appendix

Appendix Continued Disease

Etiology

General medical floor S. pneumoniae, M. pneumoniae, C. pneumoniae, H. influenzae, Legionella species, “aspiration” respiratory viruses

Intensive care unit

S. pneumoniae, Legionella species, H. influenzae, P. aeruginosa, gramnegative bacilli, S. aureus

Recommended Antimicrobial Therapy*†

If risk factors present for drugresistant Streptococcus pneumoniae: Levofloxacin 750 mg PO daily or moxifloxacin 400 mg PO daily or gemifloxacin 320 mg PO daily or clarithromycin (or XL 1000 mg daily) 500 mg PO bid or Azithromycin 500 mg PO one time, then 250 mg PO daily for 4 d plus amoxicillin 1 g PO tid or Augmentin 875 mg PO bid Fluoroquinolone regimen: Levofloxacin 750 mg IV/PO daily or moxifloxacin 400 mg IV/PO daily or gemifloxacin 320 mg PO daily Macrolide regimen: Ceftriaxone 1 g IV daily or cefotaxime 1 g IV q8h plus azithromycin 500 mg IV/PO daily or clarithromycin 500 mg PO bid (or clarithromycin XL 1000 mg daily) If Pseudomonas not a consideration: Ceftriaxone 1-2 g IV q24h or cefotaxime 2 g IV q6h plus azithromycin 500 mg IV/PO q24h or levofloxacin 500-750 mg IV/PO q24h or moxifloxacin 400 mg IV/PO q24h or levofloxacin 750 mg q24h Beta-lactam allergy: Levofloxacin 750 mg IV/PO q24h or moxifloxacin 400 mg IV/PO q24h aztreonam 1-2 gm q8 hr If Pseudomonas a consideration: Piperacillin/tazobactam 4.5 g IV q6h or cefepime 1-2 g IV q8-12h or imipenem-cilastatin 500 mg IV q6h or meropenem 1 g IV q8h plus ciprofloxacin 400 mg IV q8h or levofloxacin 750 mg IV q24h or Piperacillin/tazobactam 4.5 g IV q6h or cefepime 1-2 g IV q8-12h or imipenem-cilastatin 500 mg IV q6h or meropenem 1 g IV q8h plus an aminoglycoside plus azithromycin 500 mg IV q24h or

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Appendix

895

levofloxacin 750 mg IV q24h or moxifloxacin 400 mg IV q24h Beta-lactam allergy: Aztreonam 1-2 g IV q8h plus levofloxacin 750 mg IV q24h or moxifloxacin 400 mg IV q24h with aminoglycoside Hospital-Acquired Pneumonia Early onset (<5 days)

Late onset (>5 days)

Tuberculosis

Fungal Infections Aspergillosis

Ceftriaxone 2 g IV q24h or levofloxacin 750 mg IV q24h or moxifloxacin 400 mg IV q24h or ciprofloxacin 400 mg IV q8h or ampicillin-sulbactam 3 g IV q6h or ertapenem 1 g IV q24h P. aeruginosa, Piperacillin/tazobactam 4.5 g IV q6h Enterobacter species, or Cefepime 1-2 g IV q8-12h or Acinetobacter species, ceftazidime 2 g IV q8h or K. pneumoniae, imipenem/cilastatin 500 mg IV S. marcescens, E. coli, q6h or meropenem 1 g IV q8h other gram-negative plus ciprofloxacin 400 mg IV q8h bacilli, S. aureus or levofloxacin 750 mg IV q24h (MRSA) or an aminoglycoside plus linezolid 600 mg IV q12h or vancomycin 15 mg/kg IV q12h Mycobacterium First-line agents: (see Chapter 25 tuberculosis for specific regimens) • Isoniazid • Rifampin • Pyrazinamide • Ethambutol • Streptomycin Second-line agents: • Cycloserine 10-15 mg/kg/d (max dose,1000 mg) • Ethionamide 15-20 mg/kg/d (max dose, 1000 mg) • Amikacin 15 mg/kg/d (max dose, 1000 mg) • Kanamycin 15 mg/kg/d (max dose, 1000 mg) • Capreomycin 15 mg/kg/d (max dose, 1000 mg) • p-Aminosalicylic acid (PAS) 200 mg/kg/d (max dose, 12 g) • Levofloxacin 500-750 mg/d • Moxifloxacin 400 mg/d • Gatifloxacin 400 mg/d

S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus

First-line therapy: • Voriconazole 6 mg/kg IV q12h for 2 doses, then 4 mg/kg IV q12h or 400 mg PO bid for Continued

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896

Appendix

Appendix Continued Disease

Etiology

Recommended Antimicrobial Therapy*†

2 doses, then 200 mg PO bid or amphotericin B 0.8-1.25 mg/kg IV daily Second-line therapy: • Caspofungin 70 mg IV loading dose, then 50 mg IV daily or • Itraconazole 200 mg tid for 4 d, then 200 mg bid PO or • AmBisome 1-5 mg/kg IV daily or • Abelcet 5 mg/kg IV daily or • Amphotec 4-6 mg/kg IV daily Blastomycosis Mild-to-moderate pulmonary disease

Severe pulmonary disease

Mild-to-moderate disseminated disease

Severe disseminated disease

Central nervous system

First-line therapy: Itraconazole 200-400 mg/d Second-line therapy: Fluconazole 800 mg/d. First-line therapy: AmBisome 3-5 mg/kg/d IV or Abelcet 5 mg/kg/d IV until stable, then change to Itraconazole 400 mg/d. Second-line therapy: Amphotericin B 0.7-1 mg/kg/d IV until stable, then change to Itraconazole 400 mg/d. First-line therapy: Itraconazole 200-400 mg/d Second-line therapy: Fluconazole 800 mg/d First-line therapy: AmBisome 3-5 mg/kg/d IV or Abelcet 5 mg/kg/d IV until stable, then change to itraconazole 400 mg/d Second-line therapy: Amphotericin B 0.7-1 mg/kg/d IV until stable, then change to itraconazole 400 mg/d First-line therapy: AmBisome 3-5 mg/kg/d IV or Abelcet 5 mg/kg/d IV, total dose unknown. Consider long-term therapy with fluconazole 400 mg/d or itraconazole 400 mg/d. Second-line therapy: Amphotericin B 0.7-1 mg/kg/d, total dose of 2 g. Consider long-term therapy with fluconazole 800 mg/d or itraconazole 400 mg/d

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Appendix

Candidemia

Coccidioidomycosis Mild-to-moderate pulmonary disease (cavitary or localized)

Severe pulmonary disease (diffuse or progressive cavitary)

Disseminated (mildto-moderate)

Disseminated (severe)

Central nervous system

897

• Fluconazole 800 mg loading dose, then 400 mg IV or PO daily • Anidulafungin 200 mg IV day one, then 100 mg daily or • Caspofungin 70 mg IV loading dose, then 50 mg IV daily or • Voriconazole 6 mg/kg IV q12h loading dose, then 3 mg/kg IV or PO q12h or • Amphotericin B 0.7 mg/kg IV daily or • AmBisome 3-5 mg/kg IV daily or • Abelcet 3-5 mg/kg IV daily First-line therapy: Fluconazole 400 mg/d or itraconazole 400 mg/d Second-line therapy: Amphotericin B 0.7 mg/kg/d IV or AmBisome 3-5 mg/kg/d IV or Abelcet 5 mg/kg/d IV First-line therapy: AmBisome 3-5 mg/kg/d IV or Abelcet 5 mg/kg/d IV until stable then change to itraconazole 400 mg/d or fluconazole 400 mg/d. Second-line therapy: Amphotericin B 0.7 mg/kg/d IV until stable, then change to itraconazole 400 mg/d or fluconazole 400 mg/d First-line therapy: Itraconazole 400 mg/d or fluconazole 400 mg/d Second-line therapy: Amphotericin B 0.7 mg/kg/d IV or AmBisome 3-5 mg/kg/d IV or Abelcet 5 mg/kg/d. First-line therapy: AmBisome 3-5 mg/kg/d or Abelcet 5 mg/kg/d until stable, then change to itraconazole 400 mg/d or fluconazole 400 mg/d. Second-line therapy: Amphotericin B 0.7-1 mg/kg/d IV until stable, then change to itraconazole 400 mg/d or fluconazole 400 mg/d. First-line therapy: Fluconazole 800 mg/d Second-line therapy: Amphotericin B intrathecal or itraconazole 400 mg/d. Continued

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Appendix

Appendix Continued Disease

HIV-infected patients Pregnant patients Histoplasmosis (pulmonary) Mild-to-moderate

Severe diffuse

Chronic cavitary

Granulomatous mediastinitis

Fibrosing mediastinitis Pericarditis

Histoplasmosis (disseminated) Mild-to-moderate (acute, chronic)

Severe (acute, chronic)

Etiology

Recommended Antimicrobial Therapy*†

Lifelong suppressive therapy with fluconazole or itraconazole Amphotericin B 0.6-1.0 mg/kg/d IV

First-line therapy: Itraconazole 200-400 mg/d Second-line therapy: Fluconazole 800 mg/d First-line therapy: AmBisome 3-5 mg/kg/d or Abelcet 5 mg/kg/d until stable, then change to itraconazole 200 mg bid. Second-line therapy: Amphotericin B 0.7 mg/kg/d until stable, then change to itraconazole 200 mg bid. First-line therapy: Itraconazole 200 mg bid Second-line therapy: Fluconazole 800 mg/d or amphotericin B 0.7 mg/kg/d or lipid amphotericin formulation 3-5 mg/kg/d First-line therapy: Itraconazole 200 mg bid Second-line therapy: Amphotericin B 0.7 mg/kg/d or lipid amphotericin formulation 3-5 mg/kg/d Itraconazole 200 mg bid (no evidence for effectiveness) First-line therapy: Nonsteroidal anti-inflammatory agents Second-line therapy: Corticosteroids

First-line therapy: Itraconazole 200 mg bid Second-line therapy: Fluconazole 800 mg/d First-line therapy: AmBisome 3-5 mg/kg/d or Abelcet 5 mg/kg/d until stable, then change to itraconazole 200 mg bid.

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899

Second-line therapy: Amphotericin B 0.7 mg/kg/d until stable, then change to itraconazole 200 mg bid. First-line therapy: AmBisome 3-5 mg/kg/d or Abelcet 5 mg/kg/d until stable, then change to itraconazole 200 mg bid or fluconazole 800 mg/d Second-line therapy: Amphotericin B 0.7-1 mg/kg/d until stable, then change to itraconazole 200 mg bid or fluconazole 800 mg/d

Central nervous system

Viral Respiratory Infections, Including Influenza Herpesviruses Herpes simplex virus (HSV) Varicella-zoster virus (VZV)

Acyclovir 5-10 mg/kg IV q8h Acyclovir 10-12 mg/kg IV q8h for 7-10 d. For patients at high risk for complications of varicella, VZIG can decrease risk of infection or severity of illness substantially if administered within 96 h of exposure. Ganciclovir 5 mg/kg IV q12h for 21 d, followed by oral valganciclovir 900 mg PO daily or ganciclovir 5 mg/kg IV daily

Cytomegalovirus (CMV)

Paramyxoviruses Respiratory syncytial virus (RSV) Human metapneumovirus Parainfluenza Measles virus Influenza virus

Supportive care. No proven therapy. Supportive care. No proven therapy. Supportive care. No proven therapy. Supportive care. No proven therapy. For influenza A and B: Oseltamivir 75 mg PO bid for 5 d or zanamivir two inhalations (2 × 5 mg) bid for 5 d. Supportive care. No proven therapy. Supportive care. No proven therapy.

Adenovirus Hantavirus SKIN AND SOFTTISSUE INFECTIONS Superficial Bacterial Skin Infections Impetigo

Streptococcus pyogenes, S. aureus

Topical: Mupirocin, bacitracin Oral: Continued

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900

Appendix

Appendix Continued Disease

Cellulitis/Erysipelas

Folliculitis, furuncles, carbuncles

Etiology

Recommended Antimicrobial Therapy*†

Cloxacillin 250-500 mg PO q6h or dicloxacillin 250-500 mg PO q6h or cephalexin 250-500 mg PO q6h or cefadroxil 250-500 mg PO q12h or azithromycin 500 mg on day 1 followed by 250 mg/d or clarithromycin 500 mg PO q12h or clindamycin¶ 300 mg PO tid penicillin VK 250-500 mg PO bidqid (only if group A streptococci documented). The following if concern for CA-MRSA: SXT 1 DS PO bid (does not cover beta-hemolytic streptococci), minocycline 100 mg PO bid, or doxycycline 100 mg PO bid. Cellulitis: S. aureus, Oral: S. pyogenes, and other Cloxacillin 250-500 mg PO q6h or beta-hemolytic dicloxacillin 250-500 mg PO q6h streptococci; erysipelas: or cephalexin 250-500 mg PO usually S. pyogenes and q6h or cefadroxil 250-500 mg PO other beta-hemolytic q12h or azithromycin 500 mg on streptococci day 1 followed by 250 mg/d or clarithromycin 500 mg PO q12h or clindamycin¶ 300 mg PO tid or levofloxacin 500-750 mg PO daily or moxifloxacin 400 mg PO daily. Penicillin VK 250-500 mg PO bidqid (only if group A streptococci documented) The following if concern for CA-MRSA: SXT 1 DS PO bid (does not cover beta-hemolytic streptococci), or minocycline 100 mg PO bid, or doxycycline 100 mg PO bid. Intravenous: Nafcillin or oxacillin 0.5-2.0 g IV q4-6h or cefazolin 0.5-1.0 g IV q8h or cephalothin 0.5-2.0 g IV q4-6h Intravenous for MRSA: Vancomycin 15 mg/kg IV q12h or linezolid 600 mg IV q12h or daptomycin 4 mg/kg IV q24h S. aureus Warm saline compresses with or without topical antimicrobials are often sufficient for folliculitis.

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Appendix

Recurrent furunculosis

Check for nasal or perianal carrier of S. aureus

Whirlpool folliculitis

P. aeruginosa

Hidradenitis suppurativa

Acute: S. aureus; chronic: S. aureus, Enterobacteriaceae, Pseudomonas species, anaerobes

901

Incision and drainage with or without topical antimicrobial often suffices for furuncles. Oral: Cloxacillin 250-500 mg PO q6h or dicloxacillin 250-500 mg PO q6h or cephalexin 250-500 mg PO q6h or cefadroxil 250-500 mg PO q12h or clindamycin¶ 300 mg PO tid or levofloxacin 500-750 mg PO daily or moxifloxacin 400 mg PO daily Intravenous: Nafcillin or oxacillin 0.5-2.0 g IV q4-6h or cefazolin 0.5-1.0 g IV q8h or cephalothin 0.5-2.0 g IV q4-6h or clindamycin¶ 600-900 mg IV q8h Intravenous for MRSA: Vancomycin 15 mg/kg IV q12h or linezolid 600 mg IV q12h or daptomycin 4 mg/kg IV q24h If nasal culture positive, nasal mupirocin. Oral: Cloxacillin 250-500 mg PO q6h or dicloxacillin 250-500 mg PO q6h or cephalexin 250-500 mg PO q6h or cefadroxil 250-500 mg PO q12h or clindamycin¶ 300 mg PO tid The following if concern for CA-MRSA: Rifampin 300 mg PO bid plus SXT 1 DS PO bid (does not cover betahemolytic streptococci) or minocycline 100 mg PO bid or doxycycline 100 mg PO bid Self-limiting; treatment not necessary. Antistaphylococcal agents for MSSA or MRSA based on susceptibility. Empirical: Ampicillin-sulbactam 3 g IV q6h or ticarcillin-clavulanate 3.1 g IV q46h or piperacillin-tazobactam 3.375 g IV q6h or imipenem/ cilastatin 0.5-1.0 g IV q8h or cefoxitin 1-2 g IV q6h or clindamycin¶ 600-900 mg IV q8h plus ciprofloxacin 400 mg IV q8h or levofloxacin 750 mg IV daily Continued

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902

Appendix

Appendix Continued Recommended Antimicrobial Therapy*†

Disease

Etiology

Necrotizing Skin Infections

Staphylococcus species, Streptococcal infection: Streptococcus species, Preferred: Clostridium species, Penicillin G 2-4 MU IV q4-6h plus polymicrobial or clindamycin 600-900 mg mixed infection IV q8h Alternative: Cefotaxime 2 g IV q6h or ceftriaxone 1-2 g IV q24h plus clindamycin 600-900 mg IV q8h S. aureus infection: Nafcillin or oxacillin 1-2 g IV q4h or cefazolin 1 g IV q8h. If MRSA, vancomycin 15 mg/kg IV q12h or linezolid 600 mg q12h or daptomycin 4 mg/bg Q 24h Consider clindamycin¶ 600-900 mg IV q8h if CA-MRSA. Mixed infection: Ampicillin-sulbactam 1.5-3 g IV q6-8h, or piperacillin-tazobactam 3.375-4.5 g IV q6h or imipenem/ cilastatin 0.5-1.0 g IV q6-8h or meropenem 1 g IV q8h or ertapenem 1 g IV q24h (does not cover Pseudomonas) or cefotaxime 2 g IV q6h plus metronidazole 500 mg IV q6h or clindamycin¶ 600-900 mg IV q8h or clindamycin¶ 600-900 mg IV q8h plus ciprofloxacin 400 mg IV q12h or levofloxacin 750 mg IV q24h

Infected Ulcers and Diabetic Foot Infections Mild

Moderate-to-severe

Staphylococcus species, Streptococcus species

Staphylococcus species, Streptococcus species, Enterococcus species, Enterobacteriaceae, P. aeruginosa anaerobes

Dicloxacillin 500 mg PO q6h or clindamycin¶ 300 mg qid or cephalexin 500 mg PO q6h or SXT ‡ 160/800 mg PO bid or tid or amoxicillin-clavulanate 500/125 mg PO tid or 875/125 mg PO bid or levofloxacin 500-750 mg PO daily Oral: SXT ‡ 160/800 mg PO bid or tid or Amoxicillin-clavulanate 500/ 125 mg PO tid or 875/125 mg PO bid or levofloxacin 750 mg PO daily

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Appendix

903

Intravenous: Ceftriaxone 2 g IV daily or ampicillin-sulbactam 3 g IV q6h or ertapenem 1 g IV daily or piperacillin-tazobactam 3.375 g IV q6h or ticarcillin-clavulanate 3.1 g IV q6h or imipenem/cilastatin 500 mg IV q6h or meropenem 1 g IV q8h plus one of the following if MRSA is proven or likely: vancomycin 15 mg/kg IV q12h or linezolid 600 mg IV/PO q12h or daptomycin 4 mg/kg IV q24h Infected Bites (Human and Animal) Human Anaerobes, Staphylococcus species, alphahemolytic Streptococci, Eikenella corrodens

Cat

Oral: Monotherapy: Amoxicillin-clavulanate 500/125 mg PO tid or 875/125 mg PO bid or moxifloxacin 400 mg PO daily Combination therapy: Clindamycin 300 mg PO qid plus one of the following: ciprofloxacin 500-750 mg PO bid or levofloxacin 500-750 mg PO daily or SXT ‡ 160/800 mg PO bid or tid Intravenous: Monotherapy: Ampicillin-sulbactam 1.5-3 g IV q6h or cefoxitin 2 g IV q6h or ticarcillinclavulanate 3.1 g IV q6h or piperacillin-tazobactam 3.375 g IV q6h or imipenem-cilastatin 500-750 mg IV q6h or meropenem 1 g IV q8-12h or ertapenem 1 g IV q24h or moxifloxacin 400 mg IV daily Combination therapy: Clindamycin 600-900 mg IV q6h plus one of the following: ciprofloxacin 400 mg IV q12h or levofloxacin 500-750 mg IV q24h or SXT ‡ 160/800-320/1600 mg IV q8h Pasteurella multocida, Oral: Staphylococcus Monotherapy: species, Streptococcus Amoxicillin-clavulanate 500/125 mg species, aerobic PO tid or 875/125 mg PO bid or gram-negative bacilli moxifloxacin 400 mg PO daily or gatifloxacin 400 mg PO daily Combination therapy: Clindamycin 300 mg PO 3 or 4 times daily plus one of the following: ciprofloxacin 500-750 mg PO bid or levofloxacin 500-750 mg PO daily or SXT‡ Continued

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904

Appendix

Appendix Continued Disease

Dog

Etiology

Pasteurella canis, P. multocida, S. aureus, Streptococcus species, aerobic gram-negative bacilli, anaerobes

Recommended Antimicrobial Therapy*†

160/800 mg PO bid or tid or doxycycline 100 mg PO bid. or cefuroxime axetil 500 mg PO bid plus metronidazole 250-500 mg PO tid Intravenous: Monotherapy: Ampicillin-sulbactam 1.5-3 g IV q6h or ticarcillin-clavulanate 3.1 g IV q6h or piperacillin-tazobactam 3.375 g IV q6h or imipenemcilastatin 500 mg IV q6h or meropenem 1 g IV q8-12 h or ertapenem 1 g IV q24h or cefoxitin 2 g IV q6h or moxifloxacin 400 mg IV q24h Combination therapy: Clindamycin 600-900 mg IV q6h plus one of the following: ciprofloxacin 400 mg IV q12h or levofloxacin 500-750 mg IV q24h or SXT ‡ 160/800-320/1600 mg IV q8h Same as cat bite.

VIRAL INFECTIONS Herpesvirus Infections (Including CMV, EBV, VZV) Chickenpox

Herpes zoster

Epstein-Barr virus and infectious mononucleosis Cytomegalovirus

Acyclovir 10-12 mg/kg IV q8h for 5-7 d or acyclovir 800 mg PO 5 times daily for 5-7 d or valacyclovir 1000 mg PO tid for 5 d or famciclovir 500 mg PO tid Acyclovir 800 mg PO 5 times daily for 7 d or valacyclovir 1000 mg PO tid for 7 d or famciclovir 500 mg PO tid for 7 d Supportive care.

CMV infection in immunocompetent patient is rare. For treatment, see CMV under immunocompromiserelated infections.

