Medical Management of Infectious Disease (Clinical Guides to Medical Management)

Medical Management of Infectious Disease edited by

Christopher Grace University of Vermont Burlington, Vermont, U.S.A.

MARCEL DEKKER, INC.

NEW YORK • BASEL

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0850-4 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright 䉷 2003 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3

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PRINTED IN THE UNITED STATES OF AMERICA

To my wife, Dr. Julie Olin, for her support, encouragement, and meticulous review of each chapter.

Foreword

Perhaps no advances in medicine have reduced morbidity and mortality as effectively as those improving prevention, diagnosis, and treatment of infectious disease. The developed world takes for granted eradication of smallpox (until the potential recrudescence spawned by the specter of bioterrorism), control of malaria, and prevention of polio. We now have remarkably effective treatment for diverse, formerly uniformly life-threatening bacterial and some viral infections such as mastoiditis, endocarditis, and liver abscess to name but a few. Judicious use of diagnostic, prophylactic, and therapeutic tools by physicians in virtually all disciplines is needed to realize the benefits that are now so attainable. The medical management series, of which this volume is a key component, was developed in collaboration with the late Graham Garratt to bring eminently practical information to clinicians in a format fashioned to optimize its accessibility and utility. The series is designed to provide ‘‘consultation’’ simulating that provided in practice by specialists to generalists and those in other specialties as well as to medical students, house staff, and fellows. The information presented is linked to cardinal signs and symptoms to enhance its accessibility relevant to specific clinical entities encountered in ambulatory care, emergency, and in-patient settings. Dr. Grace and his colleagues have fulfilled the objectives of the medical management series admirably. The individual chapters provide detailed descriptions of manifestations and pathophysiology of infections, pragmatic presentation of pharmacologic principles and practice, characterization of clinical syndromes and their management, consideration of populations at increased risk, and articulation of lynchpins of health maintenance in a post9/11 world. The contributing authors are knowledgeable. They are consummate clinicians as well as scholars. Their guidance is predicated on practical experience and in-depth knowledge. Their insights are compelling, and their opinions are authoritative. Their material is presented clearly and cogently. Diagrams, tables, and other aids enhance assimilation and facilitate comprehension. All who care for patients can benefit from this volume. Dr. Grace and his colleagues have provided a firm foundation for enhancing quality of care by enabling clinicians to access and utilize comprehensive information pertinent to the prevention, diagnosis, and treatment of infectious disease. Dr. Grace has, indeed, edited a volume that can serve well as a clinician’s consultant. Burton E. Sobel v

Preface

The practice of medicine has been shifting to a greater and greater extent to the outpatient setting. This is true for the management of infectious diseases as it is for all other disciplines. This shift has occurred because of economic pressures, improved outpatient and home care, enhanced diagnostics, better understanding of antibiotic pharmacokinetics and dynamics, and a growing armamentarium of antibiotic agents. All of these advances have improved our ability to manage common infections such as pneumonia, bronchitis, cellulitis, and gastrointestinal and genitourinary infections in the community locale. More complex illnesses such as osteomyelitis, septic arthritis, endocarditis, and infections involving immunocompromised hosts and in those receiving renal dialysis or using injection drugs are often being managed in the outpatient setting. Confounding these advances are new and emerging infections, globalization with greater international travel, an increasing number and complexity of immunocompromised patients, and now the threat of bioterrorism. This text was written for those providing primary care to patients, including family physicians, internists, emergency department physicians, gynecologists, surgeons, nurse practitioners, physician assistants, and medical subspecialists who provide primary care to their specialty patients. It is directed toward the adult patient and deals with infections encountered in the outpatient setting. The text also supplies the provider with initial diagnostic and therapeutic options and suggestions for the office patient needing to be hospitalized because of infections. The book can be read as a general review or used as a quick and practical reference to help the provider manage a large array of infections. Liberal use of tables, charts, photographs, and flow diagrams has been made to help keep the book practical and user-friendly. Every chapter is summarized with ‘‘Key Points’’ boxes to help the busy clinician access needed information quickly. Part I includes reviews of the pathogenesis, interpretation, and treatment of fever, the evaluation of the patient with fever and rash, the febrile patient without an obvious fever source, and noninfectious etiologies of fever. The approach to treating the patient with various infectious disease emergencies or positive blood cultures is summarized. Reviews are provided of antibiotic pharmacokinetics and dynamics, appropriate use of the microbiology laboratory, and commonly used outpatient-based oral and intravenous antibiotics. vii