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MISCELLANEOUS INFECTIONS Lyme Disease Erythema migrans

Doxycycline 100 mg PO bid for 14-21 d or tetracycline 250 mg PO qid for 14-21 d or amoxicillin 500 mg PO tid for 14-21 d or cefuroxime axetil 500 mg PO bid for 14-21 d or erythromycin 250 mg PO qid for 14-21 d or azithromycin 500 mg PO on first d, then 250 mg PO daily for 4 d Mild: Doxycycline 100 mg PO bid for 28 d or amoxicillin 500 mg PO tid for 28 d or cefuroxime axetil 500 mg PO bid for 28 d or erythromycin 250 mg PO qid for 28 d Severe: Ceftriaxone 2 g/d IV for 14-28 d or penicillin G 20-24 MU/d IV for 28 d Facial nerve palsy: Doxycycline 100 mg PO bid for 21-28 d or amoxicillin 500 mg PO tid for 21-28 d or cefuroxime axetil 500 mg PO bid for 21-28 d or erythromycin 250 mg PO qid for 21-28 d Severe neurological disease: Ceftriaxone 2 g/d IV for 14-28 d or cefotaxime 2 g IV q8h for 14-28 d or penicillin G 20-24 MU/d IV for 14-28 d Mild: Doxycycline 100 mg PO bid for 14-28 d or amoxicillin 500 mg PO tid for 14-28 d or cefuroxime axetil 500 mg PO bid for 14-28 d or erythromycin 250 mg PO qid for 14-28 d Severe: Ceftriaxone 2 g/d IV for 14-21 d or penicillin G 20-24 MU/d IV for 14-21 d

Arthritis

Neurological disease

Carditis

Ehrlichiosis and Anaplasmosis Treatment

Malaria Treatment

Doxycycline 100 mg IV or PO q12h for 5-14 d or tetracycline 500 mg PO q6h for 5-14 d or rifampin 300 mg PO q12h for 7 d Chloroquine-sensitive Plasmodium

• Chloroquine phosphate 1000 mg initially, followed by 500 mg in Continued

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Appendix

Appendix Continued Disease

Etiology

falciparum, P. vivax, P. ovale, and P. malaria

Chloroquine-resistant P. falciparum

Prophylaxis

Chloroquine-sensitive P. falciparum, P. vivax, P. ovale, and P. malaria Chloroquine-resistant P. falciparum

Recommended Antimicrobial Therapy*†

6 h, then 500 mg on days 2 and 3 plus primaquine phosphate 30 mg/d for 14 d • Atovaquone/proguanil 1 g/400 mg (4 tabs) PO daily for 3 d • Atovaquone/proguanil 1 g/400 mg (4 tabs) PO per d for 3 d • Quinine sulfate 650 mg PO tid for 3-7 d plus doxycycline 100 mg PO bid for 7 d • Quinine sulfate 650 mg PO tid for 3-7 d plus tetracycline 250 mg PO qid for 7 d • Quinine sulfate 650 mg PO tid for 3-7 d plus clindamycin 900 mg orally tid for 7 d • Mefloquine 750 mg PO initial dose followed by 500 mg PO 6-12 h later • Artesunate# 4 mg/kg/d PO for 3 d plus mefloquine 750 mg PO initial dose followed by 500 mg PO 6-12 h later Parenteral therapy: • Quinidine gluconate 10 mg/kg loading dose (maximum 600 mg) infused in normal saline over 1-2 h, then 0.02 mg/kg/min for 72 h • Quinine dihydrochloride# 20 mg salt/kg loading dose in D5W over 4 h, then 10 mg salt/kg over 2-4 h q 8 h (max dose, 1800 mg/d) for 72 h or until patient is able to take oral medication • Artemether # 3.2 mg/kg IM, then 1.6 mg/kg daily for 5-7 d • Chloroquine phosphate 500 mg PO per wk (begin 2 wk before exposure and continue for 6 wk after exposure) • Mefloquine 250 mg PO per wk (begin 1 wk before exposure and continue for 4 wk after exposure) • Doxycycline 100 mg PO daily (begin 2 d before exposure and continue for 28 d after exposure) • Chloroquine phosphate 500 mg PO per wk. (begin 2 wk before

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exposure and continue for 6 wk after exposure) plus proguanil 200 mg PO daily • Atovaquone/proguanil 1 tablet PO daily (begin 2 d before exposure and continue for 7 d after exposure) These recommendations have been taken from the text of this book. For more information, see appropriate chapter(s). Abbreviations: bid, twice daily; CA-MRSA, community-acquired methicillin-resistant S. aureus; CMV, cytomegalovirus; CSF, cerebrospinal fluid; d, day; EBV, Epstein-Barr virus; ESBL, extended-spectrum beta-lactamase; FEV1, forced expiratory volume at 1 second; h, hour; HSV, herpes simplex virus; IM, intramuscularly; IV, intravenously; LCMV, lymphocytic choriomeningitis virus; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; PO, orally; q, every; qid, four times daily; SQ, subcutaneously; SXT, sulfamethoxazole/trimethoprim; tid, three times daily; VZIG, varicella-zoster immunoglobulin; VZV, varicella-zoster virus; wk, week. * Suggested dosages are for adults and assume patients with normal renal function and hepatic function. In patients with renal or hepatic dysfunction, doses may have to be adjusted. † In pregnant patients, check appropriateness of the individual agent for use in pregnancy prior to prescribing. ‡ Trimethoprim-sulfamethoxazole. The recommended intravenous dosing of trimethoprim-sulfamethoxazole is based on the trimethoprim component. § Beta-lactam/beta-lactamase inhibitors are amoxicillin/clavulanate (no Pseudomonas coverage), ampicillin/sulbactam (no Pseudomonas coverage), piperacillin/tazobactam, and ticarcillin/clavulanate. ⎢⎢ Quinolone-resistant N. gonorrhoeae (QRNG) is prevalent in Asia, Australia, the Pacific Islands, England, Wales, Hawaii, and California, and in men who have sex with men. Quinolones are not recommended to be used in these settings. ¶ If a community-acquired methicillin-resistant Staphylococcus aureus isolate is resistant to erythromycin and positive for inducible resistance to clindamycin, then clindamycin should be avoided. # Not available in the United States.

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A Abdomen abscess of. See Abscess, intraabdominal pain in appendicitis-related, 212 diverticular abscess-related, 238 peritonitis-related, 207 splenic abscess-related, 229 urinary tract infection-related, 251 Abelcet as aspergillosis treatment, 572 as blastomycosis treatment, 524t Abscess Bezold, 379 dental, 651 diabetic foot infection-related, 669–670 hepatic, 159–160, 224–228 acute calculous cholecystitisrelated, 174 amebic, 159–160, 224, 226, 227, 228, 231t biliary tract infection-related, 173 as brain abscess cause, 92 cholangitis-related, 182 clinical manifestations of, 226 diagnosis of, 226–227 etiology of, 225 pyogenic, 224, 225, 226, 227–228, 231t treatment of, 227–228, 231t intra-abdominal, 223–241 antifungal prophylaxis for, 223 appendiceal, 231t, 235–237 candidiasis-related, 531 definition of, 223 diverticular, 231–232t, 237–239 etiology and pathogenesis of, 644, 647 hepatic, 224–228 as peritonitis cause, 215 polymicrobial, 644 retroperitoneal, 223 treatment of, 223, 231t, 879–880t

lateral pharyngeal, 375, 376t, 377, 379–381 myocardial, 116 of oral cavity, 365 pancreatic, 231t, 232–235 pericholecystic, 172, 176 perinephric, 258 as pyelonephritis risk factor, 260–261 peritonsillar (quinsy), 368, 375, 376t, 377, 378 perivascular, excision of, 133 prostatic, 271 pulmonary as brain abscess cause, 92 mycotic aneurysm-related, 128 renal cortical, 259 retropharyngeal, 368, 375, 376t, 377, 378–379 splenic, 229–230, 231t tubo-ovarian, 314, 317, 318, 322–323 Absorption, of drugs, 8 N-Acetylcysteine (NAC), 413 Acinetobacter, as nosocomial pneumonia cause, 490t Acquired immunodeficiency syndrome (AIDS). See also Human immunodeficiency virus (HIV) infection case definition of, 728, 728t, 729t CD4+ T lymphocyte count in, 760 definition of, 760 epidemic of, 723–724, 725–726, 726f opportunistic infections in, 760–776, 889–891t acalculous cholecystitis, 178 as AIDS-defining conditions, 762t candidiasis, 529 cerebral toxoplasmosis, 760, 765–767, 767t coccidioidomycosis, 542, 544, 547 cryptococcosis, 760, 768–770, 769t cytomegalovirus infections, 771–775, 773–774t 909

histoplasmosis, 550, 554–556 malignant or invasive otitis externa, 398–399 Mycobacterium avium complex (MAC) infection, 760, 770–771 Pneumocystis jiroveci pneumonia, 760, 761–765, 762t, 764t, 765t tuberculosis, 495 Acremonium, diagnostic assay for, 569 Actinobacillus actinomycetemcomitans, as infective endocarditis cause, 112 Actinomyces israeli, as cervicitis cause, 346 Acute cough syndrome, 404 Acyclovir as genital herpes treatment, 299, 299t as herpes simplex virus infection treatment, 437, 804t, 805–806 as varicella (chickenpox) treatment, 811 as viral encephalitis treatment, 88 Acyclovir resistance, in cytomegalovirus, 822 Adefovir, as hepatitis B treatment, 193 Adenoviruses as bronchitis cause, 403 as chronic bronchitis exacerbation cause, 410 as cystitis cause, 251 as pharyngotonsillitis cause, 369 as pneumonia cause, 432 as respiratory infection cause, 443–444 Adolescents, chlamydial infections in, 292 Adult respiratory distress syndrome, 523 Aerobic/anaeorbic soft-tissue infections, 644, 647–648 Aerobic bacteria classification and identification of, 29–30t cultures of, 18t

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as pharyngotonsillitis cause, 366, 367t, 368 in polymicrobial infections, 644, 647–648 Aeromonas, as diarrhea cause, 158t Aeromonas hydrophila as necrotizing fasciitis cause, 653 as necrotizing soft-tissue infection cause, 649 as septic arthritis cause, 585 AIDS. See Acquired immunodeficiency syndrome (AIDS) Airway obstruction epiglottitis-related, 365 Epstein-Barr virus-related, 817 Alcohol abuse as meningitis risk factor, 53 as pancreatitis risk factor, 233, 233t as pneumonia risk factor, 451 Algorithms for chronic bronchitis treatment, 411, 414f for diabetic foot infection treatment, 667f, 671f, 672f, 673f for epididymitis treatment, 281f for joint pain evaluation, 590–591, 591f for meningitis treatment, 69t for monoarticular arthritis treatment, 591–592, 593f for pelvic inflammatory disease treatment, 319f for urethritis treatment, 278f for viral respiratory infection treatment, 422f Alice in Wonderland syndrome, 816 Allergic reactions to Candida, 339 as otitis media cause, 394 as sinusitis cause, 390 as vaginitis cause, 343, 344, 344t as vulvitis cause, 343, 344, 344t Amantadine, as influenza treatment, 425–426 Amantadine resistance, in influenza viruses, 418, 425, 427 AmBisome as aspergillosis treatment, 572 as blastomycosis treatment, 524t as coccidioidomycosis treatment, 546t as histoplasmosis treatment, 550, 555t, 556–557 Amebiasis, 227 as gastroenteritis cause, 157, 159–160, 159t Amebic liver abscess, 159–160, 224, 226, 227, 228, 231t Amikacin, as tuberculosis treatment, 507t Aminoglycosides as meningitis treatment, 65 pharmacodynamics of, 12–13 use in elderly patients, 239 p-Aminosalicyclic acid, as tuberculosis treatment, 507t Amiodarone, as epididymitis cause, 275 Amoxicillin as bite-wound infection treatment, 690

as chronic bronchitis treatment, 413t as Lyme disease treatment, 833, 838, 839t as otitis treatment, 387, 396 as pelvic inflammatory disease treatment, 318 as pharyngotonsillitis treatment, 372, 372t as pyelonephritis treatment, 257 as sinusitis treatment, 391, 392t Amoxicillin-clavulanate, as pharyngotonsillitis treatment, 372t, 375 Amphotericin B as aspergillosis treatment, 569–570, 570t, 572, 574 as blastomycosis treatment, 522, 525 as candidiasis treatment, 528, 534, 536, 537t, 538 as coccidioidomycosis treatment, 541, 546, 547 as cryptococcal meningitis treatment, 768–769, 769t fungal resistance to, 572 as histoplasmosis treatment, 549, 550, 555t, 556–557 side effects of, 572 use during pregnancy, 546 Ampicillin as bacterial meningitis treatment, 70t, 71–72, 73 contraindication in infectious mononucleosis, 815–816 as pelvic inflammatory disease treatment, 321t Amputation diabetic foot infection-related, 663, 665, 668, 671–672 osteomyelitis-related, 626 prosthetic joint infection-related, 606 Amylase, in pancreatitis, 234 Anaerobic bacteria as bite-wound infection cause, 685 classification and identification of, 29–31t cultures of, 18t as liver abscess cause, 225 as pharyngotonsillitis cause, 367t, 369 in polymicrobial infections, 644, 647–648 as septic arthritis cause, 585 Anaplasma phagocytophilum, 843–44, 838. See also Anasplasmosis, human granulocytotropic Anaplasmosis, human granulocytotropic, 833, 841t, 843–846, 843t clinical manifestations of, 845, 848–849, 849t diagnosis of, 845–846, 850 prognosis in, 848 treatment of, 838, 847t Anemia antiretroviral therapy-related, 732t autoimmune hemolytic, 816, 818 infective endocarditis-related, 116 sickle cell, 784, 790, 791 Aneurysm, mycotic, 126–134

clinical manifestations of, 127–128 cryptogenic, 127 diagnosis of, 128 endocarditis associated with, 126–127, 128, 129, 130 infected false, 130–134 primary, 127–128 prognosis and prevention of, 129–130 rupture of, 127, 128 secondary, 127 treatment of, 128–129, 887t Angiography digital subtraction, of infected false aneurysm, 131, 132 of mycotic aneurysm, 128, 129 as mycotic aneurysm cause, 130 Anidulafungin, as candidiasis treatment, 528, 536, 537t Animals. See also Cat bites; Dog bites as bacterial enteropathogen reservoir, 144 as Campylobacter reservoir, 151 as Escherichia coli reservoir, 153 as Giardia lamblia reservoir, 160 as Yersinia enterocolitica reservoir, 155 Antacids, interaction with antiretroviral agents, 746 Antibiogram, 44, 45t Antibiotic-impregnated acrylic beads, 624 Anticoagulation therapy contraindication in infective endocarditis, 119 for septic thrombophlebitis, 138 Antigen detection tests, 16, 16t enzyme immunoassays, 22, 24, 25 fluorescent antibody tests, 22, 24–25, 34 latex agglutination tests, 22, 24, 25–26, 27 Antigenic drift, 424, 425 Antigenic shift, 424–425 Antigens cryptococcal, 768, 769 super, 648–649 Antimalarial drugs, 853, 858–868, 861–862t Antimicrobial assays, 44 Antimicrobial therapy, 3–14. See also names of specific antimicrobial agents for abscesses, 377–378, 377t brain abscess, 98, 99–100t, 100 intra-abdominal abscess, 231t liver abscess, 227–228 antibacterial killing activity of, 11–13 antimicrobial activity of, 10–11 for bite-wound injuries and infections, 681, 690–691, 692–694t for bone infections, 871–872t for bronchitis, 401, 406–408, 411, 412–413t as Candida vaginitis risk factor, 337 for central nervous system infections, 874–875t

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Index for cholangitis, 183 for cholecystitis, 176–178, 177t as clostridial diarrhea risk factor, 156–157 for community-acquired pneumonia, 450, 464–470, 466–68t as cystitis risk factor, 247 for diabetic foot infections, 671–675, 675t empirical, 3, 4 for epididymitis, 278 for gastrointestinal infections, 876–880t for genitourinary infections, 880–884t for gonorrhea, 290–291, 291t for heart and vsacular infections, 884–888t for herpes simplex virus pneumonia, 437–438 in immunocompromised patients, 888–891t inappropriate, 3, 4 ineffectiveness in acute bronchitis, 401 for infective endocarditis, 119–122, 120–121t inoculum effect of, 11 for Lyme disease, 838, 839t, 840 microorganisms’ resistance to. See Resistance, antimicrobial for miscellaneous conditions, 905–907t for mycotic aneurysm, 129–130 for necrotizing soft-tissue infections, 657–659, 658t for neutropenia, 786–788 new developments in, 3 for nosocomial pneumonia, 487–493, 488f, 489f, 490t optimal dosage in, 3 for osteomyelitis, 616, 620–623, 622t, 872–873t overuse of, 480 for peritonitis, 209–210, 213–214, 214t, 215, 217–218 for pharyngotonsillitis, 371–373, 372t postantibiotic effect (PAE) of, 11 for prostatitis, 269–270, 271, 272–273t, 274 for respiratory tract infections, 891–899t for septic arthritis, 592, 594 for skin and soft-tissue infections, 899–904t for superficial skin infections, 631–633, 632–633t, 639–640 as surgical prophylaxis, 4–5, 5–7t time-dependent, 3 for viral infections, 904t Antimycotic agents as aspergillosis treatment, 559, 560, 568–575, 568t, 570t azole, 340–341, 341t as vulvovaginal candidiasis treatment, 340–342, 341t Antiretroviral therapy commercially available, 731, 733–734t, 736 for enteroviral meningitis, 83 highly-active (HAART), 509, 761

adherence to, 747–748 CD4+ T cell count in, 740–741, 742, 743 drug interactions in, 745–747, 746t drug-resistant, 738–739 failure of, 748–749 immune reconstitution syndrome and, 752 initiation of, 729, 740–742, 740t, 741t lifelong use of, 747 optimal, 737–738 in patients with AIDS-defining illnesses, 750–751 in patients with hepatic disease, 751–752 in patients with kidney disease, 749–750 recurrent acute retroviral syndrome and, 752–753 in treatment-experienced patients, 745 in women, 743–744, 744t HIV protease inhibitors, 731, 735t interaction with rifampin, 509 nonnucleoside reverse transcriptase inhibitors, 731, 734t nucleoside reverse transcriptase inhibitors, 731, 733–734t toxicity of, 731, 732–733t Anti-tumor necrosis factor agents, 550, 553, 795–796 Antitussives, 408 Aortic coarctation, mycotic aneurysm-associated, 128 Aortitis, syphilitic, 127–128 Appendectomy, 237 antimicrobial prophylaxis in, 5t Appendicitis as abscess cause, 235 diagnosis of, 236 differentiated from calculous cholecystitis, 174 pain of, 236 treatment of, 237 Appendix, rupture of, 236 Arboviruses, as encephalitis cause, 85, 86t Arcanobacterium haemolyticum, as pharyngotonsillitis cause, 368t Arrhythmia, infective endocarditis-related, 116 Artemisinin (Qinghaosu), 866–867 Arterial bypass, as mycotic aneurysm treatment, 129 Arteriography, of infected false aneurysm, 131, 132 Arthritis acute polyarticular inflammatory, 591t Lyme disease-related, 835, 836t, 837, 837t, 840 pyogenic, 58 reactive, 582–583, 589t rheumatoid as ascites cause, 204–205 septic arthritis associated with, 582 synovial fluid analysis in, 589t septic, 581–598 bite wound-related, 681, 688, 691, 695

911

Candida-related, 531 clinical management of, 586–587 diagnosis of, 582, 587–592, 588t, 589t, 591f, 591t etiology of, 584–586, 584t gonococcal, 586–587, 588, 589t, 592, 594, 595, 596 microbiology of, 581 outcome of, 596 pathogenesis of, 582–583, 583t physical examination of, 581 risk factors for, 583, 583t treatment of, 582, 592–596, 593f, 594t, 691, 871–873t syphilitic, 301 Yersinia enterocolitica-related, 155 Arthrocentesis, 592 Arthroplasty, excisional, 606 Ascaris lumbricoides, as hepatic abscess cause, 225 Ascites, peritonitis-related, 205–206, 219–220 Ascitic fluid analysis, in peritonitis, 204, 208–209, 209t, 210 Aspergilloma, 564–565 treatment of, 571, 572, 574–575 Aspergillosis, 559–578 allergic bronchopulmonary, 564, 570, 572 as brain abscess cause, 91–92 chronic necrotizing pulmonary, 572 differentiated from tuberculosis, 500 clinical manifestations of, 559, 563–567, 563t cutaneous, 567 diagnosis of, 559 epidemiology of, 560–561 in immunocompromised patients, 559, 560, 561 as infective endocarditis cause, 112 invasive, 559, 560, 561, 561t, 563, 563t, 565–566 diagnosis of, 567–569, 567t pulmonary, 565 treatment of, 571–575, 572 mortality rate in, 562t as otitis externa cause, 398 pathogenesis of, 562 as peritonitis cause, 207t prevention of, 575 risk factors for, 559, 571 as sinusitis cause, 391 treatment of, 559, 560, 568–575, 568t, 570t immunoadjuvants in, 574 surgical, 574–575 Aspergillus. See also Aspergillosis distribution of, 560, 561t Aspirates, endotracheal handling of, 20t interpretation of results of, 23t in nosocomial pneumonia, 485–486 quality of, 21t Aspiration of brain abscess, 101, 102–103 of liver abscess, 228 oropharyngeal, 644 of pancreatic abscess, 234 of prosthetic joint infections, 603

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of septic joints, 595 sinus, 390 Aspiration pneumonia, 456 Asplenia, 783, 789–791, 790t humoral immunity in, 783, 784 systemic lupus erythematosusrelated, 793 Asthma allergic bronchopulmonary aspergillosis and, 564 as bronchitis cause, 402, 405 Ataxia-telangiectasia, 780t Atherosclerosis, 127–128 Atopobium vaginae, 328 Atovaquone, 861t, 865–866, 868 Atripla, 724 Atrophy, vaginal, 343 Auramine-rhodamine fluorescent acid-fast stain, 24 Autosplenectomy, 790, 791 Avian influenza, 418, 427 Avulsion wounds, bite wounds as, 687 Azithromycin as bronchitis treatment, 413t as Campylobacter infection treatment, 152 as chancroid treatment, 307t as chlamydial urethritis/cervicitis treatment, 295, 295t as Mycobacterial avium complex infection treatment, 771 as otitis media treatment, 396 as pelvic inflammatory disease treatment, 322t as pneumonia treatment, 468–469 as syphilis treatment, 304, 304t Azole antimycotic agents, 340–341, 341t B Babesiosis, 840 Bacille-Guérin Calmette vaccination, 516 Bacillus, as brain abscess cause, 99t, 100 Bacillus cereus, as food poisoning cause, 162–163 Back pain, bacterial meningitisrelated, 55 Bacterascites, 211 Bacteremia bacterial meningitis-related, 58, 59 bite wound-related, 688 Campylobacter-related, 152 clinical specimen collection in, 19t endocarditis-related, 112, 119, 122 intravenous drug abuserelated, 94 as meningitis risk factor, 53 mycotic aneurysm-related, 128 prosthetic joint infectionrelated, 599, 606 septic thrombophlebitisrelated, 134 shigellosis-related, 155 as skin lesion cause, 61 staphylococcal, 459, 789 Bacteria. See also names of specific bacteria growth in cultures, 18

laboratory identification of, 27, 28–30t multidrug-resistant antimicrobial therapy for, 488–489, 489f, 490t as nosocomial pneumonia cause, 484, 488–489, 489f, 490t resistance to antimicrobial agents, 785–786 Bacterial infections. See also specific bacterial infections cell-mediated immunity in, 780t, 782 neutropenia as risk factor for, 785–786 Bacterial overgrowth syndrome, 165 Bacteriuria asymptomatic, 245, 248t, 249, 249t, 253 treatment of, 257–258, 258t low count, 252–253 Bacteroides as calculous cholecystitis cause, 171 as infected false aneurysm cause, 131 as pelvic inflammatory disease cause, 315 as pharyngotonsillitis cause, 374 in polymicrobial soft-tissue infections, 647 as septic arthritis cause, 585 as vaginosis cause, 327 Bacteroides fragilis as appendiceal abscess cause, 235 as cellulitis cause, 635–636 as peritonitis cause, 212 as septic thrombophlebitis cause, 134 Bactibilia, 169 Bartonella, as infective endocarditis cause, 114, 117 Bartonella henselae as cat-bite infection cause, 684 as infective endocarditis cause, 114 B cells in cell-mediated immunity, 779, 781 in humoral immunity, 782–783 Beads, antibiotic-impregnated acrylic, 624 Behçet syndrome, 64 Beta2-agonists, ineffectiveness as bronchitis treatment, 402, 408 Beta-hemolytic Streptococcus. See Streptococcus, β-hemolytic Beta-lactam antibiotics bacterial resistance to, 72, 132, 133 as chronic bronchitis treatment, 412t as cystitis treatment, 254–255, 255t as meningitis treatment, 65 as necrotizing soft-tissue infection prophylaxis, 660 as necrotizing soft-tissue infection treatment, 658–659 as pyelonephritis treatment, 257

as ventilator-associated pneumonia treatment, 491 Beta-lactamase-producing bacteria, 366, 374, 374t, 375, 377 Bile, 169 Biliary tract infections of, 168–184 acute acalculous cholecystitis, 178–180 acute calculous cholecystitis, 171–178 cholelithiasis, 169–171 treatment of, 177t inflammation of. See Cholangitis perforation of, 209 Bilirubin, conjugated, 182 Biofilm, osteomyelitis-related, 613 Biological agents, effect on immunity, 781t, 783 Biopsy of bone, in osteomyelitis, 616 cerebral in brain abscess, 98 in cerebral toxoplasmosis, 768 in encephalitis, 87 endometrial, 317 hepatic, in hepatitis C, 196 in histoplasmosis, 554 specimen interpretation in, 38–39 Bite-wound injuries and infections, 680–698 cat, 681, 682, 684 classification of, 687 epidemiology of, 682 etiology and microbiology of, 683 treatment of, 693t as cellulitis cause, 636t classification of, 687 clinical manifestations of, 688 complications of, 688 diagnosis of, 688–689 dog, 681–682, 684 epidemiology of, 681–682 etiology and microbiology of, 683 treatment of, 693t etiology of, 683–687 fatal, 680–681 human, 681, 682, 685 as cellulitis cause, 636t classification of, 687 clinical manifestations of, 688 epidemiology of, 682 etiology and microbiology of, 683 treatment of, 693–694t microbiology of, 683–687 monkey, 686–687 as necrotizing fasciitis cause, 650 pathophysiology of, 683 rabies prophylaxis for, 681, 685–686, 685t, 686t, 688, 694 as septic arthritis cause, 585, 585t tetanus prophylaxis for, 685t treatment of, 680, 681, 689–696 antimicrobial therapy, 690–691, 692–694t débridement, 683, 690

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Index elevation and immobilization, 695 hospitalization, 694 immunizations, 691, 694 medico-legal considerations in, 696 surgical management, 695 wound closure, 690 wound irrigation, 683, 689–690 wild-animal, 681, 685 Bladder washout technique, 253 Blastomyces dermatitidis, 521–522. See also Blastomycosis serologic test for, 36t tissue growth of, 523 Blastomycosis, 521–526 animal bite transmission of, 687 of the central nervous system, 526 clinical manifestations of, 522–523 cross-reactivity with histoplasmosis, 555 cutaneous manifestations of, 521, 522, 523–524, 525, 526 diagnosis of, 523–524 disseminated, 523 epidemiology of, 521–522 hematogenous dissemination of, 521 pathogenesis of, 522 pulmonary, 521, 522–523, 524t, 525, 526 treatment of, 522, 524–526, 524t, 571 Blindness brain abscess-related, 104 herpes simplex virus-related, 805 Blood, for serology tests, handling of, 20t Blood-brain barrier, in bacterial meningitis, 54 Blood cultures in bacterial meningitis, 60 in brain abscess, 98 of Candida, 531, 532, 537 in candidemia, 537 in community-acquired pneumonia, 459, 472 handling of, 20t in infective endocarditis, 117, 118t interpretation of results of, 24t in peritonitis, 208 in pneumonia, 461 in septic arthritis, 587 in splenic abscesses, 230 in urinary tract infections, 253 Blood flow, cerebral, in bacterial meningitis, 55 Blood smears, of Plasmodium, 857–858 Blood transfusions cytomegalovirus transmission via, 820–821 Epstein-Barr virus transmission via, 814 hepatitis B transmission via, 190 Blunt trauma, as septic arthritis risk factor, 583 Body piercing, as cellulitis cause, 636t

Bone cultures, in osteomyelitis, 616 Bone formation, in osteomyelitis, 613 Bone infections. See also Osteomyelitis candidiasis as, 531 treatment of, 871–873t Bordetella pertussis, as bronchitis cause, 403 Borrelia burgdorferi as Lyme disease cause, 833, 835 as septic arthritis cause, 590 Borreliosis, Lyme. See Lyme disease Brain. See also Central nervous system infections abscess of. See Brain abscess edema of, 104 bacterial meningitis-related, 54, 55, 57–58, 61 malaria of, 857 toxoplasmosis of, 760, 765–767, 767t, 890t Brain abscess, 90–106 amebic, 160 bite wound-related, 688 in children, 90–91, 93, 94, 96 clinical manifestations of, 95–96, 95f, 95t cryptogenic, 92, 94, 98 definition of, 91 diagnosis of, 97–100, 97f differential diagnosis of, 91–92 epidemiology of, 93–95 infective endocarditis-related, 112 location of, 93, 99t medical conditions associated with, 94t meningitis-related, 63 microbiology of, 98, 99–100t multiple, 94–95, 96, 103 pathogenesis of, 92–95, 94t rupture of, 96 sinusitis-related, 392 treatment of, 91, 98, 99–100t, 100–105 Brain stem, abscess of, 93 Brain tumors, as meningitis cause, 64, 82t Breastfeeding cytomegalovirus transmission through, 820 human herpes virus type 6 transmission through, 822 otitis media prevention and, 397 tuberculosis treatment during, 510 Bronchiectasis, aspergilloma associated with, 564 Bronchitis acute, 401–408, 409f clinical manifestations of, 403–405, 404t diagnosis of, 405–406 differentiated from pneumonia, 405–406, 408 epidemiology of, 402, 410 etiology of, 401, 403 prevention of, 408 treatment of, 401, 406–408, 409t

913

chronic acute exacerbations of, 409–415 clinical manifestations of, 410 definition of, 409 diagnosis of, 411 epidemiology of, 410 etiology of, 410 pathogenesis of, 410 prevention of, 411, 413 treatment of, 401, 411, 412–413t, 414f clinical specimen collection in, 19t Bronchoalveolar lavage, 486 of aspergillosis, 569 in immunocompromised patients, 796 interpretation of results of, 23t specimen quality in, 21t Bronchodilators as bronchitis treatment, 408, 411, 413 inhaled, 401 Bronchoscopy, 486, 487, 491, 498–499, 569, 796 Brucellosis animal bite transmission of, 687 as brain abscess cause, 92 as urinary tract infection cause, 251 Brudzinski sign, in bacterial meningitis, 55 Budd-Chiari syndrome, as ascites cause, 204–205 Bullae, necrotizing soft-tissue infection-related, 655 C Calcium-channel blockers, interaction with antiretroviral agents, 746 Caliciviridae, 186t, 199 Campylobacter as diarrhea cause, 158t, 165 as food poisoning cause, 162, 163 as gastroenteritis cause, 151–152 as traveler’s diarrhea cause, 164 Campylobacter fetus, as septic thrombophlebitis cause, 134 Campylobacteriosis, treatment of, 158t Cancer cell-mediated immunity in, 780t, 782 cervical cancer human papilloma virusrelated, 353, 354, 355–356, 355t, 359 treatment of, 360 hematologic cancer, 787, 788 as meningitis risk factor, 53 as neutropenia cause, 785 as tuberculosis risk factor, 498 vaginal cancer, 353, 356, 359 Candida. See also Candidemia; Candidiasis; Candiduria allergic reactions to, 339 diagnostic assay for, 569 Candida albicans, 527, 528, 528t Candida glabrata, 527, 528, 528t

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914

Index

Candida tropicalis, 527, 528, 528t Candidemia, 527, 528, 529, 531–532 treatment of, 536–538, 537t Candidiasis, 527–540 as acalculous cholecystitis cause, 179 as calculous cholecystitis cause, 171–172 clinical management of, 529–532 diagnosis of, 532–533 diagnostic assay for, 569 disseminated, 532 treatment of, 536–538, 537–538, 537t epidemiology of, 528–529 focal invasive, 530–531 treatment of, 534–536 as folliculitis cause, 633, 638 as infective endocarditis cause, 112 intertriginous, 532 mucocutaneous, 527, 529, 530 treatment of, 533–534 ocular, 531, 535 oropharyngeal, 529, 530, 532, 533–534, 763, 765 osteoarticular, 531, 535 as otitis externa cause, 398 as pancreatic abscess cause, 233 pathogenesis of, 529 as peritonitis cause, 213, 215 as pharyngotonsillitis cause, 367t prevention of, 538 as prosthetic valve endocarditis cause, 114 as splenic abscess cause, 230 treatment of, 528, 533–538, 535t, 571, 572, 573 as trichomoniasis superinfection, 335 as urinary tract infection cause, 250, 250t as vaginitis cause, 330t vulvovaginal, 330t, 335–342 classification of, 341–342, 342t clinical features of, 339–340 diagnosis of, 340 epidemiology of, 335–336 pathogenesis of, 336–339, 336t recurrent and chronic, 338–339, 342 risk factors for, 336, 336t, 337–338, 339 treatment and prevention of, 340–342, 341t Candiduria, 261–262, 527, 528, 530–531 Capillaria, 165 Capnocytophaga canimorsus in asplenic patients, 790 as bite-wound infection cause, 684, 692t Capreomycin, as tuberculosis treatment, 507t Carbuncles, 629, 632t, 634, 640 Cardiobacterium hominis, as endocarditis cause, 112 Cardiothoracic surgery patients, antimicrobial prophylaxis in, 5t

Cardiovascular disease congenital heart disease, 704 as brain abscess risk factor, 90–911, 93, 94, 96 congestive heart failure as ascites cause, 204–205 infective endocarditis-related, 116 in human immunodeficiency virus (HIV)-infected patients, 753–754 Cardiovascular infections treatment of, 884–888t Caspofungin as aspergillosis treatment, 573–574 as candidiasis treatment, 528, 534, 535, 536, 537–538, 537t, 573 side effects of, 573–574 Caspofungin acetate, as aspergillosis treatment, 570t Castleman disease, multicentric, 825–826, 827 Catalase-producing organisms, 784 Cat bites, 681, 682, 684 as cellulitis cause, 636t classification of, 687 epidemiology of, 682 etiology and microbiology of, 683 treatment of, 693t Catheterization cardiac, as infected false aneurysm risk factor, 130, 133–134 central venous, as candidiasis risk factor, 528–529 indwelling intravascular, as endocarditis risk factor, 109–110 indwelling urinary as candidiasis risk factor, 530, 534, 535 as candiduria risk factor, 261–262 as epididymo-orchitis risk factor, 253 as urinary tract infection risk factor, 248, 249t, 261–262, 263 Cat scratch disease, 684, 687, 688 CD4+ T cell count in AIDS, 728, 728t, 760–761 in cerebral toxoplasmosis, 766, 767 in cryptococcosis, 769–770 in cytomegalovirus infections, 775 in HIV infection, 726, 727f, 760 in antiretroviral therapy, 740–741, 742, 743, 745 in coccidioidomycosis, 544 in histoplasmosis in tuberculosis, 508, 509 in Mycobacterial avium complex infections, 771 in Pneumocystis jiroveci pneumonia, 763 CD8+ T cell count, in human immunodeficiency virus (HIV) infection, 726

Cefaclor, as pharyngotonsillitis treatment, 372t Cefadroxyl, as pharyngotonsillitis treatment, 372t Cefepime, as bacterial meningitis treatment, 73–74 Cefixime as gonorrhea treatment, 290, 291t as pelvic inflammatory disease treatment, 322t as pharyngotonsillitis treatment, 372t Cefotaxime as bacterial meningitis treatment, 70t, 73–74 as pneumonia treatment, 468–469 Cefoxitin as bite-wound infection treatment, 690–691 as pelvic inflammatory disease treatment, 320t, 321t Cefprozil as bronchitis treatment, 413t as pharyngotonsillitis treatment, 372t Ceftazidime, as bacterial meningitis treatment, 70t, 72, 73–74 Ceftetan, as brain abscess treatment, 101 Ceftibuten, as pharyngotonsillitis treatment, 372t Ceftriaxone as bacterial meningitis treatment, 73–74 as brain abscess treatment, 99t, 101 as gonorrhea treatment, 290, 291t as Lyme disease treatment, 839t, 840 as meningitis prophylaxis, 76 as pelvic inflammatory disease treatment, 320t, 322t Cefuroxime as Lyme disease treatment, 838, 839t as pharyngotonsillitis treatment, 372t Cefuroxime axetil, as chronic bronchitis treatment, 413t Cell-mediated immunity, 779 disorders of, 779, 780–781t, 781–782 in multiple myeloma, 792 in systemic lupus erythematosus, 793 Cellulitis, 612, 635–636 anaerobic gas-forming, 645–646t bite wound-related, 688 clostridial, 648 definition of, 635 diabetic foot infection-related, 666, 673 differentiated from necrotizing soft-tissue infections, 650–651, 655–656 microbiology of, 635 necrotizing fasciitis-related, 650 orbital, sinusitis-related, 392 peritonsillar, 369 retropharyngeal, 368

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Index as superficial skin infection, 629, 632t at surgical sites, 636, 641–642 synergistic necrotizing, 645–646t, 653 Center for Disease Control and Prevention (CDC), 2 acquired immunodeficiency syndrome (AIDS) case definition of, 728, 728t acute bronchitis treatment guidelines of, 407 Central nervous system infections aspergillosis, 562, 566 blastomycosis, 523 histoplasmosis, 553–554 mycobacterial, 770 risk for, 50 sinusitis-related, 392–393 syphilis, 301, 302 in systemic diseases, 59–60 systemic lupus erythematosusrelated, 793–794 treatment of, 874–875t varicella (chickenpox)-related, 808 Cephalexin, as pharyngotonsillitis treatment, 372t Cephalosporins as bacterial meningitis treatment, 73–74 as brain abscess treatment, 99t, 101 as peritonitis treatment, 210, 218 as pharyngotonsillitis treatment, 372t, 373 Cerebellum, abscess of, 93 Cerebritis, 92 lupus, 794 Cerebrospinal fluid in amebic encephalitis, 59 antimicrobial bactericidal activity in, 65–67 in aseptic enteroviral meningitis, 61–62 in bacterial meningitis, 59–60, 61, 62, 65–67 in brain abscess, 98 in encephalitis, 87 in fungal meningitis, 62 in herpes virus infections, 59 in lupus cerebritis, 794 in meningitis, 59, 83, 83t, 84t Cerebrum, abscess of, 93 Cervical cancer human papilloma virus-related, 353, 354, 355–356, 355t, 359 treatment of, 360 Cervicitis, 284–285, 285t, 344–349 chlamydial, 295, 296, 315–316, 347 epidemiology of, 344–348, 345f, 346f, 347f genital herpes-related, 297 gonococcal, 344–345, 347–349 herpetic, 344–345, 348, 349 mucopurulent, 344–345 Cervix, “strawberry,” 348 Chancre, 302 Chancroid, 305–307, 307t Charcot-Leyden crystals, 563

Charcot osteoarthropathy, 664 Charcot’s triad, 168, 182 Chédiak-Higashi syndrome, 784 Chemical meningitis, 64 Chemotherapy as candidiasis risk factor, 528–529 effect on cell-mediated immunity, 781t, 782 “Chest cold,” 407 Chest pain, infective endocarditis-related, 115t Chest x-rays. See X-rays, chest Chickenpox. See Varicella (chickenpox) Children. See also Infants Bacille-Guérin Calmette vaccination in, 516 bacterial meningitis in, 61 brain abscess in, 90–91, 93, 94, 96 bronchitis in, 402 dexamethasone use in, 68, 70–71 diarrhea in, 144 dog bites in, 681 epiglottitis in, 381–383 ethambutol contraindication in, 506 gastroenteritis in, 149–150 Haemophilus influenzae-related meningitis in, 50 hepatitis A in, 187 hepatitis B in, 190 hepatitis B vaccination in, 190, 193, 194 human-bite wounds in, 682 human granulocytotropic anaplasmosis treatment in, 847–848 human metapneumovirus infections in, 432–433 human monocytotropic ehrlichiosis in, 842 Lyme disease treatment in, 838, 840 measles vaccination in, 704 osteomyelitis in, 610–611, 613, 621 otitis media in, 394–397 overwhelming postsplenectomy infection (OPSI) in, 789 parainfluenza in, 433 pneumococcal vaccination in, 474 respiratory syncytial virus antigen detection in, 463 respiratory syncytial virus infections in, 430–432 septic arthritis in, 584, 584t, 585t tuberculosis in, 497 urinary tract infections in, 276 varicella (chickenpox) in, 811 Chills, as Charcot’s triad component, 168 Chlamydia as infective endocarditis cause, 117 as meningitis cause, 81t as pelvic inflammatory disease cause, 315, 317, 318 as pharyngotonsillitis cause, 367t, 369

915

Chlamydia trachomatis in adults, 292–296 as cervicitis cause, 285t, 344–345, 347 clinical manifestations of, 293 diagnosis of, 288–289, 294–295, 294t etiology of, 292 as pelvic inflammatory disease cause, 315 prevention of, 295 as prostatitis cause, 268 treatment of, 290, 295, 295t as urethritis cause, 285t Chlamydophila pneumoniae as bronchitis cause, 403 as pneumonia cause, 454, 468t Chloramphenicol as bacterial meningitis treatment, 74 as brain abscess treatment, 99t, 102 Chloroguanide (Proguanil), 862t, 865, 868 Chloroquine, as amebic liver abscess treatment, 228 Chloroquine phosphate, 858–859, 860t resistance to, 860t, 861–862t, 863 Cholangiography, magnetic resonance imaging, 182 Cholangiopancreatography endoscopic retrograde (ERCP), 168, 176t, 181, 182 as pancreatic abscess cause, 232–233 magnetic resonance, 176t Cholangitis, 168, 175t, 180–183 acute calculous cholecystitisrelated, 173 choledocholithiasis-related, 182–183 diagnosis of, 174 as hepatic abscess cause, 225 Cholecystectomy, 178, 180 Cholecystitis, 161 acute acalculous, 168, 178–180 acute calculous, 171–178, 175t chronic, 169 definition of, 171 emphysematous, 173, 788 as hepatic abscess cause, 225 suppurative, 172–173 Choledocholithiasis, 175t as cholangitis cause, 182–183 as hepatic abscess cause, 225 Cholelithiasis, 169–171 as cholangitis cause, 180 complications of, 170–171, 170f Cholera, 154, 158t Cholescintigraphy, 175, 175t Cholesterol gallstones, 169–170 Chorioamnionitis, 328, 329t Choriomeningitis, lymphocytic, 62–63 Chronic active Epstein-Barr virus infection (CAEBV), 819 Chronic fatigue syndrome, 816, 836, 837 Chronic obstructive pulmonary disease (COPD) aspergillosis-related, 564

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916

Index

coccidioidomycosis associated with, 541, 544 etiology of, 402 pathogenesis of, 410 as pneumonia risk factor, 417 Cidofovir as cytomegalovirus retinitis treatment, 772 as herpes simplex virus infection treatment, 805–806 Cierny-Mader classification, of osteomyelitis, 614–615, 615t, 616t Ciprofloxacin as gonorrhea treatment, 290, 291t as meningitis prophylaxis, 76 as pelvic inflammatory disease treatment, 314, 322t as prosthetic joint infection treatment, 604–605 Cirrhosis as cholelithiasis risk factor, 170 hepatitis-related, 185, 191, 193, 195 as isoniazid contraindication, 513 Citrobacter, as liver abscess cause, 225 Citrobacter freundii, as infected false aneurysm cause, 131 Clarithromycin as bronchitis treatment, 413t as pharyngotonsillitis treatment, 372t Clavulinic, as pelvic inflammatory disease treatment, 318 Clearance, of drugs, 9–10 Clenched-fist injuries, 682, 687 Clindamycin as malaria treatment, 861t, 863 as necrotizing soft-tissue infection treatment, 657–659, 658t as pelvic inflammatory disease treatment, 321t as pharyngotonsillitis treatment, 372t, 375 Clinical Laboratory Standards Institute, 39 Clinical Pulmonary Infection Score (CPIS), 485, 491–493, 492t Clostridium as calculous cholecystitis cause, 171 as cellulitis cause, 635–636 as myonecrosis cause, 643 as necrotizing soft-tissue infection cause, 648 as septic arthritis cause, 585 Clostridium difficile asymptomatic carriage of, 155–156 as diarrhea cause, 143, 149, 155–157 treatment of, 158t epidemic strain of, 144 as gastroenteritis cause, 155–157 Clostridium perfringens as food poisoning cause, 163 as myonecrosis cause, 654 as necrotizing infection cause, 631 necrotoxins of, 650

Clotrimazole, as trichomoniasis treatment, 335 Clotrimazole lozenges, 533 Clubbing, of the digits, 115 Coagulation, disseminated intravascular in bacterial meningitis, 58 bite wound-related, 688 Coagulopathy, bacterial meningitis-related, 58 Coccidioides, 541–542. See also Coccidioidomycosis differentiated from Blastomyces dermatitidis, 553 Coccidioides immitis, 541, 545 as abscess cause, 377 serologic test for, 36t Coccidioides posadasii, 545 Coccidioidomas, 544 Coccidioidomycosis, 541–548 asymptomatic, 541, 543 as brain abscess cause, 92 clinical manifestations of, 543–544, 543t diagnosis of, 545 disseminated, 547 epidemiology of, 541–542 pathogenesis of, 542–543 treatment of, 542, 545–547, 546t Codeine, as antitussive, 408 Cold sores, 803, 804t Colic, 172 Colitis amebic, 157, 159 Campylobacter-related, 152 hemorrhagic, 152 pseudomembranous, 156 Colon, rupture of, 212 Colony-forming units (CFUs), 10–11, 252–253 Colony-stimulating factor, 788 Colpitis macularis, 333, 345 Colposcopy, 349, 356 Common variable immunodeficiency, 783 Communication, between clinician and laboratory, 16–17 Complement/complement system, 783–784, 789 Complement fixation assay for coccidioidomycosis, 545 for histoplasmosis, 554 Computed tomography (CT) of aspergillosis, 569 of bacterial meningitis, 60, 61–62 of biliary tract infections, 175t, 176t of brain abscess, 91, 92–93, 103 of candidiasis, 533 of diverticular abscesses, 238–239 of infected false aneurysm, 131 of invasive pulmonary aspergilosis, 565 of liver abscesses, 226 of necrotizing soft-tissue infections, 656 of osteomyelitis, 617–619 of pancreatic abscesses, 234 of septic arthritis, 590 of septic thrombophlebitis, 137

of sinusitis, 390 of splenic abscesses, 230 of urinary tract infections, 254 of viral encephalitis, 88 Condoms as chlamydial infection prophylaxis, 295–296 as cystitis risk factor, 247 as sexually transmitted disease prophylaxis, 291–292 Condyloma lata, 301, 302 Congenital diseases, cellmediated immunity in, 779, 780t, 781–782 Congenital heart disease, 704 as brain abscess risk factor, 90–91, 93, 94, 96 Congenital rubella syndrome, 704–705 Congestive heart failure as ascites cause, 204–205 infective endocarditis-related, 116 Conidia of Aspergillous, 560 of Blastomyces dermatitdis, 522 of Coccidioides, 542 Conjunctivitis chlamydial, 293–294 gonococcal, 287–288 Consultations for bite-wound management, 694 for prostatitis management, 270 Continuous ambulatory peritoneal dialysis (CAPD), as peritonitis cause, 215, 216–218, 531, 536 Coronaviruses as chronic bronchitis exacerbation cause, 410 as pneumonia cause, 455 severe acute respiratory syndrome-associated, 403, 428, 429, 454, 455 Corticosteroids as amebic colitis risk factor, 157 as candidiasis risk factor, 528, 531, 532 as cerebral edema treatment, 104 as chronic bronchitis treatment, 411, 413 discontinuation in vulvovaginal candidiasis, 342 effect on cell-mediated immunity, 781t, 782 as Epstein-Barr virus infection treatment, 818 immunosuppressive effects of, 794–795 as oral thrush risk factor, 530 as splenic abscess risk factor, 230 as tuberculosis adjunct treatment, 508 Corynebacterium as bite-wound infection cause, 684 as normal skin microorganism, 630 as prosthetic joint infection cause, 601