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Preface

Part II examines common infectious syndromes involving the oral, respiratory, genitourinary and gastrointestinal tracts, as well as infections involving intra-abdominal organs, heart, skin and soft tissues, joints, bones, and the eye. An approach to the testing and initial evaluation of the person with human immunodeficiency virus infection is presented. Patients with unique geographic exposure such as those with regionally acquired fungal, parasitic, and viral syndromes, and those with tick-borne infections are presented. Part III reviews infections in special hosts such as the immunocompromised or pregnant patient, those receiving renal dialysis or living in nursing homes, the international traveler, and patients with animal contact–related illnesses. The continued epidemic of injection drug use necessitated a chapter involving infections in these patients. Epstein Barr virus–related infections are reviewed, as is the poorly understood chronic fatigue syndrome. Part IV summarizes infectious disease–related health maintenance issues such as vaccination and postexposure prophylaxis. The anthrax attacks in the fall of 2001 necessitated the final chapter on bioterrorism. Increasing bacterial resistance and widespread drug toxicities have made it imperative that all providers prescribe antibiotics judiciously. The epidemics of vancomycinresistant enterococci, methicillin-resistant Staphylococcus aureus, resistant aerobic gramnegative bacilli, and Clostridium difficile colitis have made it very clear that the overuse of antibiotics is dangerous. Ballooning health care costs and insurance policies with inadequate prescription coverage highlight the importance of being cognizant of antibiotic costs. This is emphasized throughout the text by comparing the average wholesale costs of antibiotics that may be used to treat infections. The book begins and concludes with quotations from Sir William Osler to emphasize the importance of the primary care clinician’s role in the recognition, diagnosis, and appropriate management of infections in the office setting. It is my hope that this text assists the primary provider in achieving these goals. Christopher J. Grace

Contents

Foreword Burton E. Sobel Preface Contributors

I.

v vii xiii

INTRODUCTION 1.

Fever Christopher J. Grace

1

2.

Infectious Disease Emergencies: Recognition and Initial Management Robert E. Levitz

17

3.

Commonly Used Oral Antibiotics Thomas Lamarre, William Maher, and Robert Fass

41

4.

Pharmacokinetics and Dynamics John W. Ahern

77

5.

The Clinician and the Microbiology Laboratory Daniel J. Diekema

97

6.

Outpatient Parenteral Antibiotic Therapy Donald M. Poretz

115

7.

Fever and Rash Mary Beth Ramundo

129

8.

Noninfectious and Cryptic Fevers Brad E. Robinson and Christopher J. Grace

151

9.

Blood Cultures Cheryl A. Smith

169

ix

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Contents

II.

CLINICAL SYNDROMES

A.

B.

C.

Respiratory Tract 10.

Upper Respiratory Tract Infections W. Kemper Alston and Kristen I. Fahrner

187

11.

Common Oral Infections H. Charles Hill II, Thomas W. Connolly, and Susan M. Hill

209

12.

Community-Acquired Pneumonia and Bronchitis John G. Bartlett and Christopher J. Grace

227

13.

Tuberculosis C. Fordham von Reyn

251

14.

Common Cold and Influenza Sherif B. Mossad

265

Genitourinary Tract 15.

Urinary Tract Infections Kevin D. Dieckhaus

279

16.

Gynecological Infections Rebecca A. Clark

301

17.

Male Urogenital Syndromes Craig S. Conover, Sheila M. Badri, and Mark Potter

319

Cardiac 18.

D.

E.

Endocarditis JoAnn Tufariello and Franklin D. Lowy

347

Skin and Soft Tissue 19.

Bacterial Infections of the Skin and Soft Tissues Jeffrey Parsonnet

373

20.

Nonbacterial Infections of the Skin Anita Licata

393

21.