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Index Corynebacterium diphtheriae, as pharyngotonsillitis cause, 368t, 373 Corynebacterium haemolyticum, as pharyngotonsillitis cause, 368, 368t Cosmetic damage, bite woundrelated, 688 Cough blastomycosis-related, 522 bronchitis-related, 401–402, 403, 404t, 409 effect of antibiotic therapy on, 406–407 coccidioidomycosis-related, 543 pneumonia-related, 456 tuberculosis-related, 498 Cowdry type A intranuclear inclusion bodies, 437 Coxiella burnetii as infective endocarditis cause, 117 as pharyngotonsillitis cause, 367t Coxsackie viruses, 369, 811 Crackles bronchitis-related, 404, 406 pneumonia-related, 406, 450, 456, 458 Cranial nerves in bacterial meningitis, 58 in basilar meningitis, 63 in encephalitis, 87 in herpes zoster (shingles), 809–810 in syphilis, 301 Craniopharyngioma, as meningitis cause, 64 C-reactive protein in folliculitis, 639 in Lyme disease, 849–850 in necrotizing soft-tissue infections, 655–656 in osteomyelitis, 617 in pelvic inflammatory disease, 317 in prosthetic joint infections, 602 in septic arthritis, 587 Croup, 433 Crush injuries, bite woundrelated, 683, 688, 689 Cryptococcosis, acquired immunodeficiency syndrome (AIDS)-related, 760, 768–770, 769t Cryptococcus, differentiated from Blastomyces dermatitidis, 553 Cryptococcus neoformans as cryptococcosis cause, 768 as meningitis cause, 63 treatment of, 571 Cryptosporidiosis as diarrhea cause, 161, 165 as food poisoning cause, 162 treatment of, 144, 159t Cullen sign, 233 Cultures, 16t. See also Blood cultures in bite wounds, 689 of Chlamydia trachomatis, 294t, 295 in cholangitis, 180–181

in coccidioidomycosis, 545 of cytomegalovirus, 821 of endotracheal aspirates, 485–486 of herpes simplex virus, 297, 298 identification of organisms in bacteria, 27, 28–30t fungi, 32, 32t mycobacteria, 30, 31t parasites, 32, 33t of uncultivable/difficult-toculture organisms, 30t viruses, 33–34, 34–35t of influenza viruses, 423 interpretation of results of, 22, 23–24t laboratory evaluation of, 268–269 of Neisseria gonorrhoeae, 287, 289 in nosocomial pneumonia, 486 in osteomyelitis, 609, 616 in peritonitis, 208, 213, 219 in prostatitis, 268 specimens in, 19–21 collection of, 20–21 handling of, 17, 20, 20t screening for quality of, 21–22, 22t selection of, 19t transportation of, 20, 20t of sputum smears, 499 in viral encephalitis, 86t Cycloporidiosis, treatment of, 159t Cycloserine, as tuberculosis treatment, 507t Cyclospora as diarrhea cause, 162 as food poisoning cause, 162 as gastroenteritis cause, 147 Cyst intracranial, as meningitis cause, 82t renal, infected, 260 Cystic fibrosis, as sinusitis risk factor, 391 Cystitis acute differential diagnosis of, 251 treatment of, 254–256, 255 in women, 247 bacterial, in women, 245 diagnosis of, 252–253, 253 hemorrhagic, 251 interstitial, 251 in men, 252 recurrent, in women, 247–248 urinary tract infection-related, 251 in women, 245, 247, 251–252 risk factors for, 247–248 Cytochrome P-450 enzymes, 9, 745, 746, 747 Cytomegalovirus, 801t, 819–822 in AIDS patients, 771–775, 773–774t assays for, 87 as cervicitis cause, 344–345, 348 as encephalitis cause, 86t epidemiology of, 819–820 as hepatic abscess cause, 225 hepatitis-associated, 185

917

as infectious mononucleosis cause, 708 in utero infections with, 820 mononucleosis-like syndrome of, 440 as pelvic inflammatory disease cause, 315 as pneumonia cause, 440–443 as respiratory infection cause, 421 serologic test for, 36t treatment of, 761, 772–775, 773–774t Cytotoxins, 145 D Daptomycin, 610 Daycare attendance as cytomegalovirus risk factor, 820 as gastroenteritis risk factor, 144 as otitis media risk factor, 394–395, 397 as upper respiratory infection risk factor, 387 Dead space, 623–624 Deafness. See Hearing loss Death, nosocomial pneumoniarelated, 480 Débridement of bite wounds, 683, 690 of diabetic foot ulcers, 671 of necrotizing fasciitis, 656–657 of osteomyelitis, 620, 623–624, 625 of pancreatic abscesses, 234, 235 Decompression, urgent biliary tract, 182 Dehydration, diarrhea-related, 144 Deltaviridae, 186t Dengue fever, 85, 185 Dental infections, as sinusitis cause, 387, 389 Dental procedures, antibiotic prophylaxis for, 606–607 Dermatophyte infections, treatment of, 571 Dexamethasone, as bacterial meningitis treatment, 68, 70–71, 72 Dextromethorphan, as antitussive, 408 Diabetes mellitus as brain abscess risk factor, 94 coccidioidomycosis in, 541 foot care in, 626, 675–677 foot infections in, 650, 663–679, 788, 789 as amputation cause, 663, 665, 668, 671–672 classification of, 665–666, 666t clinical management of, 665–666 diagnosis of, 670 microbiology of, 667–670, 668t, 669t as osteomyelitis cause, 614, 626 pathophysiology of, 664–665 prevention of, 675–677 treatment of, 664, 670–675, 671f, 672f, 673f, 675t, 676f

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918

Index

HIV infection-related, 753–754 infection prevention in, 789 infections associated with, 788–789 intertriginous candidiasis in, 530 as meningitis risk factor, 53 as necrotizing fasciitis risk factor, 652 as osteomyelitis risk factor, 614, 626 as otitis externa risk factor, 398–399 prevalence of, 663–664 as pyelonephritis risk factor, 248, 260–261, 788 rhinocerebral mucormycosis in, 391, 788, 789t soft-tissue infections in, 788 tight glucose control in, 788, 789 as tuberculosis risk factor, 498 as urinary tract infection risk factor, 260–261 as vulvovaginal candidiasis risk factor, 336t, 337 Dialysate fluid analysis, in peritonitis, 216–217 Diarrhea, 143–162 antibiotic-associated, 156 bacterial, 143, 145–146 cholera-related, 154 chronic, 165 clinical specimen collection in, 19t clostridial, 143, 149, 155–157, 158t cryptosporidial, 161 diagnosis of, 146–147 epidemiology of, 144 Escherichia coli-related, 152–153 etiology of, 145–146 food poisoning-related, 146, 163 inflammatory, 145–146, 147–148, 150 microsporidial, 161 noninflammatory, 145, 146, 148–149 nosocomial, 165–166 pathogenesis of, 143, 145 protozoal, 143, 145, 160–162 “rice water,” 154 severe acute respiratory syndrome-related, 428 traveler’s, 143, 144, 146, 152–153, 164–165 treatment of, 147–149, 148f, 158–159t viral, 143, 145 Digital rectal examination, in prostatitis, 270–271 Digital subtraction angiography, 131, 132 Digits, clubbing of, 115 Direct fluorescent antibody test, 294, 294t Disk-diffusion test, 41 Disseminated intravascular coagulation bacterial meningitis-related, 58 bite wound-related, 688 Diverticula, perforation of, 237–239

Diverticulitis, acute, 237 DNA (deoxyribonucleic acid) probes, 26 Dog bites, 681–682, 684 as cellulitis cause, 636t epidemiology of, 681–682 etiology and microbiology of, 683 treatment of, 683t, 693t Dogs, blastomycosis in, 522 Doxycycline as bronchitis treatment, 413t as chlamydial urethritis/cervicitis treatment, 295, 295t as ehrlichiosis treatment, 833, 847, 847t as human granulocytic anaplasmosis treatment, 833, 838 as Lyme disease treatment, 833, 838, 839t as malaria treatment, 838, 861t, 868 as pelvic inflammatory disease treatment, 318, 320t as pneumonia treatment, 465 Drainage of abscesses, 377–378 appendiceal abscess, 237 diverticular abscess, 238–239 lateral pharyngeal abscess, 380 liver abscess, 227–228 oral cavity abscess, 365 pancreatic abscess, 234–235 retropharyngeal abscess, 379 of septic arthritis, 592, 595–596 of superficial skin infections, 640 Drug fever, 59 Drug interactions, 9 Drugs. See also Antimicrobial therapy; names of specific drugs absorption of, 8 clearance of, 9 effect on cell-mediated immunity, 780–781t, 782 half-life of, 9–10 as humoral immunity deficiency cause, 783 as meningitis cause, 82t volume of distribution (Vd) of, 8–9 Duke diagnostic criteria, for infective endocarditis, 118–119 Dysentery amebic, serologic test for, 36t fulminant, 154–155 Dysentery syndrome, 153 Dysphasia, in bacterial meningitis, 58 Dyspnea, bronchitis-related, 403, 404, 404t, 409 Dysuria chlamydial infection-related, 293 gonorrhea-related, 286 E Ear canal, overaggressive cleaning of, 397 Ear infections. See also Otitis externa; Otitis media aspergillosis, 563

Ebola virus, 185 Echinocandins, as aspergillosis treatment, 574 Echocardiography, in infective endocarditis, 118t Echoviruses, as meningitis cause, 62 Ectocervicitis, mucopurulent, 345 Eczema herpeticum, 804–805, 804t Edema cerebral, 104 bacterial meningitis-related, 54, 55, 57–58, 61 necrotizing fasciitis-related, 650 necrotizing soft-tissue infection-related, 649–650 Efavirenz, 746 Effusions from joints osteomyelitis-related, 613 synovial fluid analysis of, 588 pleural blastomycosis-related, 523 coccidioidal, 543t community-acquired pneumonia-related, 471 Egophony, pneumonia-related, 405–406 Ehrlichia chaffeensis, 840, 841, 843–844. See also Ehrlichiosis, human monocytotropic Ehrlichiosis, human granulocytotropic Ewingii, 841t, 846, 847t, 848 monocytotropic, 833, 841t clinical manifestations of, 841–842, 848–849, 849t prognosis in, 848 treatment of, 847–848, 847t Eikenella corrodens as bite-wound infection cause, 685, 686–687, 692t as infective endocarditis cause, 112 as septic arthritis cause, 585 Elderly patients acute calculous cholecystitis in, 172, 173 aminoglycoside use in, 239 asymptomatic bacteriuria in, 249t bacterial meningitis in, 57 bronchitis in, 402, 403 coccidioidomycosis in, 542 epididymo-orchitis in, 253 gastroenteritis in, 144, 150–151 gastroenteritis treatment in, 147–148 human granulocytic anaplasmosis in, 834 human monocytotropic ehrlichiosis in, 834, 842 infective endocarditis in, 110–111 influenza vaccination in, 424 pneumococcal vaccination in, 474 pneumonia in, 417, 453, 458 postherpetic neuralgia in, 810 respiratory syncytial virus infections in, 431 tuberculosis in, 497, 498

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Index Electroencephalography, in viral encephalitis, 88 Embolism infective endocarditis-related, 112 pulmonary, septic thrombophlebitis-related, 136 Emphysema, bullous, 564 Empyema, 172–173, 176 Encephalitis amebic, cerebrospinal fluid in, 59 cerebral toxoplasmosis-related, 766 definition of, 84 viral, 84–89 eastern equine, 85 herpes simplex virus-related, 80 Japanese, 81, 86t St. Louis encephalitis, 85 varicella (chickenpox)-related, 808 western equine, 85 West Nile virus-related, 85 Encephalomyelitis, postinfectious, 85 Encephalopathy hepatic, peritonitis-related, 207 Lyme disease-related, 836, 837 Endarteritis obliterans, 302 Endocarditis antibiotic prophylaxis for, 123 in mycotic aneurysm patients, 129, 130 bacterial, 109 enterococcal, 43 gonococcal, 288 infective, 109–125 acute, 112, 113t, 114, 116–117 antimicrobial prophylaxis for, 123 aspergillosis-related, 566 in bacterial meningitis, 58 as brain abscess cause, 92, 94 clinical manifestations of, 114–115, 115t culture-negative, 114, 117, 119, 887t diagnosis of, 116–119, 118t Duke diagnostic criteria for, 118–119 etiology of, 112–114, 113t in intravenous drug abusers, 113t pathogenesis of, 109, 111–112 pathophysiology of, 112 physical findings in, 115–116 prosthetic valve, 114, 121t, 123 relapse rate in, 122–123 subacute, 112, 114, 116 treatment of, 119–123, 120–121t malignant, 109 meningitis as risk factor for, 53 as splenic abscess cause, 229 Endocervicitis, mucopurulent, 345 Endometritis, 313, 317 chlamydial infection-related, 293 Endophthalmitis aspergillosis-related, 564 candidiasis-related, 531, 536

Endotracheal aspirates handling of, 20t interpretation of results of, 23t in nosocomial pneumonia, 485–486 quality of, 21t Enfuvirtide, 724 Entamoeba histolytica, 227 as gastroenteritis cause, 147, 149, 157, 159–160, 159t serologic test for, 36t Entecavir, as hepatitis B treatment, 193 Enterobacter as calculous cholecystitis cause, 171 as liver abscess cause, 225 as urinary tract infection cause, 250t Enterobacter cloacae, as folliculitis cause, 633 Enterobacteriaceae as brain abscess cause, 101, 102 as necrotizing soft-tissue infection cause, 649 in neutropenic patients, 786 as prosthetic joint infection cause, 601 Enterococcus antimicrobial resistance determination in, 42t as cholangitis cause, 181, 183 as infective endocarditis cause, 122 as intra-abdominal sepsis cause, 239 as osteomyelitis cause, 622t as pancreatic abscess cause, 233 as prostatitis cause, 268 vancomycin-resistant, 787 Enterococcus faecalis in polymicrobial soft tissue infections, 647 as septic arthritis cause, 592 as urinary tract infection cause, 250 Enterocolitis, undiagnosed, 18 Enteropathy, tropical, 165 Enterotoxins, 145, 163 Enteroviruses as aseptic meningitis cause, 80, 81t, 82, 83, 84t assays for, 87 as encephalitis cause, 85 as pharyngotonsillitis cause, 369 as respiratory infection cause, 716–717 Enzyme immunoassays (EIA), 22, 24, 25 for chlamydial antigens, 294t, 295 for histoplasmosis, 554–555 for identification of viruses, 34 for Lyme disease, 838 Enzyme-linked immunoabsorbent assay (ELISA) for aspergillosis, 568–569 galactomannan, 568–569 for human immunodeficiency virus (HIV), 727 for Lyme disease, 838

919

Epidemics acquired immunodeficiency syndrome (AIDS), 723–724, 725–726, 726t influenza, 421, 423 rubella, 704–705 Epididymitis, 275–280 chlamydial, 293 clinical manifestations of, 276 diagnosis of, 276–277, 276t, 277t etiology of, 275–276 treatment of, 267, 278, 278f, 280, 281f, 281t, 282t, 884t urethritis associated with, 278, 278t, 279t, 280, 280t Epididymo-orchitis, 253, 275, 276, 277, 278 Epiglottitis, 381–383 as airway obstruction cause, 365 Epstein-Barr virus, 185, 801t, 814–819 assays for, 87 clinical manifestations of, 815–816, 815t complications of, 816–817 culture of, 814, 815 diagnosis of, 817–818 as encephalitis cause, 86t epidemiology of, 814 as infectious mononucleosis cause, 706–707, 708 pathogenesis of, 815 prevention of, 818 serologic tests for, 708–709 treatment of, 818 Epstein-Barr virus antibodies, 817–818, 818t Erysipelas, 629, 632t, 636–637 Erythema pharyngotonsillitis-related, 370 vulvar, 333, 340 Erythema infectiosum (fifth disease), 701t, 711–712 Erythema migrans, Lyme disease-related, 836, 837, 840 Erythema nodosum, 543 Erythrocyte sedimentation rate (ESR) in osteomyelitis, 614, 617 in prosthetic joint infections, 602 Erythromycin as Lyme disease treatment, 838, 839t as pharyngotonsillitis treatment, 372t Escherichia coli as acute calculous cholecystitis cause, 171 antimicrobial resistance determination in, 42t as appendiceal abscess cause, 235 as cellulitis cause, 635 as cholangitis cause, 181, 183 as cystitis cause, 247–248 as diarrhea cause, 146, 158t, 164 enterohemorrhagic, 153 enteroinvasive, 153 enterotoxigenic, 152–153, 164 food-borne transmission of, 163, 246

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920

Index

as gastroenteritis cause, 147, 152–153 as infected false aneurysm cause, 131 as infective endocarditis cause, 111 as meningitis cause, 52–53 as pancreatic abscess cause, 233 as pelvic inflammatory disease cause, 315 as peritonitis cause, 206, 212 in polymicrobial soft-tissue infections, 647 as prostatitis cause, 268 as septic arthritis cause, 585 as sinusitis cause, 391 as traveler’s diarrhea cause, 164 trimethoprim-sulfamethazole resistance in, 256 as urinary tract infection cause, 246, 249–250, 250t, 794 Escherichia coli 0157:H7, 144, 153, 1585t as food poisoning cause, 162 Esophagitis, candidal, 529, 530, 532, 534 Estrogen, as atrophic vaginitis treatment, 343 E-test, 41 Ethambutol side effects of, 506 as tuberculosis treatment, 495, 501, 502t, 504t, 505, 506 use during pregnancy and lactation, 510 Ethionamide, as tuberculosis treatment, 507t Exanthems, viral, 699–719 erythema infectiosum (fifth disease), 701t, 711–712 hand-foot-mouth disease, 701t, 717–718 infectious mononucleosis, 706–709, 707t, 708t measles (rubeola), 702–704 atypical, 703 differentiated from rubella, 702 roseola (exanthem subitum), 709–710, 823 rubella, 699–700, 704–706 as arthritis cause, 586 serologic test for, 36t varicella-zoster virus infection, 712–716, 715f Exanthem subitum (roseola/sixth disease), 709–710 human herpes virus type 6related, 823 Exfoliative toxin, 631 Exotoxins, 631, 648 External fixation, of osteomyelitis, 624 Eye infections aspergillosis, 564 candidiasis, 531, 535 herpetic, 805 Eye surgery patients, antimicrobial prophylaxis in, 5t F Fallopian tubes inflammation of, 293, 313

tubo-ovarian abscess of, 314, 317, 318, 322–323 Famciclovir as genital herpes treatment, 299, 299t as herpes simplex virus infection treatment, 805–806 Fasciitis, necrotizing, 631 clinical manifestations of, 650–651, 656–656t diagnosis of, 656 differentiated from cellulitis, 650–651 etiology of, 643, 648 as Fournier gangrene, 651 risk factors for, 649 streptococcal, 643, 651–652 treatment of, 656–657 varicella (chickenpox)-related, 809 Femoral artery false aneurysm of, 131 mycotic aneurysm of, 133 Fever bacterial meningitis-related, 55, 59, 62 bacterial vaginosis-related, 328 blastomycosis-related, 522 brain abscess-related, 95–96, 95t calculous cholecystitis-related, 172 as Charcot’s triad component, 168 cholangitis-related, 181 encephalitis-related, 86 human herpes virus type 6-related, 823 infective endocarditis-related, 114–115, 115t Lyme disease-related, 836, 836t, 837t malaria-related, 853, 857 meningitis-related, 82 neutropenia-related, 786, 787 pneumonia-related, 405, 456 postpartum, 328 septic thrombophlebitis-related, 135 severe acute respiratory syndrome-related, 428 sinusitis-related, 388 varicella (chickenpox)-related, 807 Fifth disease (erythema infectiosum), 701t, 711–712 Fight wounds, 687 Filariasis, 165 Fistula, cholecystenteric, 173 Fitz-Hugh and Curtis syndrome, 174 Flaps, for osteomyelitis treatment, 624–625 Flaviviridae, 186t, 194 Flesh-eating bacteria syndrome, 648 Fluconazole as blastomycosis treatment, 525 as candidiasis treatment, 528, 534, 535, 536, 537–538, 537t as coccidioidomycosis treatment, 541, 542, 546t as cryptococcal meningitis treatment, 768–769

as vulvovaginal candidiasis prophylaxis, 342 as vulvovaginal candidiasis treatment, 341 Flucytosine as aspergillosis treatment, 574 as cryptococcal meningitis treatment, 768–769 Fluorescent antibody tests, 22, 24–25, 34 for herpes simplex virus, 805 for varicella-zoster virus, 810–811 Fluoridation, 163 Fluoroquinolones bacterial resistance to, 144, 152, 452–453 as cystitis treatment, 255 as pneumonia treatment, 468–469, 470 as tuberculosis treatment, 496, 507t Flutacasone, as bronchitis treatment, 411, 413 Folic acid, 10 Folliculitis, 629, 632t, 633–634 staphylococcal, 630 whirlpool, 632t, 633–634 Food-borne disease amebiasis, 157 Cyclospora diarrhea, 162 food-poisoning, 144, 146, 150, 153, 162–166 giardiasis, 160 hepatitis A, 187, 188 urinary tract infections, 246 Vibrio parahaemolyticus-related, 154 Food poisoning, 144, 146, 150, 153, 162–166 Foot infections, in diabetic patients, 650, 663–679, 788, 789 as amputation cause, 663, 665, 668, 671–672 classification of, 665–666, 666t clinical management of, 665–666 diagnosis of, 670 microbiology of, 667–670, 668t, 669t pathophysiology of, 664–665 prevention of, 675–677 treatment of, 664, 670–675, 671f, 672f, 673f, 675t, 676f Foscarnet as cytomegalovirus retinitis treatment, 772, 773t, 774t, 775 as herpes simplex virus infection treatment, 805–806 Fosfomycin, as cystitis treatment, 256 Fractures, bite wounds-related, 688, 689 Francisella tularensis, 368 Frontal lobe, abscess of, 93 Fungal infections. See also Fungi; specific fungal infections cell-mediated immunity in, 780t diagnostic tests for, 24 as liver abscess cause, 225 as meningitis cause, 63, 81t neutropenia as risk factor for, 785