Ocular Infections Martin Mayers, Essene Bell, and Michael H. Miller

409

Gastrointestinal Tract 22.

Infectious Diarrhea Beth D. Kirkpatrick

437

23.

Hepatitis Jayant A. Talwalkar and Michael R. Charlton

455

24.

Intra-Abdominal Infections Neil H. Hyman and Christopher J. Grace

473

Contents

F.

Human Immunodeficiency Virus 25.

26.

G.

H.

III.

xi

The Patient with Human Immunodeficiency Virus Infection: Recognition, Testing, and Initial Assessment Kenneth H. Mayer and Daniel E. Cohen

495

Evaluation of the Symptomatic Human Immunodeficiency Virus–Infected Patient Janine Maenza

513

Bone and Joint 27.

Septic Arthritis and Bursitis Ellis H. Tobin and Eric S. Brecher

535

28.

Osteomyelitis Keith Collins

557

29.

Diabetic Foot Infections Christopher J. Grace and Michael A. Ricci

581

Geographic Exposure 30.

Tick-Borne Infections Robert P. Smith

599

31.

Endemic Fungal and Viral Infections Harold Henderson

621

32.

Common Manifestations of Parasitic Infections Sampath Kumar and Gordon M. Trenholme

633

INFECTIONS IN SPECIAL HOSTS 33.

The Pregnant Patient Mary-Margaret Andrews

645

34.

The Immune-Compromised Patient Robert W. Lyons

661

35.

Infections in the Injection Drug User Audrey L. French

677

36.

Infections in the Dialysis Patient Michael Berkoben

695

37.

Infections in the Patient with Animal Contact Anthony L. Esposito and George Abraham

709

38.

The Patient with Fatigue Irving E. Salit

723

39.

Epstein-Barr Virus Infection and Infectious Mononucleosis–Like Illnesses Irving E. Salit

40.

Evaluation of the International Traveler Beth D. Kirkpatrick

735 749

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Contents

41.

IV.

The Patient Living in a Nursing Home Henry S. Sacks

771

HEALTH MAINTENANCE 42.

Postexposure Prophylaxis Judith L. Steinberg

787

43.

Adult Immunization W. Kemper Alston

807

44.

Bioterrorism Christopher J. Grace

821

Index

855

Contributors

George Abraham Department of Medicine, Saint Vincent Hospital at Worcester Medical Center, and University of Massachusetts, Worcester, Massachusetts, U.S.A. John W. Ahern Department of Pharmacotherapy, Fletcher Allen Health Care, Burlington, Vermont, U.S.A. W. Kemper Alston Infectious Diseases Unit, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Mary-Margaret Andrews Infectious Disease Section, Dartmouth-Hitchcock Medical Center, and Department of Medicine, Dartmouth Medical School, Lebanon, New Hampshire, U.S.A. Sheila M. Badri Division of Infectious Diseases, Rush Medical College, and Cook County Hospital, Chicago, Illinois, U.S.A John G. Bartlett Infectious Diseases Division, School of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A. Essene Bell Department of Ophthalmology, Bronx Lebanon Hospital Center, Bronx, New York, U.S.A. Michael Berkoben Duke University Medical Center, Durham, and Gambro Healthcare, Henderson, North Carolina, U.S.A. Eric S. Brecher

Pennsylvania Hospital, Philadelphia, Pennsylvania, U.S.A.

Michael R. Charlton Division of Hepatology and Liver Transplantation, Mayo Clinic and Foundation, Rochester, Minnesota, U.S.A. Rebecca A. Clark Department of Medicine, Louisiana State University Health Science Center, New Orleans, Louisiana, U.S.A. Daniel E. Cohen Department of Research and Evaluation, Fenway Community Health, Boston, Massachusetts, U.S.A. Keith Collins

Champlain Valley Physician’s Hospital, Plattsburgh, New York, U.S.A. xiii

xiv

Contributors

Thomas W. Connolly U.S.A.