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Index as pancreatic abscess cause, 233 as peritonitis cause, 207t as pharyngotonsillitis cause, 367t serologic test for, 36t as urinary tract infection cause, 794 Fungemia, 93, 531, 537 Fungi classification of, 32t cultures of, 18t identification of, 32 isolation from intra-abdominal fluid, 239 morphology of, 32 Fungitell assay, 533 Fungus balls, 531, 564–565 Furuncles, 632t, 634, 640 Furunculosis, 629, 630, 639 recurrent, 632t, 901t Fusarium diagnostic assay for, 569 treatment of, 571 Fusobacterium as abscess cause, 377 as infected false aneurysm cause, 131 as pharyngotonsillitis cause, 374 G Galactomannan enzyme-linked immunoabsorbent assay, 568–569 Gallstone disease. See Cholelithiasis Gallstone ileus, 173 Ganciclovir as cytomegalovirus retinitis treatment, 772, 773t, 774t, 775 as herpes simplex virus infection treatment, 805–806 Gangrene diabetic foot infection-related, 666, 668, 673 Fournier, 651 gas. See Myonecrosis, clostridial infected vascular, 645–646t necrotizing fasciitis-related, 650 progressive bacterial synergistic, 653 Gardnerella vaginalis as pelvic inflammatory disease cause, 315 as vaginosis cause, 327, 328, 329, 331 Gas, in soft tissue, 649–650 Gastroenteritis, 143–162 bacterial, 143, 146–147, 150–157 diagnosis of, 146–147 epidemiology of, 144–145 etiology of, 145–146 pathogenesis of, 143, 145 protozoal, 143, 146–147, 157, 158–159t, 159–160 treatment of, 147–149, 148f viral, 143, 146–147, 149–150 Gastrointestinal infections. See also Diarrhea; Gastroenteritis aspergillosis, 566–567 risk of, 146 treatment of, 876–880t Gastrointestinal surgery patients, antimicrobial prophylaxis in, 5t

Gastrointestinal tract, perforation of, 205, 211, 214 Gatifloxacin, as bronchitis treatment, 413t Gaze disorders, 58 Gemifloxacin as bronchitis treatment, 413t as pneumonia treatment, 464, 466 Genital herpes infections. See Herpes simplex virus, as genital infection cause Genital ulcerative diseases (GUDs), 284–312, 285t chancroid, 305–307, 307t Genitourinary infections, treatment of, 880–884t Gentamicin as bacterial meningitis treatment, 73 as infected false aneurysm treatment, 132 as pelvic inflammatory disease treatment, 321t German measles. See Rubella Gianotti-Crosti syndrome, 823 Giardiasis, 147 as diarrhea cause, 160–161, 165 treatment of, 144, 158t Giemsa stain, 24 of Ehrlichia chaffeensis, 840 of Plasmodium, 857–858 Gingivostomatitis, herpetic, 802–803, 804t Glomerulonephritis membranous, 190 post-streptococcal, 635 syphilitic, 301 Glucocorticoids, as meningitis treatment, 68, 70–71 Glucose, in cerebrospinal fluid, 60, 62–63 Glucose tolerance testing, 337 prior to antiretroviral therapy, 754 Gonococcal infections arthritis, 584t, 586–587 cervicitis, 344–345, 347–439 conjunctivitis, 287–288 disseminated, 288, 288t pharyngitis, 287 rectal, 287 septic arthritis, 586–587, 588, 589t, 592, 594, 595, 596 treatment of, 290–291, 291t urethritis, 279, 287–289, 288t, 292 Gonorrhea in adults, 286–292 coinfection with pelvic inflammatory disease, 316 diagnosis of, 288–290, 288t, 290t in men, 286–287 treatment of, 349 in women, 287 Gout, 588, 589t, 590 Gram-negative bacteria antimicrobial resistance in, 42t, 785–786 classification and identification of, 28–30t as meningitis cause, 52, 73–74 as septic arthritis cause, 585

921

Gram-positive bacteria antimicrobial resistance in, 42t classification and identification of, 28t as peritonitis cause, 206–207, 215, 217–218 Gram stain, 24, 25t for gonorrhea diagnosis, 288–289, 290t of synovial fluid, 590, 592 Granulocyte count, 785 Granulocyte growth factors, 788 Granulomatous disease, chronic, 784 as aspergillosis risk factor, 561t Grey Turner sign, 233 Groin, false aneurysm in, 131 Guaifenesin, 408 Guillain-Barré syndrome, 152, 810 Gummata, 301–302 Gynecologic surgery patients, antimicrobial prophylaxis in, 5t H HACEK organisms as infective endocarditis cause, 112–113, 113t, 117, 118t, 119, 121t treatment of, 887t Haemophilus as bite-wound infection cause, 692t as infective endocarditis cause, 112 Haemophilus aphrophilus, as infective endocarditis cause, 112 Haemophilus ducreyi, as genital ulcer cause, 285t, 305, 306 Haemophilus influenzae antigen detection tests for, 25 antimicrobial resistance determination in, 42t as bacterial meningitis cause, 60 blood culture of, 60 as bronchitis cause, 401, 403 as chronic bronchitis exacerbation cause, 410 as chronic obstructive pulmonary disease cause, 402 as epiglottitis cause, 383 humoral immunity and, 783 as meningitis cause, 50, 52, 53, 54, 61 prevention of, 76–77 treatment of, 75t as otitis media cause, 395, 396 as pelvic inflammatory disease cause, 315 as pharyngotonsillitis cause, 368, 374 as pneumonia cause, 423, 454, 467t, 490t as septic arthritis cause, 584t, 587 as sinusitis cause, 390 Haemophilus influenzae type B vaccine, use in asplenic patients, 791 Haemophilus influenzae vaccine, 365 Half-life, of drugs, 9–10 Hallucinations, encephalitisrelated, 87 Halofantrine, 867

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922

Index

Hand-foot-mouth disease, 701t, 717–718 Hantavirus infections, 444–445, 454 Headaches bacterial meningitis-related, 55, 62 brain abscess-related, 95–96, 95t cerebral toxoplasmosis-related, 766 cryptococcosis-related, 768 encephalitis-related, 86 genital herpes-related, 297 human granulocytic anaplasmosis-related, 849 human monocytic erhlichiosisrelated, 849 infective endocarditis-related, 115t influenza-related, 423 Lyme disease-related, 836, 836t, 837t meningitis-related, 82 sinusitis-related, 389 Head and neck surgery patients, antimicrobial prophylaxis in, 5t Health care workers hepatitis B risk in, 193–194 influenza vaccination in, 424 varicella-zoster virus exposure in, 812 Hearing loss bacterial meningitis-related, 58 otitis media-related, 395 Heart block, Lyme diseaserelated, 836–837, 838, 840 Heart murmurs, infective endocarditis-related, 116 Heat therapy, for otitis externa, 399 Heavy metal poisoning, 163 Helicobacter pylori, 729 serologic test for, 36t Helminths, classification of, 33t Hemagglutination tests indirect, 227 inhibition antibody, 706 Hematogenous infections, of joints, 582 Hematologic cancer, as neutropenia cause, 787, 788 Hematologic diseases, cellmediated immunity in, 781t, 782 Hematoma infected, excision of, 133 as prosthetic joint infection risk factor, 600–601 Hematuria, 252 Hemiparesis, bacterial meningitisrelated, 58 Hemodialysis, in diabetic patients, 789 Hemolysin, 250 Hemolytic uremic syndrome, 94, 144, 152, 153, 155 Hemoptysis aspergilloma-related, 565, 574–575 tuberculosis-related, 498 Hepadnaviridae, 186t, 189 Hepatitis, 185–203 A, 185, 186–189, 186t, 187f antibodies in, 188t as arthritis cause, 586

B, 185, 186t, 189–194, 191f, 192t, 193f bite wound-related, 687, 688 coinfection with hepatitis D, 197–198, 198f C, 185, 186t, 194–197 bite wound-related, 687, 688 D, 185, 186t, 197–199 drug-induced, 501 E, 185, 186t, 199–200, 200f human herpes virus type 6related, 823 as isoniazid contraindication, 513 serologic test for, 36t sexual transmission of, 285t syphilitic, 301 tuberculosis therapy-related, 511 varicella (chickenpox)-related, 809 Hepatitis vaccines, 189, 189t, 190, 193–194, 197 Hepatocellular carcinoma, 185, 190, 195 Herpes gladiatorum, 803–804, 804t Herpes rugbiorum, 803–804 Herpes simplex virus assays for, 87 as cervicitis cause, 344–345, 348 clinical manifestations of, 801t, 802–805 diagnosis of, 805 as encephalitis cause, 80, 84t, 85, 86, 87, 88 epidemiology of, 800, 802 as genital infection cause, 285t, 296–300, 800, 801t, 802 clinical manifestations of, 296–297 diagnosis of, 297–298 epidemiology of, 296 etiology of, 296 first-episode, 297, 299 prevention of, 300 recurrent, 297, 299–300 treatment of, 299–300, 299t pathophysiology of, 802 as respiratory infection cause, 436–438 treatment of, 804t, 805–806 Herpes simplex virus antigen detection, 298 Herpesviridae, 435 Herpes virus infections, 800–830 cerebrospinal fluid in, 59 Epstein-Barr virus, 185, 801t, 814–819 clinical manifestations of, 815–816, 815t complications of, 816–817 culture of, 814, 815 diagnosis of, 817–818 as encephalitis cause, 86t epidemiology of, 814 as infectious mononucleosis cause, 706–707, 708 pathogenesis of, 815 prevention of, 818 serologic tests for, 708–709 treatment of, 818 herpes simplex virus as cervicitis cause, 344–345, 348

clinical manifestations of, 801t, 802–805 diagnosis of, 805 as encephalitis cause, 80, 84t, 85, 86, 87, 88 epidemiology of, 800, 802 genital, 285t, 296–300, 800, 801t, 802 pathophysiology of, 802 as respiratory infection cause, 436–438 treatment of, 804t, 805–806 human herpes virus type 6, 709–710, 801t, 822–824 human herpes virus type 7, 700, 701, 709, 801t, 824–825 human herpes virus type 8, 801t, 825–828 as respiratory infection cause, 421, 435–440 varicella-zoster virus, 806–814 clinical manifestations of, 807–810 diagnosis of, 810–812 epidemiology of, 806–807 pathophysiology of, 807 prevention of, 812–814 as respiratory infection cause, 421, 438–440 Herpesvirus simiae, 687 Herpes zoster (shingles), 439–440, 701, 713, 715t, 716 clinical manifestations of, 809–810 diagnosis of, 810–811, 811–812 epidemiology of, 807 as necrotizing soft-tissue infection risk factor, 649 pathophysiology of, 807 treatment of, 811–812 Hidradenitis suppurativa, 633t, 637, 640 Highly active antiretroviral therapy (HAART) Highly-active antiretroviral therapy (HAART). See Antiretroviral therapy, highly-active Histoplasma, differentiated from Blastomyces dermatitidis, 553 Histoplasma capsulatum. See also Histoplasmosis serologic test for, 36t Histoplasmosis, 549–558 AIDS-related, 550 aspergillomas associated with, 564 asymptomatic, 549, 551 of central nervous system, 553–554, 557 clinical manifestations of, 551–554, 552t conidia in, 551 cross-reactivity with blastomycosis, 555 definition of, 549 diagnosis of, 554–555 differentiated from tuberculosis, 500 disseminated, 552t, 556–557 epidemiology of, 549–551, 550f fibrosing mediastinitis and, 552–553, 552t, 555t granulomatous mediastinitis and, 552–553, 552t, 554, 555t, 556

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Index hematogenous dissemination of, 551 latent, 551 pathogenesis of, 551 progressive disseminated, 549, 550, 553, 554, 557 prophylaxis for, 557 pulmonary, 549, 551–553, 552t, 554, 556 reactivation of, 551 reinfection with, 551 treatment of, 549, 550, 555–557, 555t, 571 as tuberculosis mimic, 552 Hodgkin’s lymphoma, 780t, 782 Hospitalization of bite-wound patients, 694 of pneumonia patients, 451, 460–473 of prostatitis patients, 271 of pyelonephritis patients, 256, 256t Host defense mechanisms, 779 Hot tub folliculitis, 638 Howell-Jolly bodies, 790 Human B-cell lymphotropic virus (HBLV), 822 Human bite wounds, 681, 682, 685 as cellulitis cause, 636t classification of, 687 clinical manifestations of, 688 epidemiology of, 682 etiology and microbiology of, 683 treatment of, 693–694t Human herpes virus(es), assays for, 87 Human herpes virus type 6, 709–710, 801t, 822–824 Human herpes virus type 7, 700, 701, 709, 801t, 824–825 Human herpes virus type 8, 801t, 825–828 Human immunodeficiency virus (HIV) infection, 284, 723–759 antiretroviral therapy for, 724, 730–756 commercially available, 731, 733–734t, 736 HIV protease inhibitors, 731, 735t interaction with rifampin, 509 nonnucleoside reverse transcriptase inhibitors, 731, 734t nucleoside reverse transcriptase inhibitors, 731, 733–734t with nucleoside reverse transcriptase inhibitors, 723 with protease inhibitors, 723 toxicity of, 731, 732–733t arthritis associated with, 586 assays for, 87 bacterial vaginosis as risk factor for, 328, 329t bite wound-related, 687, 688 as brain abscess risk factor, 90, 91–92, 94t, 101 cell-mediated immunity in, 782 chancroid associated with, 306–307 cryptosporidial diarrhea associated with, 161 diagnosis of, 727–730 drug-resistant, 730

epidemiology of, 725–726 hepatitis C associated with, 195 highly-active (HAART) antiretroviral therapy for, 509, 723, 761 adherence to, 747–748 CD4+ T cell count in, 740–741, 742, 743 drug interactions in, 745–747, 746t drug-resistant, 738–739 failure of, 748–749 immune reconstitution syndrome and, 752 initiation of, 729, 740–742, 740t, 741t lifelong use of, 747 optimal, 737–738 in patients with AIDS-defining illnesses, 750–751 in patients with hepatic disease, 751–752 in patients with kidney disease, 749–750 recurrent acute retroviral syndrome and, 752–753 in treatment-experienced patients, 745 in women, 743–744, 744t HIV superinfection in, 729 laboratory tests for, 730t maternal-fetal transmission of, 743–744, 744t as meningitis cause, 84t natural history of, 726–727, 727f nonoccupational exposurerelated, 754–756, 755t occupational exposure-related, 754–756, 755t oral thrush associated with, 530 pneumococcal pneumonia associated with, 452 prevention of, 754–756, 755t serologic test for, 36t sexual transmission of, 285t syphilis associated with, 302 testing for, 724 trichomoniasis associated with, 333 in tropical countries, 165 tuberculosis associated with, 508–509, 729 tuberculosis treatment in, 505 tubo-ovarian abscess associated with, 314 viral load in, 727, 728 virology of, 724–725 vulvovaginal candidiasis associated with, 339 Human metapneumovirus, 418, 432–433, 454 Human papilloma virus, 352–361 cervicitis and, 346 clinical manifestations of, 354–356, 355t diagnosis of, 285 epidemiology of, 353–354 as molluscum contagiosum cause, 285t pathogenesis of, 353 patient education about, 360t prevention of, 359, 360t testing for, 352

923

Human papilloma virus vaccine, 352, 359 Humoral immunity, 781, 782–784 deficiencies in, 783–784, 783t in multiple myeloma, 792 in systemic lupus erythematosus, 793 Hydrocephalus, bacterial meningitis-related, 57 Hydrosalpinx, 317 Hydroxymethylglutarylcoenzyme A reductase inhibitors, 746, 754 Hyperbaric oxygen therapy for necrotizing soft-tissue infections, 659 for osteomyelitis, 610, 625 Hypergammaglobulinemia, 112 Hyperglycemia, 788–789 pneumonia-related, 471 Hyperinsulinemia, 753, 754 Hyperpnea, bacterial meningitisrelated, 58 Hyponatremia, bacterial meningitis-related, 61 Hyposplenia, 784 Hypotension bacterial meningitis-related, 58 as necrotizing fasciitis risk factor, 652 I Ileal conduit, as urinary tract infection cause, 262 Ileus, gallstone, 173 Imaging with computed tomography. See Computed tomography with magnetic resonance imaging. See Magnetic resonance imaging with ultrasound. See Ultrasonography with x-rays. See X-rays Immobilization in bite-wound infections, 695 of septic joints, 596 Immune complexes, in infective endocarditis, 112 Immune reconstitution inflammatory syndrome (IRIS), 509, 752, 770 Immune response to fungi, 551 in human immunodeficiency virus (HIV) infection, 726–727, 727f in sinusitis, 389t in trichomoniasis, 332–333 Immunity cell-mediated, 779 disorders of, 779, 780–781t, 781–782 in multiple myeloma, 792 in systemic lupus erythematosus, 793 humoral, 781, 782–784 disorders of, 783–784, 783t in multiple myeloma, 792 in systemic lupus erythematosus, 793 serologic tests for, 37 Immunization. See Vaccines Immunoblot tests, for Lyme disease, 838

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924

Index

Immunocompromised patients. See also Acquired immunodeficiency syndrome (AIDS); Human immunodeficiency virus (HIV) infection antifungal prophylaxis in, 538 aspergillosis in, 559, 560, 561, 567 invasive, 565–566 asplenia in, 792–793 bacterial meningitis in, 52 biliary tract infections in, 169 brain abscess in, 90, 91, 92, 100 cell-mediated immunity in, 779, 780–781t, 781–782 coccidioidomycosis in, 541, 546, 547 corticosteroids use and, 794–796 cryptosporidial diarrhea in, 161 cytomegalovirus infections in, 441, 819, 822 gastroenteritis in, 147–148, 150–151 herpes zoster (shingles) in, 810 histoplasmosis in, 553, 554–555, 556–557 human monocytotropic ehrlichiosis in, 842 humoral immunity in, 782–784, 783t influenza vaccination in, 424 measles prophylaxis in, 434–435 mechanical defense barriers in, 779 neutropenia in, 785–788 opportunistic infections in, 777–799 osteomyelitis in, 616 otitis externa in, 398–399 pneumonia in, 417 polymorphonuclear leukocytes in, 784, 785t respiratory syncytial virus infections in, 431 respiratory tract infections in, 422f, 435–436 rhinocerebral mucormycosis in, 391 sinusitis in, 387 systemic lupus erythematosus in, 793–794, 795 tuberculosis in, 497, 498 viral encephalitis treatment in, 88 Immunodiffusion assays for coccidioidomycosis, 545 for histoplasmosis, 554 Immunoglobulin A deficiency, 160 Immunoglobulin G human varicella, 812–813 in humoral immunity, 782, 783 serologic detection of, 37–38 Immunoglobulin M in humoral immunity, 782 serologic detection of, 37 splenic production of, 789 Immunopathy, as osteomyelitis risk factor, 612 Immunosuppressed patients. See Immunocompromised patients

Immunosuppression, as pyelonephritis risk factor, 248 Immunosuppressive drugs discontinuation in vulvovaginal candidiasis, 342 effect on cell-mediated immunity, 782 effect on polymorphonuclear neutrophils, 784, 785t as infection risk factor, 795–796 Impetigo, 629, 632t, 634–635, 638, 639, 641 bullous, 634, 635 differentiated from varicellazoster virus, 810 Infants antiretroviral therapy in, 744 bacterial meningitis in, 57 congenital rubella syndrome in, 704–705 hematogenous osteomyelitis in, 610–611, 613 human herpes virus type 6 infections in, 822–824 respiratory syncytial virus infections in, 430–432 septic arthritis in, 584, 584t, 585t varicella infection in, 809 Infections cell-mediated immunity in, 780t, 782 inflammatory response to, 38–39 Infectious mononucleosis, 706–709, 707t, 708t, 814–819 clinical manifestations of, 815–816, 815t complications of, 816–817 diagnosis of, 817–818 epidemiology of, 814 etiology of, 369 pathogenesis of, 815 prevention of, 818 treatment of, 818 Infertility chlamydial infection-related, 293 orchitis-related, 275 pelvic inflammatory diseaserelated, 313, 323–324 Infiltrates, pulmonary, 786–787 Inflammation brain abscess-related, 92 cervical, 328, 333, 345–346 endocardial. See Endocarditis gastrointestinal, 145–146 joint infection-related, 582 meningeal. See Meningitis necrotizing soft tissue infection-related, 649, 650 otitis externa-related, 399 pelvic. See Pelvic inflammatory disease peritoneal. See Peritonitis prosthetic joint infectionrelated, 601 septic thrombophlebitisrelated, 134, 135 streptococcal infection-related, 649, 650 vulvar, 343, 344t

Inflammatory bowel disease, 94t, 95 Inflammatory diarrhea, 145–146, 147–148, 150 Inflammatory disease, as brain abscess risk factor, 90, 94t Inflammatory response in bacterial meningitis, 54, 55 to infection, 38–39 Infliximab as necrotizing fasciitis risk factor, 649 as reactivated tuberculosis risk factor, 511 Influenza avian, 418, 427 as bronchitis cause, 403 as chronic bronchitis exacerbation cause, 410 diagnosis of, 423–424 diagnostic tests for, 434 epidemics of, 421, 423 etiology of, 423 high risk groups for, 424, 425t pandemics of, 427, 455 pathogenesis of, 423 as pneumonia cause, 455 with superimposed bacterial infections, 423 treatment of, 424–427 Influenza vaccine, 397, 408, 413, 424, 474 Influenza viruses, 417, 421 amantadine-resistant, 418, 425, 427 antigenic drift in, 424, 425 antigenic shift in, 424–425 N5N1, as pneumonia cause, 454–455 rimantadine-resistant, 418, 425, 427 Inhibitory concentration measurement (IC50), 737 Inhibitory quotient, 737 Insect bites, as necrotizing fasciitis risk factor, 651 Intensive care unit admission, of pneumonia patients, 460–461 Interferon as hepatitis B treatment, 193 as hepatitis C treatment, 196–197 as hepatitis D treatment, 199 as severe acute respiratory syndrome treatment, 430 Interleukin(s), in urinary tract infections, 249–250 Interleukin-1 in bacterial meningitis, 54 in streptococcal soft-tissue infections, 648–649 Interleukin-5, in bacterial meningitis, 54 International Classification of Diseases, 9th Edition, 17 Intertriginous areas, candidiasis of, 530 Intra-abdominal fluid, isolation of fungi from, 239 Intra-articular injections, as septic arthritis cause, 582 Intracranial pressure elevation in bacterial meningitis, 57, 58, 60

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Index brain abscess-related, 96 in encephalitis, 87 Intracranial tumors, as meningitis cause, 64, 82t Intraepithelial neoplasia, cervical, 352, 353, 354, 355, 355t diagnosis of, 356–357 treatment of, 358–359, 358t Intramedullary rods, infection of, 621 Intraocular lens, Candida contamination of, 531, 536 Intrauterine devices (IUDs), 322–323 Intravenous access sites, as splenic abscess cause, 229 Intravenous drug abuse as AIDS risk factor, 726t as aspergillosis risk factor, 566, 567 as bacteremia risk factor, 94 as candidiasis risk factor, 531 as endocarditis risk factor, 566 as hepatitis B risk factor, 190 as hepatitis C risk factor, 195 as infected false aneurysm risk factor, 130, 133 as infective endocarditis risk factor, 110, 113t, 116 as necrotizing soft tissue infection risk factor, 649 as septic arthritis risk factor, 585 as splenic abscess risk factor, 229 as superficial skin infection risk factor, 630 Intravenous immunoglobulin as cytomegalovirus pneumonia treatment, 442–443 as necrotizing fasciitis treatment, 657 as necrotizing soft-tissue infection treatment, 657, 659 use in multiple myeloma patients, 792 Intravenous-line infections, 887 In-vitro antimicrobial susceptibility tests, 39 antibiograms, 44, 45t antimicrobial assays, 44 minimum inhibitory concentration test, 39–41 Irrigation, of bite wounds, 683, 689–690 Irritable bowel syndrome, 164–165 Ischemia, as osteomyelitis risk factor, 612 Isolation, of varicella-zoster virus-infected patients, 812 Isoniazid resistance to, 510 side effects of, 505–506, 512–513, 516 as tuberculosis treatment, 495, 501, 502t, 504t, 505–506 for latent disease, 514, 515t, 516 use during pregnancy and lactation, 510 Isosporiasis, treatment of, 159t Itraconazole as aspergillosis treatment, 570, 570t, 572–573

as blastomycosis treatment, 521, 524t, 525, 526 as candidiasis treatment, 341, 341t, 534, 572 as coccidioidomycosis treatment, 541, 542, 545, 546t drug interactions of, 573 as histoplasmosis treatment, 549, 555t, 556 side effects of, 573 as vulvovaginal candidiasis treatment, 341, 341t J Janeway lesions, 115 Jaundice acute calculous cholecystitisrelated, 172 as Charcot’s triad component, 168 cholangitis-related, 181 hepatitis-related, 187, 199, 586 Job syndrome, 630–631 Joint effusions osteomyelitis-related, 613 synovial fluid analysis of, 588 Joint infections, treatment of, 871–873t Joint replacement-related infections. See Prosthetic joint infections Joints, inflammed/swollen. See also Arthritis, septic differential diagnosis of, 581, 588, 588t K Kaposi sarcoma, 825–826 Kaposi sarcoma-associated herpesvirus (KSHV), 825–828 Kaposi varicelliform eruption, 804–805, 804t Keratitis, herpetic, 804t Keratoconjunctivis, herpetic, 805 Kernig sign, 55 Ketoacidosis, diabetic, 789 Ketoconazole hepatotoxicity of, 341 as vulvovaginal candidiasis treatment, 341, 341t Ki, as infective endocarditis cause, 112 Kidney polycystic, 260 single, 260 Kingella kingae, as septic arthritis cause, 584, 590 Kinyoun acid-fast stain, 24 Klebsiella antimicrobial resistance determination in, 42t as cholangitis cause, 181, 183 as infected false aneurysm cause, 131 as urinary tract infection cause, 250, 250t Klebsiella pneumoniae as calculous cholecystitis cause, 171 as nosocomial pneumonia cause, 490t as pancreatic abscess cause, 233 as peritonitis cause, 206 in polymicrobial soft tissue infections, 647