College of Medicine, University of Vermont, Burlington, Vermont,

Craig S. Conover Division of Infectious Diseases, Rush Medical College, and Cook County Hospital, Chicago, Illinois, U.S.A. Kevin D. Dieckhaus Division of Infectious Disease, Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, U.S.A. Daniel J. Diekema Department of Internal Medicine and Pathology, College of Medicine, University of Iowa, Iowa City, Iowa, U.S.A. Anthony L. Esposito Department of Medicine, Saint Vincent Hospital at Worcester Medical Center, and University of Massachusetts, Worcester, Massachusetts, U.S.A. Kristen I. Fahrner Department of Surgery, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Robert Fass† Division of Infectious Diseases, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, U.S.A. Audrey L. French Division of Infectious Diseases, Cook County Hospital, and Rush Medical College, Chicago, Illinois, U.S.A. Christopher J. Grace Infectious Diseases Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Harold Henderson Division of Infectious Disease, University of Mississippi Medical Center, Jackson, Mississippi, U.S.A. H. Charles Hill II Vermont, U.S.A. Susan M. Hill mont, U.S.A.

Department of Dental Hygiene, University of Vermont, Burlington,

Department of Dental Hygiene, University of Vermont, Burlington, Ver-

Neil H. Hyman Division of General Surgery, Department of Surgery, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Beth D. Kirkpatrick Infectious Diseases Unit, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Sampath Kumar Rush College of Medicine, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A. Thomas Lamarre U.S.A.

Infectious Disease Consultants of Cincinnati, Cincinnati, Ohio,

Robert E. Levitz Department of Medicine, University of Connecticut, Farmington, and Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, U.S.A. Anita Licata Dermatology Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Franklin D. Lowy Departments of Medicine and Pathology, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A. †

Deceased.

Contributors

xv

Robert W. Lyons Department of Medicine, University of Connecticut, Farmington; Department of Infectious Disease, Saint Francis Hospital, Hartford; and Department of Internal Medicine, Yale University, New Haven, Connecticut, U.S.A. Janine Maenza Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, U.S.A. William Maher Division of Infectious Diseases, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, U.S.A. Kenneth H. Mayer Division of Infectious Disease, Department of Medicine, Brown University, and The Miriam Hospital, Providence, Rhode Island, U.S.A. Martin Mayers Department of Ophthalmology, Bronx Lebanon Hospital Center, and Albert Einstein College of Medicine, Bronx, New York, U.S.A. Michael H. Miller Infectious Disease Section, Departments of Medicine and Ophthalmology, Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, U.S.A. Sherif B. Mossad Infectious Disease Department, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A. Jeffrey Parsonnet Infectious Disease Section, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A. Donald M. Poretz

Inova Fairfax Hospital, Falls Church, Virginia, U.S.A.

Mark Potter School of Medicine, Loyola Stritch University, and Provident Hospital of Cook County, Chicago, Illinois, U.S.A. Mary Beth Ramundo Infectious Diseases Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Michael A. Ricci Division of Vascular Surgery, Department of Surgery, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Brad E. Robinson Infectious Diseases Unit, Fletcher Allen Health Care, University of Vermont, Burlington, Vermont, U.S.A. Henry S. Sacks Thomas C. Chalmers Clinical Trials Unit, Mount Sinai School of Medicine, New York, New York, U.S.A. Irving E. Salit Immunodeficiency Clinic, Department of Medicine and Infectious Diseases, Toronto General Hospital, and University of Toronto, Toronto, Ontario, Canada Cheryl A. Smith Division of Infectious Diseases, St. Francis Hospital and Medical Center, Hartford, Connecticut, U.S.A. Robert P. Smith Maine Medical Center, Portland, Maine, and Infectious Diseases Unit, College of Medicine, University of Vermont, Burlington, Vermont, U.S.A. Judith L. Steinberg School of Medicine, Boston University, Boston, and Neponset Health Center, Dorchester, Massachusetts, U.S.A. Jayant A. Talwalkar Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota, U.S.A.

xvi

Contributors

Ellis H. Tobin Upstate Infectious Disease Associates, and Department of Medicine, Albany Medical College, Albany, New York, U.S.A. Gordon M. Trenholme Department of Infectious Disease, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A. JoAnn Tufariello Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, U.S.A. C. Fordham von Reyn Infectious Disease Section, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