925

Koch, Edward, 127 Koplik spots, 435, 702–703 Kunjin virus, 85 Kupffer cells, 226 L Laboratory tests and diagnoses, microbiological, 15–46, 16t antigen detection, 16, 16t biopsy of bone, in osteomyelitis, 616 cerebral, 87, 98, 768 endometrial, 317 hepatic, in hepatitis C, 196 in histoplasmosis, 554 specimen interpretation in, 38–39 clinician-laboratory communication regarding, 16–17 culture, 16t classification and identification of organisms in, 27, 28–30t, 30, 32, 32t, 33–34, 34–35t collection of specimens, 20–21 handling of specimens, 17, 20, 20t interpretation of results in, 22, 23–24t principles of, 18–19 screening of specimens, 21–22, 21t selection of specimens for, 19t specimen handling in, 17 specimens for, 19–21 transportation of specimens, 20, 20t histopathologic examinations, 16t in-vitro antimicrobial susceptibility tests, 39 antibiograms, 44, 45t antimicrobial assays, 44 minimum inhibitory concentration test, 39–41 new developments in, 15–16 non-culture-based tests, 19, 22, 24–26 enzyme immunoassays (EIA), 25 fluorescent antibody screening, 24–25 latex agglutination tests, 22, 23, 25–26, 27, 768 microscopic examinations, 16t, 24 molecular assays/probes, 26, 26t serologic tests, 16, 16t, 36–38, 37t nuclear acid detection test, 16, 16t processing in, 17–18 rapid testing, 22, 24–26 synergy testing, 43 Lactation. See also Breastfeeding tuberculosis treatment during, 510 Lactobacillus as gastroenteritis prophylaxis, 149 interaction with Candida, 337–338 vaginal, 327–328, 331, 343 recolonization with, 332

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926

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Lamivudine, as hepatitis B treatment, 193 Laparoscopic treatment, of pyogenic liver abscesses, 228 Lassa virus, 185 Latex agglutination assays, 22, 24, 25–26, 27, 768 Left upper quadrant pain, infective endocarditis-related, 116 Legionella, as pneumonia cause, 452, 453, 468t, 484, 490t Legionella pneumophila, as pneumonia cause, 454 Legionella urinary antigen test, 463 Leptomeningeal infections, 57 Leptospirosis, 687 serologic test for, 36t Leukemia, chronic lymphocytic, 783 Leukergy, 617 Leukocyte(s) fecal, 145–146, 146f, 147 in osteomyelitis, 617 polymorphonuclear in bacterial meningitis, 59 in cervicitis, 348 in trichomoniasis, 332, 333 Leukocyte adhesion molecules, 54 Leukocyte count. See also Leukocytosis in bacterial meningitis, 62 in brain abscess, 100 in infective endocarditis, 116 in osteomyelitis, 617 in pelvic inflammatory disease, 316–317 in septic arthritis, 588 in synovial fluid, 592, 595 Leukocyte esterase test, 252 Leukocytosis bronchitis-related, 404 cholangitis-related, 182 cholecystitis-related, 173 diverticular abscess-related, 238 Epstein-Barr virus infectionrelated, 817 false aneurysm-related, 131 infective endocarditis-related, 116 liver abscess-related, 227 mycotic aneurysm-related, 127 necrotizing soft tissue infection-related, 655 nosocomial pneumonia-related, 485 Leukopenia, 845 Levofloxacin as bronchitis treatment, 413t as pelvic inflammatory disease treatment, 314, 320t, 321t, 322t as pneumonia treatment, 464–465 Lincomycin, as pharyngotonsillitis treatment, 375 Linezolid, 610, 674–675 Lipoatrophy, antiretroviral therapy-related, 753, 754 Listeria as food poisoning cause, 162 as meningitis cause, 73, 75t

Listeria monocytogenes, as meningitis cause, 52–53 Liver abscess of, 159–160, 224–228 acute calculous chlecystitisrelated, 174 acute calculous cholecystitisrelated, 174 amebic, 159–160, 224, 226, 227, 228, 231t biliary tract infection-related, 173 as brain abscess cause, 92 cholangitis-related, 182 clinical manifestations of, 226 diagnosis of, 226–227 etiology of, 225 pyogenic, 224, 225, 226, 227–228, 231t treatment of, 227–228, 231t candidiasis of, 533 Liver cancer, as hepatic abscess cause, 225 Liver transplantation, 185, 193 Low birth weight, 248 Lumbar puncture. See also Cerebrospinal fluid in bacterial meningitis, 57 contraindication to, 60 in cryptococcosis, 769 Lung abscess of, 92, 128 blastomycosis of, 521, 522–523, 524t, 525, 526 embolism in, 136 histoplasmosis of, 549, 551–553, 552t, 554, 556 Lupus erythematosus. See Systemic lupus erythematosus Lyme disease, 833–840 clinical manifestations of, 836–837, 837t, 848–849, 848t diagnosis of, 833, 837–838 epidemiology of, 835, 841t etiology of, 835 prognosis in, 848 serologic test for, 36t treatment of, 833, 838, 839t, 840 Lymphocytic choriomeningitis virus, 84t, 586 Lymphoma Burkitt, 816 cell-mediated immunity in, 780t, 782 Hodgkin’s, 780t, 782 primary effusion, 825–826, 827 Lymphosarcoma, 783 M Macrolide antibiotics, as pharyngotonsillitis treatment, 373 Magnetic resonance imaging (MRI) of bacterial meningitis, 60 of brain abscess, 91, 97–98, 97f, 98, 103 of candidiasis, 533 of liver abscesses, 226 of osteomyelitis, 617–618, 619 of septic arthritis, 590 of septic thrombophlebitis, 137 of splenic abscesses, 230

Malaria, 853–869 cerebral, 857 clinical manifestations of, 856–857 diagnosis of, 857–858 epidemiology of, 853–854 etiology of, 854, 856 multiple-drug-resistant, 867–868 prevention of, 853, 860t, 868 treatment of, 853, 858–868, 861–862t Malorone, 862t, 865–866, 868 Marburg virus, 185 Massage, prostatic, 270 Mastoiditis, 395 Measles, 434–435, 702–704 atypical, 703 differentiated from rubella, 702 German. See Rubella serologic test for, 36t Measles-mumps-rubella vaccine, 699–700 Measles vaccine, 434–435, 704 Mechanical defense barriers, 779 Mechanical ventilation, in chronic bronchitis patients, 411 Mediastinitis, histoplasmosisrelated, 552t fibrosing, 552–553, 552t, 555t granulomatous, 552–553, 552t, 554, 555t, 556 Medico-legal considerations, in bite wound treatment, 696 Mefloquine, 860, 861t, 863 Megacolon, 157 Men cystitis in, 252 gonorrhea in, 286–287 Meningismus, cryptococcosisrelated, 768 Meningitis amebic, 60 aseptic, 62–63 enteroviral, 57, 62–63 varicella (chickenpox)-related, 808 West Nile virus-related, 85 asplenia as risk factor for, 790 bacterial, 49–79 clinical evaluation of, 55–59 diagnosis of, 50, 55–59 differential diagnosis of, 62–65, 82–83 differentiated from aseptic meningitis, 82–83 epidemiology of, 50, 52 etiology of, 52–53 laboratory diagnosis of, 59–61 meningococcal, 55, 56 mortality rate in, 49 nosocomial, 53 pathophysiology of, 53–55 radiologic studies of, 61–62 treatment of, 65–75 cerebrospinal fluid in, 65–67 empiric, 68, 69f, 70–71 hazards of, 67 initiation of, 67–68 bite wound-related, 688 brain abscess associated with, 96 chemical, 64

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Index coccidioidal, 541, 544, 545, 547 community-acquired, 50, 51 cryptococcal, 760, 768–769, 890–891t fungal, 63 cerebrospinal fluid in, 60 genital herpes-related, 297 granulomatous, 56 hypersensitivity, 64–65 immunization against, 53 leptospiral, 63 Lyme disease-related, 838 Mollaret, 64–65 mycotic aneurysm-related, 128 neonatal, 52–53 overwhelming postsplenectomy infection (OPSI)-related, 789–791, 790t prevention of, 75–77 pyogenic, 63, 64 sinusitis-related, 392 syphilis-related, 301 systemic lupus erythematosusrelated, 793–794 treatment of, 65–75 tuberculous, 60, 63, 508 viral, 50 aseptic, 62, 80–83, 81–82t, 84t echovirus-related, 62 Meningococcal vaccines, 76 use in asplenic patients, 791 Meningoencephalitis definition of, 84 herpes zoster (shingles)related, 810 Menstruation, as pelvic inflammatory disease risk factor, 316 Mental status evaluation, in brain abscess patients, 96 Metabolic syndrome, 753–754 Methicillin resistance, in Staphylococcus aureus. See Staphylococcus aureus, methicillinresistant Metronidazole as amebic liver abscess treatment, 228 bacterial resistance to, 331, 334–335 as bacterial vaginosis treatment, 330–331, 332 as brain abscess treatment, 99t, 101 as clostridial diarrhea treatment, 156–157 as giardiasis treatment, 161 as infected false aneurysm treatment, 132, 133 as pelvic inflammatory disease treatment, 320t, 321t side effects of, 335 tetragenicity of, 335 as trichomoniasis treatment, 333, 334–335 Micafungin as aspergillosis treatment, 574 as candidiasis treatment, 536 Microsporidiosis, 159t, 161 Minimum inhibitory concentration (MIC), 3, 12, 39–41 breakpoint in, 40 in surgical patients, 3 as synergy test surrogate, 43

Minimum inhibitory concentration90 (MIC90) Minocycline, 75–76 Mobiluncus curtisii, 329, 331 Molds, 32, 32t Molecular assays/probes, 26, 26t Molluscum contagiosum, 285t Monkey bites, 686–687 Monomicrobial soft-tissue infections, 648–649 Mononucleosis, infectious. See Infectious mononucleosis Mononucleosis-like syndrome cytomegalovirus-related, 820 human herpes virus type 6related, 823 human immunodeficiency virus (HIV) infection-related, 63 Monospot tests, 817–818 Moraxella, as bite-wound infection cause, 684 Moraxella catarrhalis antimicrobial resistance determination in, 42t as bronchitis cause, 401 as chronic bronchitis exacerbation cause, 410 as chronic obstructive pulmonary disease cause, 402 coaggregation with group A βhemolytic Streptococcus as otitis media cause, 395, 396 as pneumonia cause, 467t Morbilliform eruptions, 823 Mortality rate in aspergillosis, 562t in meningitis, 49 in necrotizing fasciitis, 651 in pneumonia, 459 Mosquito-borne diseases encephalitis, 85, 86t malaria, 853–869 Mouth abscess of, 365 bacteria of, 685 Moxifloxacin as bronchitis treatment, 413t as pneumonia treatment, 464, 466 as tuberculosis treatment, 496 Mucocutaneous infections candidiasis, 527, 529, 530 treatment of, 533–534 herpes simplex virus-related, 802–803, 804t Mucormycosis, rhinocerebral, 391, 788, 789t Mud-wrestling, as folliculitis cause, 633 Multiple myeloma, 792–793 Mumps virus as arthritis cause, 586 as encephalitis cause, 86t as meningitis cause, 84t Mupirocin, nasal application of, 641 Murphy sign, in cholecystitis, 175t, 179 Muscle flaps, for osteomyelitis treatment, 624–625 Myalgia bacterial meningitis-related, 55 blastomycosis-related, 522

927

Mycobacteria atypical, differentiated from tuberculosis, 500 as brain abscess cause, 92 classification and terminology of, 3t diagnostic tests for, 24 drug susceptibility testing of, 500 growth in culture, 499 identification of, 30 as meningitis cause, 81t Mycobacterial Growth Indicator Tube (MGIT), 499 Mycobacterium, as pharyngotonsillitis cause, 368 Mycobacterium avium complex (MAC), 760, 770–771 Mycobacterium necrophorum, 377 Mycobacterium-terium tuberculosis, 346 Mycobacterium tuberculosis cultures of, 18t, 499 growth in culture, 499 human-bite wound transmission of, 687 as tuberculosis cause, 495, 496, 497 as urinary tract infection cause, 251 Mycoplasma, as pharyngotonsillitis cause, 367t, 369 Mycoplasma hominis, as pelvic inflammatory disease cause, 315 Mycoplasma pneumoniae as bronchitis cause, 403 as pneumonia cause, 454, 467–468t Mycosis fungoides, 780t, 782 Myeloma, 783, 792–793 Myeloperoxidase deficiency, 784 Myometritis, 313 Myonecrosis clostridial, 643, 645–646t, 654, 659 streptococcal, 645–646t N Naegleria fowleri, as meningitis cause, 64 Naficillin, as brain abscess treatment, 99t, 102 Nail biting, 682 Nasal discharge, sinusitisrelated, 388 Nasogastric intubation, as pneumonia risk factor, 482–483 National Nosocomial Infections Surveillance (NNIS), 600 Neck stiffness bacterial meningitis-related, 55, 57, 62 encephalitis-related, 86 infective endocarditis-related, 115t meningitis-related, 82–83 Necrosis, osteomyelitis-related, 612, 616, 618–619 Necrotizing soft-tissue infections, 643–662 clinical manifestations of, 643–644, 645–646t, 649–654 diagnosis of, 655–656 differentiated from cellulitis, 655–656

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928

Index

etiology and pathophysiology of, 643, 644, 645–646t, 647–649 monomicrobial, 648–649 polymicrobial, 644, 647–648 prevention of, 659–660 risk factors for, 645–646t, 649 treatment of, 643, 644, 656–659, 658t Neisseria as bite-wound infection cause, 684 as infective endocarditis cause, 114 as septic arthritis cause, 583, 592 Neisseria gonorrhoeae antimicrobial resistance determination in, 42t as cervicitis cause, 285t, 344–345, 347–348 as complement deficiency cause, 784 culture of, 287, 289 detection of, 288–289, 292 as gonorrhea cause, 286 as pelvic inflammatory disease cause, 315, 317, 318 as pharyngotonsillitis cause, 368 as prostatitis cause, 268 quinolone-resistant, 290–291, 291t as septic arthritis cause, 584t, 586–587 as urethritis cause, 285t Neisseria meningitidis antigen detection tests for, 25 as bacterial meninigitis cause, 60 blood culture of, 60 as complement deficiency cause, 784 as meningitis cause, 50, 52, 73 nasopharyngeal carriage of, 75–76 as septic arthritis cause, 584t, 587 Nelfinavir, 723 Neonates. See Infants Nephrotic syndrome, 204–205, 783 Neuralgia, postherpetic, 810, 811–812 Neuroaminidase, of influenza viruses, 426 Neuroaminidase inhibitors, 426–427 Neurological disorders bacterial meningitis-related, 57–58 brain abscess-related, 104–105 human herpes virus type 6related, 823 Neurologic disorders brain abscess-related, 95t, 96, 97 Epstein-Barr virus-related, 816 Lyme disease-related, 836, 837 Neuropathy bite wound-related, 688 diabetic, 664, 670–671, 788, 789 as osteomyelitis risk factor, 612, 620, 626

Neurosurgery patients antimicrobial prophylaxis in, 5t meningitis in, 53 Neurosyphilis, 302, 304t Neutropenia, 785–788 as aspergillosis risk factor, 560, 561t as candidiasis risk factor, 528, 531 Neutrophils, 784, 785t in coccidioidomycosis, 542–543 in meningitis, 62 in peritonitis, 204 Nevirapine as rash cause, 743 Nitazoxanide, as giardiasis treatment, 161 Nitrofurantoin as cystitis treatment, 255–256, 255t as urinary tract infection prophylaxis, 262–263 5-Nitromidazoles, interaction with warfarin, 335 Nocardia, as brain abscess cause, 104 Nocardia asteroides, as brain abscess cause, 91–92, 95 Nonsteroidal anti-inflammatory drugs as meningitis risk factor, 64 as necrotizing fasciitis risk factor, 652 as streptococcal soft-tissue infection risk factor, 649 Norfloxacin, as peritonitis prophylaxis, 210 Noroviruses, as gastrointestinal illness cause, 143, 149 Norwalk-like viruses, 149, 163 Nosocomial infections candidiasis, 530 diarrhea, 165–166 pneumonia, 480–494 sinusitis, 391 urinary tract infections, 246–247, 257 Nuclear acid detection tests, 16, 16t Nuclear imaging, of urinary tract infections, 254 Nucleic acid amplification tests for Chlamydia trachomatis, 294t, 295 for Neisseria gonorrhoeae, 289, 290t for tuberculosis diagnosis, 499, 500t Nucleic acid probe assays for Chlamydia trachomatis, 294, 294t, 295 for Neisseria gonorrhoeae, 289, 290t Nucleic acids, 783 Nursing home residents, pneumonia treatment in, 470 Nystatin, as vulvovaginal candidiasis treatment, 340, 341t O Obstetric surgery patients, antimicrobial prophylaxis in, 5t Obtundation bacterial meningitis-related, 62 shigellosis-related, 155 Occlusional bite wounds, 682

Occupational exposure, as human immunodeficiency virus (HIV) infection cause, 754–756, 755t Ofloxacin as chlamydial urethritis/cervicitis treatment, 295, 295t as pelvic inflammatory disease treatment, 320t, 321, 321t, 322t Onychomycosis, candidal, 530 Oophoritis, 313 Ophthalmic infections aspergillosis, 564 candidiasis, 531, 535 herpetic, 805 Ophthalmic surgery patients, antimicrobial prophylaxis in, 5t Opportunistic infections AIDS-related acalculous cholecystitis, 178 as AIDS-defining conditions, 762t candidiasis, 529 cerebral toxoplasmosis, 760, 765–767, 767t, 890t coccidioidomycosis, 542, 544, 547 cryptococcosis, 760, 768–770, 769t cytomegalovirus infections, 771–775, 773–774t histoplasmosis, 550, 554–556 malignant or invasive otitis externa, 398–399 Mycobacterium avium complex (MAC) infection, 760, 770–771 Pneumocystis jiroveci pneumonia, 760, 761–765, 762t, 764t, 765t, 889t tuberculosis, 495 cell-mediated immunity in, 781–782 definition of, 761 human monocytotropic ehrlichiosis-related, 842 in immunocompromised patients, 777–799 Oral cavity, abscess of, 365 Oral contraceptives, 315–316 as genital chlamydia infection risk factor, 347 interaction with antiretroviral agents, 744 as vulvovaginal candidiasis risk factor, 336, 337, 342 Oral rehydration therapy, for diarrhea, 148–149 Orchitis, 275 epididymitis-associated, 253, 275, 276, 277, 278 Organ transplantation liver transplantation, 185, 193 renal transplantation, 262 Organ transplant patients adenovirus pneumonia in, 443 aspergillosis in, 559, 561, 561t cytomegalovirus infections in, 441, 442 Ornidazole, as trichomoniasis treatment, 333 Orolabial infections, with herpes simplex virus, 802, 804t

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Index Oropharyngeal secretions, aspiration of, 644 Oropharynx candidiasis of, 529, 530, 532, 533–534, 763, 765 Epstein-Barr virus infections of, 814 herpes simplex virus infections of, 802–803 Orthopedic surgery patients, antimicrobial prophylaxis in, 5t Oseltamivir, 426–427 Osler, William, 109, 126–127 Osler nodes, 115 Osteomyelitis, 609–628 acute, 610–612, 614 contiguous, 611–612, 615, 626 hematogenous, 610–611, 613, 614, 621 aspergillosis-related, 567 bite wound-related, 681, 687, 688, 689, 691, 695 Candida-related, 531, 535 chronic, 612–613, 614 classification of, 614–615, 616t, 621 Cierny-Mader system of, 614–615, 615t, 616t Waldvogel system of, 614 clinical manifestations of, 613–614 coccidioidal, 544 definition of, 609 diabetic foot infection-related, 672, 788 diagnosis of, 609, 616–620 etiology of, 610–613 imaging studies of, 609, 610, 616, 617–620 mycobacterial, 770 mycotic aneurysm-related, 128 posttraumatic or postoperative, 609, 626 prevention of, 626 sinusitis-related, 392 as splenic abscess cause, 229 treatment of, 609, 620–626, 620t, 691, 872–873t new developments in, 610 with vascular insufficiency, 612, 619–620, 625–626 vertebral, 378, 618–619, 620 Osteopenia, in osteomyeliris, 617 Otitis externa, 397–400 fungal, 398, 399 malignant or invasive, 398–399 noninvasive, 387 as otomycosis cause, 563 Otitis media, 394–397 in adults, 395, 396 as bacterial meningitis cause, 58 as brain abscess cause, 93, 99t chemoprophylaxis for, 396 chronic suppurative, 394 measles-related, 703–704 mycotic aneurysm-related, 128 as otitis externa cause, 398 respiratory syncytial virus infection-related, 431 risk factors for, 394–395 Otomycosis, 563 Overwhelming postsplenectomy infection (OPSI), 789–791, 790t Oxygen tension, cutaneous, 625

P Pain abdominal appendicitis-related, 212, 236 diverticular abscess-related, 238 peritonitis-related, 207, 212 splenic abscess-related, 229 urinary tract infection-related, 251 in back, bacterial meningitisrelated, 55 biliary, 172 in chest, infective endocarditisrelated, 115t in joints, evaluation of, 590–591, 591f left upper-quadrant, 116 necrotizing soft-tissue infection-related, 649–650 osteomyelitis-related, 614 otitis externa-related, 399 pelvic, 313, 323 prostatic (prostatodynia), 274–275 right upper-quadrant acute calculous cholecystitisrelated, 172, 173t, 174 appendicitis-related, 174 differential diagnosis of, 168, 173t liver abscess-related, 226 Palivizumab, 432 Pancreas, abscess of, 231t, 232–235 Pancreatitis acute, 232–235 etiology of, 232–233, 233t acute necrotizing, 233 as cholelithiasis risk factor, 170 endoscopic retrograde cholangiopancreatographyrelated, 232–233 Pandemics, of influenza, 427, 455 Panton-Valentine leukocidin genes, 451, 455, 639–640 Papanicolaou (Pap) smear, 285 with atypical squamous cells of undetermined significance (ASCUS), 349 of Blastomyces dermatitidis, 524 follow-up of, 357t in herpetic cervicitis, 349 screening, 356–357, 357t trichomonads on, 334 in vulvovaginal candidiasis, 340 Parainfluenza viruses as bronchitis cause, 403 as chronic bronchitis exacerbation cause, 410 as pharyngotonsillitis cause, 369 as respiratory infection cause, 433–434 Parameningeal infections, 63 Parametritis, 313 Paramyxoviruses measles virus, 702 as respiratory infection cause, 430–435 human metapneumovirus, 432–433 measles, 434–435

929

parainfluenza viruses, 433–434 respiratory syncytial viruses, 430–432 Parasites classification of, 33t laboratory identification of, 32 Parasitic infections. See also specific parasitic infections diagnostic tests for, 24 as meningitis cause, 81–82t Parenteral therapy for pelvic inflammatory disease, 320, 321t for urinary tract infections, 257 Parietal lobe, abscess of, 93 Paronychia, self-inflicted, 682 Parvovirus B19 as arthritis cause, 586 serologic test for, 36t Pasteurella multocida as bite-wound infection cause, 684, 692t as septic arthritis cause, 585 Pelvic inflammatory disease, 94, 313–325 diagnosis of, 316–318, 317t epidemiology of, 314 etiology of, 314–315 long-term sequelae of, 323–324 risk factors for, 315–316 sexual partners and, 321–322 treatment of, 313, 314, 318–321, 319f, 320t as tubo-ovarian abscess/complex cause, 314, 322–323 Penicillin as bacterial meningitis treatment, 70t, 71–72, 73 as brain abscess treatment, 101, 102 as Lyme disease treatment, 839t as pharyngotonsillitis treatment, 371–372, 372t failure of, 374, 374t, 375 as streptococcal pharyngitis treatment, 365 as syphilis treatment, 304, 304t Penicillin resistance in group A Streptococcus, 366 in Streptococcus pneumoniae, 49, 50, 52, 452–453, 464 Peptococcus as infected false aneurysm cause, 131 as pelvic inflammatory disease cause, 315 as septic arthritis cause, 585 Peptostreptococcus as abscess cause, 377 as pelvic inflammatory disease cause, 315 Periappendiceal masses, 235 Pericarditis histoplasmosis-related, 552t, 553, 555t mycobacterial, 770 Perihepatitis, gonococcal, 288 Periostitis, syphilitic, 301 Peritoneal dialysis, as peritonitis cause, 204 Peritoneal fluid cytology, in peritonitis, 208

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930

Index

Peritonitis, 204–222 candidiasis-related, 531, 536 continuous ambulatory peritoneal dialysis-related, 215, 216–218, 531, 536 definition of, 204 diverticular abscess-related, 238 etiology and pathogenesis of, 204–205, 644, 647 generalized, 211 microbiology of, 207t pelvic inflammatory diseaserelated, 313 primary, 205–211 clinical manifestations of, 207 diagnosis of, 208 epidemiolgy of, 206 etiology of, 206–207, 207t pathogenesis of, 206 treatment of, 214t secondary, 204, 205, 207t, 211–214, 220 clinical manifestations of, 212 diagnosis of, 212–213 differentiated from spontaneous bacterial peritonitis, 208–209 etiology of, 212 pathogenesis of, 211 treatment of, 213–214, 213t, 214t spontaneous bacterial, 204, 220 culture-negative neutrocytic, 211 differentiated from secondary peritonitis, 208–209 prophylaxis against, 210 treatment of, 205, 209–210 tertiary, 205, 208, 214–215, 220 treatment of, 214t tuberculous, 205, 207t, 219, 220 Pertussis vaccine, 402, 408 Petechiae bacterial meningitis-related, 56–57, 61 infectious mononucleosisrelated, 708 infective endocarditis-related, 115 Pets. See also Cat bites; Dog bites Escherichia coli transmission via, 246 Pharmacodynamics, 7, 10–13 definition of, 3 Pharmacokinetics, 7, 8–10 definition of, 3 Pharyngitis gonococcal, 287 group A streptococcal, 365 respiratory syncytial virusrelated, 431 Pharyngotonsillitis, 365–375 clinical manifestations of, 365, 366, 367t, 369–370 diagnosis of, 370–371 treatment of, 365 Phlebitis, septic, 888t Phlegmon, 234, 237 Photophobia cryptococcosis-related, 768 meningitis-related, 55, 83 Picornaviridae, 186, 186t

Piperacillin, as pyelonephritis treatment, 257 Pityriasis, 823 Plague, bubonic, 687 Plasmodium blood smears of, 857–858 as malaria causal organism, 853, 854t Pleural effusions blastomycosis-related, 523 coccidioidal, 543t pneumonia-related, 471 Pneumobilia, 173 Pneumococcal vaccination, 474 in asplenic patients, 791 in chronic lung disease patients, 413 in multiple myeloma patients, 792 for otitis media prevention, 397 Pneumocystis carinii pneumonia. See Pneumocystis jiroveci pneumonia Pneumocystis jiroveci pneumonia, 456, 760, 761–765, 762t, 764t, 765t AIDS-associated, 723–724 clinical manifestations of, 762–763 diagnosis of, 763 prophylaxis for, 765t treatment of, 763, 764t Pneumonia acute bronchitis-related, 405 adenovirus-related, 432, 443 aspiration, 456 asplenia as risk factor for, 790 clinical definition of, 450 clinical specimen collection in, 19t coccidioidal, 543, 543t, 544 community-acquired, 450–479 clinical manifestations of, 456, 458–459, 458t, 460t diagnosis of, 461–464, 462t epidemiology of, 451–453, 452t etiology of, 453–456, 454t, 455t, 456t, 457–458t failure of treatment in, 472–473 genetic factors in, 453 mortality rate in, 459 in nursing home residents, 470 prevention of, 474 risk factors for, 451–452 severity of, 458–459, 460t treatment of, 451, 464–470, 466–468t, 471–472 viral, 417–418, 418t cytomegalovirus, 440–443 differentiated from bronchitis, 405–406, 408, 411 Hecht giant cell, 435 herpes simplex virus-related, 436–438 histoplasmosis-related, 552 in immunocompromised patients, 796 influenza-related, 423 Legionella, 452, 453, 468t, 484, 490t measles-related, 434–435, 703–704

mycotic aneurysm-related, 128 nosocomial, 480–494 diagnosis of, 485–487 epidemiology of, 481–482 etiology of, 483–484 healthcare-associated, 480, 481, 483, 484, 490t hospital-acquired, 481, 482, 483–484, 486, 490t microbiology of, 485–487 pathogenesis and risk factors for, 482–483 prevention of, 493 treatment of, 480, 482, 487–493, 488f, 489f, 490t, 492t ventilator-associated, 481, 482, 483, 484, 486–487, 490t, 491 pneumococcal bacteremic, 461 diagnosis of, 461, 463 etiology of, 455 risk factors for, 451–452 Pneumocystis jiroveci, 456, 760, 761–765, 762t, 764t, 765t AIDS-associated, 723–724 clinical manifestations of, 762–763 diagnosis of, 763 prophylaxis for, 765t treatment of, 763, 764t respiratory syncytial virusrelated, 431 risk factors for, 452 secondary bacterial, 423 severe acute respiratory syndrome-related, 428 systemic lupus erythematosusrelated, 793–794 varicella (chickenpox)-related, 438–439, 808–809 viral, 417–418, 418t diagnosis of, 418–421, 420t etiology of, 418t laboratory tests for, 419–421 treatment of, 421 Pneumonitis histoplasmosis-related, 552t mycobacterial, 770 orophyaryngeal aspirationrelated, 644 Pneumothorax, coccidioidal, 543t Polio-like syndrome, 87 Poliomyelitis, 716 Polyarteritis nodosa, 190 Polymerase chain reaction (PCR) test, 26, 26t for cytomegalovirus, 761, 821–822 for encephalitis, 87–88 for Hemophilus ducreyi, 306 for hepatitis C, 195, 196 for herpes simplex virus, 298 for human granulocytotropic anaplasmosis, 845 of human granulocytotropic Ewingii, 850 for identification of viruses, 34 for infective endocarditis, 117 for malaria, 858 for Neisseria gonorrhoeae, 289 for prosthetic joint infections, 603

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Index for septic arthritis, 590 for Treponema pallidum, 303, 306 for viral encephalitis, 80, 86t Polymicrobial soft-tissue infections, 644, 647–658, 650, 651 Polymorphonuclear leukocytes in bacterial meningitis, 59 in cervicitis, 348 in trichomoniasis, 332, 333 Polyps, nasal, 389–390 Polysaccharides, bacterial cellwall, 783 Porphyromonas as abscess cause, 377 as pharyngotonsillitis cause, 369, 374, 375 Posaconazole as aspergillosis treatment, 560, 574 as coccidioidomycosis treatment, 542, 547 Postnasal drainage, sinusitisrelated, 388–389 Posttransplantation lymphoproliferative disorder (PTLD), 819 Potassium hydroxide (KOH)/calcofluor wet mount, 24 Povidone-iodine, as trichomoniasis treatment, 335 Pox virus, as molluscum contagiosum cause, 285t Pregnancy anaplasmosis treatment during, 847–848 bacteriuria treatment during, 257 coccidioidomycosis during, 541, 543 as contraindication to amantadine and rimantadine, 426 colposcopy, 356 measles-mumps-rubella vaccine, 700 rubella vaccine, 706 varicella vaccine, 440, 700 cytomegalovirus during, 820 ectopic chlamydial infection-related, 293 pelvic inflammatory diseaserelated, 313, 317, 323, 324 genital herpes infections during, 296 hepatitis during, 185, 199 in HIV-positive patients, 743–744 Lyme disease treatment during, 838 pyelonephritis during, 256 as pyelonephritis risk factor, 248 trichomoniasis during, 333, 335 tuberculosis treatment during, 501, 505, 510, 516 urinary tract infections during, 248–249 vaginosis during, 328, 329t, 331 vaginosis treatment prior to, 331 varicella (chickenpox) during, 808–809, 811

vulvovaginal candidiasis during, 336, 336t, 337 vulvovaginal candidiasis treatment during, 341 Preterm labor bacterial vaginosis-related, 328, 329t, 331 maternal urinary tract infection-related, 248 Prevotella as abscess cause, 377 as cellulitis cause, 635 as pelvic inflammatory disease cause, 315 as pharyngotonsillitis cause, 369, 374, 375 Primaquine, 866 Primary care physicians role in prosthetic joint infection treatment, 603, 604t, 605 role in tuberculosis treatment, 496 Prison populations, hepatitis C prevalence in, 195 Probiotic therapy, for clostridia diarrhea, 157 Proguanil (chloroguanide), 862t, 865–866, 868 Propionibacterium as normal skin microorganism, 630 as prosthetic joint infection cause, 601 Proptosis, sinusitis-related, 389 Prostatectomy, 270 Prostatic fluid cultures, 253 Prostatitis, 266–275 acute bacterial, 266–267, 270–271, 272t chronic abacterial, 266–267, 272–273t, 274–274 chronic bacterial, 266–267, 271, 272t, 274 clinical manifestations of, 268, 272–273t diagnosis of, 268–269, 280, 282 etiology of, 267–268, 272–273t pathogenesis of, 267–268 treatment of, 267, 271, 272–273t, 274, 883–884t Prostatodynia, 268, 273t, 274–275 Prosthetic heart valves aspergillosis of, 562 as infective endocarditis risk factor, 109–111 Prosthetic joint infections, 599–608 candidiasis, 535 clinical manifestations of, 601–602 diagnosis of, 600, 602–603 epidemiology of, 600–601 as osteomyelitis cause, 611 pathophysiology and etiology of, 601 prevention of, 606–607 treatment of, 599, 600, 603–606, 604t Protease inhibitors, drug interactions of, 506, 746t Protein, in cerebrospinal fluid, 60, 62 Protein C, activated, 471–472

931

Proteus as liver abscess cause, 225 as urinary tract infection cause, 250, 250t Proteus mirabilis as infected false aneurysm cause, 131 as septic arthritis cause, 585 as urinary tract infection cause, 261, 794 Proton pump inhibitors, 746 Protozoa classification of, 33t as gastroenteritis cause, 143, 146–147, 157, 158–159t, 159–160 as traveler’s diarrhea cause, 164 Pruritus varicella (chickenpox)-related, 713, 811 vulvar, 339 Pseudoaneurysm, 130–134 Pseudoappendicitis, 152, 155 Pseudocyst, pancreatic, 234 Pseudogout, 589t Pseudomonas as liver abscess cause, 225 as prostatitis cause, 268 as urinary tract infection cause, 257 Pseudomonas aeruginosa as community-acquired pneumonia cause, 468t, 469 as diabetic foot infection cause, 668 as folliculitis cause, 633–634, 638 as infected false aneurysm cause, 131 as infective endocarditis cause, 114 as meningitis cause, 74 as necrotizing soft-tissue infection cause, 649 in neutropenic patients, 786 as nosocomial pneumonia cause, 490t, 493 as osteomyelitis cause, 616 as otitis externa cause, 398 as otitis media cause, 395–396 as peritonitis cause, 207t, 218 in polymicrobial soft tissue infections, 647 as septic arthritis cause, 585, 592 as sinusitis cause, 391 as urinary tract infection cause, 250 Pulmonary function testing, in bronchitis patients, 404–405 Puncture wounds bite wounds as, 683, 687, 690 as diabetic foot infection cause, 665, 668 Purified protein derivative (PPD) skin tests, 511–512 Purine pathway enzyme deficiencies, 779 Purpura, bacterial meningitisrelated, 56–57, 61 Pyelography, intravenous, 254 Pyelonephritis acute, 245

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932

Index

complications of, 252, 252t diagnosis of, 252–253 etiology of, 250 hospitalization for, 246 misdiagnosis of, 251–252 risk factors for, 248 treatment of, 256–257 diabetes mellitus-related, 788 in renal transplant recipients, 262 as splenic abscess cause, 229 xanthogranulomatous, 259 Pyoderma, 643–644 primary, 629 staphylococcal, 650 Pyomyositis, 653–654 tropical, 653–654 Pyosalpinx, 317 Pyrazinamide side effects of, 506 as tuberculosis treatment, 495, 501, 502t, 504t, 506, 516 Pyrimethamine, 767t, 864–865 Pyuria, 245, 252, 253 Q Quadriparesis, bacterial meningitis-related, 58 Quality of care, for pneumonia patients, 472 Quinidine dihydrochloride, as malaria treatment, 861t Quinidine gluconate, as malaria treatment, 861t Quinine, as malaria treatment, 863–864 Quinine sulfate, as malaria treatment, 861t Quinolone resistance, in Neisseria gonorrhoeae, 290–291, 291t Quinolones contraindications to as gonorrhea treatment, 349 in pediatric patients, 621 as osteomyelitis treatment, 623 as pneumonia treatment, 464–465 respiratory, 464–465 Quinsy, 368, 375, 376t, 377, 378 R Rabies bite wound-related, 688 as encephalitis cause, 86t Rabies immunization/prophylaxis, 681, 685–686, 685t, 694 Radiologic evaluation, of bacterial meningitis, 61–62 Radionuclide scans, of osteomyelitis, 617–618, 620 Ramsay-Hunt syndrome, 809–810 Rapid tests, for human immunodeficiency virus (HIV), 727–728 Rash antiretroviral therapy-related, 732t aseptic enteroviral meningitisrelated, 62 bacterial meningitis-related, 56–57, 61 herpes zoster (shingles)related, 811

human monocytotropic ehrlichiosis-related, 842 infectious mononucleosisrelated, 707 Lyme disease-related, 836, 836t, 837t, 840 nevirapine-related, 743 varicella (chickenpox)-related, 807–808 Rat bite fever, 687 Rectal cultures, in vulvovaginal candidiasis, 338 Reiter syndrome, 582–583 Renal failure, tuberculosis treatment in, 511 Renal infections, suppurative, 259 Renal insufficiency, tuberculosis treatment in, 511 Renal transplantation, 262 Resistance, antimicrobial, 452–453, 785–786 to acyclovir, 822 to amantadine, 418, 425, 427 to antiretroviral therapy, 738–739 assays for, 739 to beta-lactam antibiotics, 72, 132, 133 to chloroquine phosphate, 838, 860t, 861–862t determination of, 39–41, 42t, 43–44, 45t effect of antimicrobial therapy on, 407 to fluoroquinolones, 144, 152, 452–453 to methicillin, 49 as brain abscess cause, 98, 99t, 100, 101 as diabetic foot infection cause, 664, 669, 674–675 as folliculitis cause, 638, 639–640 as herpes simplex virus pneumonia cause, 437–438 as infective endocarditis cause, 121t as necrotizing fasciitis cause, 653 as osteomyelitis cause, 610, 612, 622t, 623 as peritonitis cause, 218 as septic arthritis cause, 594–595, 594t treatment for, 490t, 493, 610, 612, 622t, 623, 664, 674–675 to metronidazole, 331, 334–335 multi-drug resistance antimicrobial therapy for, 488–489, 489f, 490t as nosocomial pneumonia cause, 484, 488–489, 489f, 490t to penicillin, 49, 50, 52, 366, 452–453, 464 to rifampin, 510 to rimantadine, 418, 425, 427 to trimethoprim-sulfamethoxazole, 256 to vancomycin, 787 Respiratory secretions, purulent, 485

Respiratory syncytial virus, 430–432 as bronchitis cause, 403 as chronic bronchitis exacerbation cause, 410 diagnosis of, 463 risk factors for, 452 Respiratory tract infections aspergillosis, 562, 564–565 bacterial meningitis and, 55 in immunocompromised patients, 422f lower, 417–449 adenovirus infections, 443–444 cytomegalovirus infections, 440–443, 446 diagnosis of, 418–421, 420t hantavirus infections, 444 herpesvirus infections, 421, 435–440 influenza, 421, 423–427, 425t, 426t laboratory tests for, 419–421 paramyxovirus infections, 430–435 as pneumonia cause, 451 severe acute respiratory syndrome (SARS), 426t, 427–430, 429t treatment of, 421 upper bacterial meningitis and, 55 human metapneumovirus infections, 432–433 respiratory syncytial virus infections, 431 sinusitis superinfection in, 387, 388, 394, 396 Respiratory viruses, assays for, 87 Retinitis, cytomegalovirus, 772, 773–774t, 775, 891t Retinopathy, diabetic, 788 Retropharyngeal abscess, 368, 375, 376t, 377, 378–379 Reye syndrome, 713, 809 Rheumatic fever, 110, 115, 368 Rheumatism, 127 Rheumatoid arthritis as ascites cause, 204–205 septic arthritis associated with, 582 synovial fluid analysis in, 589t Rheumatoid factor, 112 Rhinoviruses as bronchitis cause, 403 as chronic bronchitis exacerbation cause, 410 as pneumonia cause, 455–456 Ribavirin as hepatitis C treatment, 196–197 as measles treatment, 704 as respiratory syncytial virus infection treatment, 432 Rickettsia, as meningitis cause, 81t Rickettsioses, tick-borne, 850 Rifabutin, as tuberculosis treatment, 507 Rifampin as ehrlichiosis treatment, 847–848, 847t

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Index as meningitis prophylaxis, 75, 76 as prosthetic joint infection treatment, 604–605 resistance to, 510 side effects of, 507 as tuberculosis treatment, 495, 500–501, 502t, 504t, 506–507, 508 for latent disease, 514, 515t, 516 mycobacterial resistance to, 500 side effects of, 506 use during pregnancy and lactation, 510 Rifapentine, as tuberculosis treatment, 501 Rifaximin, 164 Rift Valley fever virus, 185 Right upper-quadrant pain appendicitis-related, 174 calculous cholecystitis-related, 172, 173t, 174 differential diagnosis of, 168, 173t liver abscess-related, 226 Rimantadine, as influenza treatment, 425–426 Rimantadine resistance, in influenza viruses, 418, 425, 427 Ritonavir, 723 Rituximab, 783 RNA (ribonucleic acid) probes, 26 Rodents, as hantavirus hosts, 444 Roseola. See Exanthem subitum Rotaviruses, 144, 147 as gastroenteritis cause, 149–150 as traveler’s diarrhea cause, 164 Roth spots, 115 Rubella, 699–700, 704–706 as arthritis cause, 586 serologic test for, 36t Rubella vaccine, 706 S Saccharomyces diagnostic assay for, 569 as gastroenteritis prophylaxis, 149 Saccharomyces boulardii, 157 Safe sex, 729 St. John’s wort, interaction with antiretroviral agents, 747 Saline irrigation, of bite wounds, 689–690 Salmeterol, as bronchitis treatment, 411, 413 Salmonella paratyphi, 150 Salmonella typhi, 150, 151 transmission route of, 144–145 Salmonellosis as diarrhea cause, 158t, 165 as food poisoning cause, 162, 163 as gastroenteritis cause, 147, 150–151 as splenic abscess cause, 229, 230 as traveler’s diarrhea cause, 164 treatment of, 158t

Salpingitis, 293, 313 Sarcoidosis, differentiated from tuberculosis, 500 Scalded-skin syndrome, 631 Scarlet fever, 704 Scedosporium, 569, 571 Sclerosis, osteomyelitis-related, 617 Scratches, bite wounds as, 687 Scrotum, acute, 276, 276t differential diagnosis of, 276t Seal finger, 687 Secretion specimens, handling of, 20t Seizures bacterial meningitis-related, 57, 58 brain abscess-related, 95t, 96, 104 human herpes virus type 6related, 823 malaria-related, 857 shigellosis-related, 155 Self-inflicted human-bite wounds, 682, 687 Sepsis bite wound-related, 688 clinical specimen collection in, 19t hepatopathy of, 181–182 hyperbilirubinemia of, 181–182 Septicemia asplenia as risk factor for, 790 bite wound-related, 681 Serologic tests, 16, 16t for herpes simplex viruses, 298 for human granulocytotropic anaplasmosis, 846 for human immunodeficiency virus (HIV), 727 for human monocytotropic ehrlichiosis, 842 for Lyme disease, 838 principles of, 36–38, 36t for syphilis, 303–304 Serratia as liver abscess cause, 225 as septic arthritis cause, 585 as sinusitis cause, 391 Serratia marcescens, as infected false aneurysm cause, 131 Serum sickness-like syndrome, 59, 190 Severe acute respiratory syndrome (SARS), 418, 427–430, 429t case definition of, 426t, 428–429 Severe acute respiratory syndrome (SARS)-associated coronavirus as bronchitis cause, 403 as pneumonia cause, 454, 455 Severe combined immunodeficiency disease, 779, 780t Sexual abuse, in children, 276 Sexually transmitted diseases, 284–312 diagnosis of, 285 differentiated from acute cystitis, 251 epididymitis, 276, 280t hepatitis B, 190, 193 hepatitis C, 195

933

hepatitis D, 197 human papilloma virus infections, 352–361 pelvic inflammatory disease, 315–316 prevention of, 291–292 treatment of, 285, 286t, 880–883t trichomoniasis, 332–335 vaginosis, 327 Sexual partners of chancroid patients, 305 of genital herpes patients, 296 as human papilloma virus infection risk factor of pelvic inflammatory disease patients, 313, 321–322 of sexually transmitted disease patients, 285–286 of syphilis patients, 300, 304–305 Shigella. See Shigellosis Shigella-like toxins, 158t Shigellosis as diarrhea cause, 158t, 164, 165 as food poisoning cause, 162 as gastroenteritis cause, 147, 149, 154–155 pathogenesis of, 145 transmission route of, 144–145 as traveler’s diarrhea cause, 164 treatment of, 158t Shingles. See Herpes zoster (shingles) Shock in bacterial meningitis, 59 hemorrhagic, 129 septic, 252 Shunts, arteriovenous, 94 Sickle cell anemia/disease, 784, 790, 791 Sinuses as brain abscess origin site, 92, 99t paranasal, anatomy of, 388 in septic thrombophlebitis, 135t, 136f, 137t Sinusitis, 387–394 allergic, 390, 394 aspergillosis-related, 562, 563–564 chronic, 393–394 clinical manifestations of, 388–390 clinical specimen collection in, 19t complications of, 392–393 diagnosis of, 390–391 etiology of, 388 fungal, 389, 390, 391 joint replacement-related, 602 maxillary, 389–390 nosocomial, 391, 393 treatment of, 391–394, 392t, 393f viral, 390–391 Sinus tract cultures, contraindication to, 616 Skene glands, in trichomoniasis, 333

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934

Index

Skin bacterial colonization of, 779 in bacterial meningitis, 56–57, 61 as mechanical defense barrier, 779 normal flora of, 630 Skin care in diabetic patients, 626. 675–677, 675–677 for furunculosis prevention, 641 Skin infections/lesions. See also Exanthems, viral; Rash aspergillosis, 567 blastomycosis, 521, 522, 523–524 candidiasis, 527, 529, 530 coccidioidal, 544 human herpes virus type 6, 823 Lyme disease-related, 836, 836t, 837t necrotizing fasciitis, 651–652 necrotizing soft-tissue infections, 645t, 649–650 superficial (pyodermas), 629–642 clinical manifestations of, 631, 633–637 diagnosis of, 637–638 pathogenesis of, 630–631 prevention of, 641–642 risk factors for, 630–631 treatment of, 638–640 systemic lupus erythematosusrelated, 793–794 Slim disease, 165 Smoking as pelvic inflammatory disease risk factor, 316 as pneumococcal risk factor, 450 Smoking cessation, in chronic lung disease patients, 413 Soap, antibacterial, 641–642 Soft-tissue fillers, for osteomyelitis, 624 Soft-tissue infections cellulitis, 612, 635–636 anaerobic gas-forming, 645–646t bite wound-related, 688 clostridial, 648 definition of, 635 diabetic foot infection-related, 666, 673 differentiated from necrotizing soft-tissue infections, 650–651, 655–656 microbiology of, 635 necrotizing fasciitis-related, 650 orbital, sinusitis-related, 392 peritonsillar, 369 retropharyngeal, 368 as superficial skin infection, 629, 632t at surgical sites, 636, 641–642 synergistic necrotizing, 645–646t, 653 diabetes mellitus-related, 788 necrotizing, 643–662 clinical manifestations of, 643–644, 645–646t, 649–654

diagnosis of, 655–656 differentiated from cellulitis, 655–656 etiology and pathophysiology of, 643, 644, 645–646t, 647–649 monomicrobial, 648–649 polymicrobial, 644, 647–648 prevention of, 659–660 risk factors for, 645–646t, 649 treatment of, 643, 644, 656–659, 658t systemic lupus erythematosusrelated, 793–794 Sore throat, pharyngotonsillitisrelated, 369–370 Spermicidal agents, 335 Spinal cord injury patients, urinary tract infections in, 248 Spinal surgery patients, antimicrobial prophylaxis in, 5t Spirochetes, as meningitis cause, 81t Spleen abscess of, 229–230, 231t asplenia and, 789–791, 790t candidiasis of, 533 host defense mechanisms of, 789 palpable, in infective endocarditis, 116 rupture of, 816 Splenectomy, 230, 790, 791 overwhelming postsplenectomy infection (OPSI) and, 789–791, 790t Splenic vein thrombosis of, 229 Splenotomy, 230 Spot testing, 27 Sprue, tropical, 165 Sputum, in bronchitis, 409, 410, 411 Sputum analysis, in nosocomial pneumonia, 485 Sputum cultures interpretation of results of, 23t specimens in handling of, 20t quality of, 21t, 22 Sputum Gram stain, in pneumonia, 462–463 Sputum smears in aspergilloma, 565 in tuberculosis, 497, 498–499, 500t, 513 Staphylococcus coagulase-negative, 779 as necrotizing fasciitis cause, 653 Staphylococcus aureus antimicrobial resistance determination in, 42t beta-lactam-resistant, 132, 133 as bite-wound infection cause, 684, 692t carriers of, 630 as cellulitis cause, 635–636 in diabetic patients, 789 as folliculitis cause, 633 as food poisoning cause, 162–163 as infected false aneurysm cause, 131, 132, 133 as infective endocarditis cause, 111, 112, 118t, 120t

as liver abscess cause, 225 as meningitis cause, 56–578, 74 methicillin-resistant, 49 as brain abscess cause, 98, 99t, 100, 101 as diabetic foot infection cause, 664, 669, 674–675 as folliculitis cause, 638, 639–640 as herpes simplex virus pneumonia cause, 437–438 as infective endocarditis cause, 121t as necrotizing fasciitis cause, 653 as osteomyelitis cause, 610, 612, 622t, 623 as peritonitis cause, 218 as septic arthritis cause, 594–595, 594t treatment for, 490t, 493, 610, 612, 622t, 623, 664, 674–675 as mycotic aneurysm cause, 128 as necrotizing pneumonia cause, 451, 455 in neutropenic patients, 786 as nosocomial pneumonia cause, 482, 484, 490t, 493 as osteomyelitis cause, 611, 621, 622t as otitis externa cause, 398 as otitis media cause, 395–396 Panton-Valentine leukocin genes in, 451 as pharyngotonsillitis cause, 368 as pneumonia cause, 423, 454 in polymicrobial soft tissue infections, 647 as prosthetic joint infection cause, 601, 605 as renal abscess cause, 259 as septic arthritis cause, 584–585, 585t as septic thrombophlebitis cause, 137–138 as sinusitis cause, 390, 391, 393 skin colonization with, 779 as superficial skin infection cause, 630, 641 as urinary tract infection cause, 250t Staphylococcus bovis, as infective endocarditis cause, 112 Staphylococcus epidermis as infective endocarditis cause, 112, 113t as osteomyelitis cause, 612 as peritonitis cause, 207t as urinary tract infection cause, 250, 250t Staphylococcus intermedius, as bitewound infection cause, 684, 692t Staphylococcus lugdunensis, as infective endocarditis cause, 112–113 Staphylococcus pyogenes, as cellulitis cause, 635 Staphylococcus saprophyticus, as urinary tract infection cause, 250, 794 Staphylococcus viridans, as infective endocarditis cause, 111

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Index Statins, 746, 754 Stem cell transplant patients aspergillosis in, 559, 561 cytomegalovirus infections in, 440 neutropenia in, 788 Stomach, aspergillosis of, 566–567 Stomatitis, denture, 530, 533–534 Stool, blood in, 165 Stool cultures in gastroenteritis, 147 in nosocomial diarrhea, 165–166 in shigellosis, 155 specimens in handling of, 20t quality of, 21t Streptococcus β-hemolytic as infective endocarditis cause, 113 as necrotizing fasciitis cause, 651 as prosthetic joint infection cause, 601 as superficial skin infection cause, 629 β-hemolytic group A carriers of, 373–374 laboratory testing for, 370–371 as necrotizing fasciitis cause, 643, 651–652 penicillin-resistant, 373–374, 375 as pharyngotonsillitis cause, 366, 367t, 368, 370–375 treatment of, 657–658 β-hemolytic group B as infective endocarditis cause, 112 as meningitis cause, 52–53 as necrotizing soft tissue infection cause, 649 as pharyngitis cause, 368 β-hemolytic group C, as pharyngitis cause, 368 β-hemolytic group G, as pharyngitis cause, 368 as brain abscess cause, 98, 99t, 100, 101 enzyme immunoassays of, 25 as Fournier gangrene cause, 651 as infective endocarditis cause, 111 as osteomyelitis cause, 622t as pelvic inflammatory disease cause, 315 penicillin-resistant, 366 Streptococcus agalactiae antigen detection tests for, 25 as meningitis cause, 73 Streptococcus anguis, as infective endocarditis cause, 111 Streptococcus bovis, as infective endocarditis cause, 120t Streptococcus mitior, as infective endocarditis cause, 111 Streptococcus pneumoniae antigen detection tests for, 25 antimicrobial resistance in, 72 as bacterial meningitis cause, 60

blood culture of, 60 as brain abscess cause, 100 as bronchitis cause, 401 as chronic bronchitis exacerbation cause, 410 as chronic obstructive pulmonary disease cause, 402 humoral immunity and, 783 as infective endocarditis cause, 114 macrolide-resistant, 469 as meningitis cause, 50, 52, 54, 58, 71–72, 75t methicillin-resistant, 467t, 469 multidrug-resistant, 465 as mycotic aneurysm cause, 128 as necrotizing fasciitis cause, 653 as nosocomial pneumonia cause, 490t as otitis media cause, 395 penicillin-resistant, 49, 50, 52, 452–453, 469 as pharyngotonsillitis cause, 368, 368t as pneumonia cause, 423, 454, 462–463, 465, 467t, 469 as septic arthritis cause, 585t, 5845 as sinusitis cause, 390 Streptococcus pyogenes as bite-wound infection cause, 684 enzyme immunoassays for, 25 as infected false aneurysm cause, 131 as necrotizing fasciitis cause, 650 as necrotizing soft-tissue infection cause, 648, 660 as otitis media cause, 395–396 in polymicrobial soft tissue infections, 647 as skin infection cause, 631 Streptococcus viridans as infective endocarditis cause, 112, 113t, 114, 120t as mycotic aneurysm cause, 128 Streptomycin, as tuberculosis treatment, 504t, 506 Strictures, biliary, 169 Strongyloides stercoralis, 165 Sulfonamides, as meningitis cause, 64 Supine position, as pneumonia risk factor, 482–483 Surgery, antimicrobial prophylaxis and, 4–5, 5–7t Surgical sites, cellulitis at, 636, 641–642 Swimmer’s ear, 398, 400 Syndrome of inappropriate secretion of antidiuretic hormone, 61 Synergy testing, 43 Synovial fluid Gram stain of, 590, 592 leukocyte count in, 592, 595 in septic arthritis, 586, 588, 589t, 590 Syphilis, 300–305 clinical manifestations of, 301–302

935

coinfection with HIV infection, 302 diagnosis, 302–304 epidemiology of, 300 etiology of, 300 gonorrhea associated with, 290 latent, 301 meningovascular, 302 prevention of, 304–305 primary, 300, 301, 303–304, 304t secondary, 300, 302, 303–304, 304t serologic test for, 36t tertiary, 300, 301–302 treatment of, 304, 304t Systemic lupus erythematosus, 793–794 as ascites cause, 204–205 complement deficiencies in, 783 as meningitis cause, 64 T Tabes dorsalis, 302 T cells. See also CD4+ T cells in candidiasis, 529, 530 in cell-mediated immunity, 779, 782 in humoral immunity, 782 Tear wounds, bite wounds as, 687 Telithromycin as bronchitis treatment, 413t as pneumonia treatment, 465 Temporal lobe, abscess of, 93 Tenosynovitis, bite-wound infection-related, 681, 688, 695 Testicular torsion, 276t, 277 Tetanus, bite wound-related, 688 Tetanus prophylaxis, for bitewound infections, 685, 685t, 691 Tetracycline as ehrlichiosis treatment, 847t, 848 as malaria treatment, 867–868 Theophylline, drug interactions of, 506 Thoracic surgery patients, antimicrobial prophylaxis in, 5t Throat cultures in infectious mononucleosis, 708 in influenza, 423 in pharyngotonsillitis, 370–371 Thrombocytopenia, 708 antiretroviral therapy-related, 732t human granulocytotropic anaplasmosis-related, 845 human monocytotropic ehrlichiosis-related, 842 Thrombocytosis, splenic abscess-related, 230 Thrombophlebitis, suppurative septic, 134–138, 135t, 136f, 137t Thrush, oral, 530, 534 Thumb sucking, 682 Tibia, osteomyelitis of, 611–612 Tick-borne diseases, 833–852 babesiosis, 840 clinical manifestations of, 833

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936

Index

differential diagnosis of, 833, 849–850, 850t encephalitis, 85, 86t human granulocytic anaplasmosis, 833, 834 human monocytic ehrlichiosis, 833, 834 human monocytotropic ehrlichiosis, 840–843 Lyme disease, 833–840 Tigecycline, 610 Tight glucose control, 788, 789 Tinea pedis, 642 Tinidazole, as trichomoniasis treatment, 333 Togaviruses, 705 Tonsillitis chronic, 373–375 nonstreptococcal, 366 recurrent, 373–375 streptococcal, 368 Toothbrushes, as streptococcal reinfection source, 366 Tooth extractions, as splenic abscess cause, 229 Torticollis, 380 Toxic shock-like syndromes, 842, 845 Toxic shock syndrome staphylocccoal, 631 streptococcal, 368, 631, 648, 658–659, 660, 713 Toxoplasma gondii. See Toxoplasmosis Toxoplasmosis cerebral in AIDS patients, 760, 765–767, 767t as brain abscess cause, 91–92, 101 as pharyngotonsillitis cause, 367t, 368 Transillumination, of the sinuses, 390 Trauma as brain abscess cause, 99t, 100 to endocardial epithelium, 111 as hepatic abscess cause, 225 as necrotizing fasciitis risk factor, 651 as necrotizing soft-tissue infection risk factor, 645t, 649 as osteomyelitis cause, 610, 611, 616 Travel-related illnesses cryptosporidiosis in, 161 diarrhea, 143, 144, 146, 152–153, 164–165 giardiasis in, 160 hepatitis A in, 186–187, 188–189 malaria in, 853 microsporidiosis in, 161 severe acute respiratory syndrome in, 427–428, 429 Treponema pallidum. See also Syphilis azithromycin-resistant, 304 detection of, 302–303 as genital ulcer disease, 285t human-bite wound transmission, 687 as pharyngotonsillitis cause, 368 serologic test for, 36t

Trichomonas vaginalis as cervicitis cause, 345 culture methods for, 334 as pelvic inflammatory disease cause, 315 as urethritis cause, 285t as vaginitis cause, 330t Trichomoniasis, 330t, 332–335 clinical features of, 333 diagnosis of, 333–334, 340 epidemiology of, 332 pathophysiology of, 332–333 treatment and prevention of, 334–335 Trichosporon, diagnostic assay for, 569 Trichrome stain, 24 Tricuspid valves, endocarditis of, 111–112, 115t, 116 Trimethoprim-sulfamethoxazole as bacterial meningitis treatment, 73 bacterial resistance to, 256 as bacteriuria treatment, 257–258 as bronchitis treatment, 413t as cystitis treatment, 254, 255, 255t, 256 as infected renal cyst treatment, 260 as Pneumocystis jiroveci pneumonia prophylaxis, 765t as Pneumocystis jiroveci pneumonia treatment, 763, 764t as prostatitis treatment, 271, 272t, 274 as pyelonephritis treatment, 256–257 as superficial skin infection treatment, 640 as urinary tract infection prophylaxis, 246, 262 Trimethoxazole, as prostatitis treatment, 269 Trophozoites, 227 Tropical pyomyositis, 653–654 Tuberculin skin testing, 497, 500, 511 Tuberculosis, 495–518 aspergillomas associated with, 564 clinical manifestations of, 498 definition of, 495 diagnosis of, 497, 498–500, 500t new developments in, 517 disseminated, 229 drug-resistant, 500, 510 epidemiology of, 496–497 etiology of, 497–498 extrapulmonary, 507–508 histoplasmosis as mimic of, 552 latent, reactivation of, 498 as liver abscess cause, 225 as meningitis cause, 63 miliary, 498–499 as mycotic aneurysm cause, 128 pathogenesis, 497–498 peritonitis associated with, 205, 207t, 219, 220 prevention and control of, 495–496, 497, 500–507, 502–504t, 505, 516

with Bacille-Guérin Calmette vaccination, 516 with directly-observed therapy (DOT), 495, 496, 505, 510 for drug-resistant disease, 510 for extrapulmonary disease, 508 with first-line antituberculous agents, 501, 505–507 hepatotoxicity of, 501, 504t, 505, 512–513, 516 in HIV-infected patients, 508–509 in latent disease, 511–516, 513t, 515t in liver disease, 511 new developments in, 496, 517 noncompliance with, 505 during pregnancy and lactation, 510 in renal disease, 511 with second-line antituberculous agents, 507, 507t toxicity of, 501 relapse in, 509 risk for, 497–498 as splenic abscess cause, 229 targeted screening for, 512, 512t transmission of, 497 Tubo-ovarian abscess, 314, 317, 318, 322–323 Tuftsin, 789 Tularemia, 687 Tumor necrosis factor, 54, 648–649 Tumor necrosis factor antagonists, 511 Tunnel-site infections, 218 Tympanic membrane, examination of, 395 Tympanostomy, 397 Typhoid fever, 151 Typhoid fever vaccine, 151 Tzanck smears, 439, 805 U Ulcers decubitus, 650 foot diabetic, 665, 666, 668 osteomyelitis-related, 614 as necrotizing fasciitis risk factor, 651 as necrotizing soft-tissue infection risk factor, 659–660 necrotizing soft tissue infections associated with, 650 pharyngotonsillitis-related, 365 syphilitic, 301, 303–304 Ultrasonography of acalulous cholecystitis, 179 of biliary tract infections, 175t of candidiasis, 533 of infected false aneurysm, 131, 132 of liver abscess, 226 of mycotic aneurysm, 128 for right upper-quadrant pain assessment, 168 of splenic abscesses, 230 testicular, 277

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Index Universal precautions, 194 Upper respiratory tract infections bacterial meningitis and, 55 human metapneumovirus, 432–433 respiratory syncytial virus, 431 sinusitis superinfection in, 387, 388, 394, 396 Ureaplasma urealyticum as pelvic inflammatory disease cause, 315 as urethritis cause, 285t as urinary tract infection cause, 250–251 Ureteral calculi, 254 Urethritis, 252, 284–285, 285t chlamydial, 295 diagnosis of, 253 diagnostic criteria for, 277t epididymitis-associated, 278, 278t, 279t, 280, 280t genital herpes-related, 297 gonococcal, 279t, 286–287, 287t with chlamydial coinfection, 292 diagnosis of, 288–289 nongonococcal, 279t, 287t, 293 Urinalysis in cystitis, 251 interpretation of results of, 23t in urinary tract infections, 252–254 Urinary tract infections. See also Bacteriuria; Cystitis; Pyelonephritis in adults, 245–265, 246–265 clinical manifestations of, 251–252, 252t diagnosis of, 252–254 differential diagnosis of, 251–252 epidemiology of, 246–249, 248t etiology of, 249–251, 250t prevention of, 262–263 treatment of, 246, 254–262, 255t asymptomatic, 247, 249, 249t Candida-related, 534 candidiasis-related, 530–531 in children, 247, 276 clinical specimen collection in, 19t complicated, 245–246, 246t epidemiology of, 248 treatment of-259, 258 definition of, 245 diabetes mellitus-associated, 260–261 diagnosis of, 246 imaging studies of, 254 microbiology of, 253 during pregnancy, 248–249 renal impairment-related, 260 systemic lupus erythematosusrelated, 793–794 treatment of, 246 uncomplicated, 245 viral, 251 in women, 249–250 Urine specimens, handling of, 20t Urography, excretory, 254

Urologic surgery patients, antimicrobial prophylaxis in, 5t V Vaccines Bacille-Guérin Calmette, 516 in bite-wound patients, 691, 694 as cell-mediated immunity abnormality cause, 782 Haemophilus influenzae, 365, 791 human papilloma virus, 352, 359 influenza, 397, 408, 424, 474 measles, 434–435, 704 measles-mumps-rubella, 699–700 for meningitis prophylaxis, 53 meningococcal, 76 in asplenic patients, 791 pertussis, 402 pneumococcal, 474 in asplenic patients, 791 in chronic lung disease patients, 413 in multiple myeloma patients, 792 for otitis media prevention, 397 varicella (chickenpox), 439–440, 699, 700, 714, 806, 813–814 Vagina atrophy of, 343 Lactobacillus colonization of, 327–328, 331 recolonization with, 332 Vaginal cancer, 353, 356, 359 Vaginal discharge atrophic vaginitis-related, 343 bacterial vaginosis-related, 327, 328, 329 chlamydial infection-related, 293 infectious vaginitis-related, 330t purulent, 344–345, 345t, 346t trichomoniasis-related, 333 vulvovaginal candidiasisrelated, 338, 339–340 Vaginitis, 326 atrophic, 343 bacterial vaginosis-related bacterial, 326–332 clinical features of, 328 complications of, 328, 329t diagnosis of, 329, 330t epidemiology of, 326–327 pathogenesis of, 327–328 treatment of, 327, 330–332 candidal, 330t hematuria in, 252 noninfectious, 343–344 treatment of, 327 Trichomonas-related, 330t trichomoniasis, 330t, 332–335 vulvovaginal candidiasis, 330t, 335–342 Vaginosis, bacterial, 326–332 asymptomatic, 328, 331 as cervical inflammation cause, 346 clinical features of, 328 complications of, 329t diagnosis of, 329, 330t, 340 epidemiology of, 326–327

937

pathogenesis of, 327–328 as pelvic inflammatory disease risk factor, 315 treatment of, 330–332 Valacyclovir as genital herpes treatment, 299, 299t as herpes simplex virus infection treatment, 805–806 Valganciclovir as cytomegalovirus infection treatment, 761 as cytomegalovirus retinitis treatment, 772, 774t, 775 Valvular regurgitation, 116 Vancomycin as brain abscess treatment, 99t, 101, 102 as clostridial diarrhea treatment, 156–157 as meningitis treatment, 65, 70t, 72 as osteomyelitis treatment, 622t Vancomycin resistance, in Enterococci, 787 Varicella (chickenpox), 438, 712–714, 715t clinical manifestations of, 807–809 diagnosis of, 810–811 epidemiology of, 806–807 group A streptococcal infections in, 649 pathophysiology of, 807 serologic test for, 36t Varicella (chickenpox) vaccine, 439–440, 699, 700, 714, 806, 813–814 Varicella-zoster immune globulin (VZIG), 439, 701, 714, 812–813 Varicella-zoster vaccine, 699–700 Varicella-zoster virus, 80t, 806–814. See also Varicella (chickenpox); Herpes zoster (shingles) assays for, 87 clinical manifestations of, 807–810 diagnosis of, 810–812 epidemiology of, 806–807 pathophysiology of, 807 prevention of, 812–814 as respiratory infection cause, 421, 438–440 Vascular access devices, as infection risk factor, 786 Vascular access sites, as splenic abscess cause, 229 Vascular infections, 126–139 aspergillosis, 562 diagnostic imaging of, 127 mycotic aneurysms, 126–134 suppurative septic thrombophlebitis, 134–138 treatment of, 884–888t Vascular insufficiency, osteomyelitis-related, 612, 619–620, 625–626 Vascular surgery patients, antimicrobial prophylaxis in, 5t Vasculitis, hepatitis B-related, 190 Venereal Disease Reference Laboratory (VDRL) test, 303–304