1 Fever Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

‘‘Humanity has but three great enemies: fever, famine and war; of these by far the greatest, by far the most terrible, is fever’’ (Osler 1896). This often quoted line from Sir William Osler’s address at the 47th annual meeting of the American Medical Association is as true today as it was in 1896. Fever is one of the most common and worrisome symptoms that primary care providers must assess. It may be a symptom of a self-limited viral infection, a life-threatening infection, or a cryptic noninfectious illness. ‘‘Fever is nature’s engine which she brings into the field to remove her enemy’’ (Paybe 1900). Thomas Sydenham’s analogy of fever as a therapeutic force is as true as Osler’s appraisal. It is now well recognized that fever is a part of a physiological response that helps the host combat both infectious and noninfectious illness. Therefore, an understanding of what defines an abnormal temperature, the pathophysiological characteristics of temperature regulation, the beneficial and harmful effects of fever, and its treatment is vital to the care of the febrile patient. This chapter reviews the history of fever and thermometry, the normal temperature and its measurement, thermoregulation, issues surrounding the controversies of treating a fever, and antipyretic therapy. 2

HISTORY

The ancients believed that illness was due to the interdiction of the gods. In Leviticus 26:12, the Lord said, ‘‘But break my covenants, then be sure this is what I will do. I will bring upon you sudden terror and recurrent fever.’’ Pre-Socratic Greek thought separated illness from religious and mythical entities and attempted to explain it with rational reasoning and observable phenomena as a part of nature. Anaximander (638–547 B.C.) and Pythagoras (580–489 B.C.) postulated that all substances were made up of fire, air, earth, and water. The four elements were paired with their opposites. Change and continuity occurred through interaction of these opposites. Empedocles (490–430 B.C.) hypothesized that disease was due to an imbalance of one of these elements. From here evolved the theory of the four humors (blood, yellow bile, black bile, and phlegm) as developed by Hippocrates (460–377 B.C.) and his followers (Figure 1). These humors were derived from the digestion of food. In the Corpus Hippocraticum, disease was discussed as an imbalance of these four humors. Each humor was associated 1

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Figure 1 Theory of humors. The inner dotted box represents the essential elements (air, fire, water, earth) that make up all matter, as developed in the fifth century B.C. These elements may be manifested as heat, dryness, coldness, and moisture (central diamond), as described by the third century B.C. The theory of humors as developed by Hippocrates and his students stated that digested food was transformed into one of four humors (outer box), blood, yellow bile, black bile, and phlegm. (Adapted from Mettler 1947.)

with a season, temperament, and personality. Blood was hot and moist and associated with a sanguine, cheerful, and warm personality. Phlegm (the white matter mixed with blood) was cold and moist and associated with a phlegmatic, sluggish, apathetic personality. Yellow bile was hot and dry and associated with a choleric, quick tempered personality. Black bile was cold and dry and associated with a melancholic, gloomy personality. Fever was due to an excess of yellow bile, which was associated with fire, which was hot and dry. Therapeutic intervention was based on rebalancing the humors by removing the offending excessive humor. Modalities included changes in diet and exercise, drugs such as hellebore that induced vomiting and diarrhea, venesection (bloodletting), and cauterization (burning) to release or consume excess humor or to cause suppuration of wounds that allowed the drainage of the humors. Galen (A.D. 129–200) perpetuated the humoral theory, which remained essentially intact for the next 1500 years. After the discovery of the circulation by William Harvey in 1628, fever was felt to be caused by either the friction of blood in the vessels or fermentation or putrefaction of liquids in the blood. Well into the 18th century, fever was still felt to be a disease in and of itself, and some medical authorities listed over 100 types of fever (putrid, essential, malign, ataxic, etc.) Francis Broussais (1772–1838) attempted to correlate febrile illness with pathological changes found at postmortem examination, thus suggesting that fever was a symptom of illness. Claude Bernard (1813–1878) introduced the concepts underlying homeostasis and recognized that metabolic processes generated heat. Carl von Liebermeister (1833–1901) proposed the theory of an internal set point that regulated the body’s temperature. William Welsh (1850–1934) hypothesized that the central nervous system controls heat regulation from a region near the thalamus. He further hypothesized that fever may be beneficial to the host immune system. He suggested that microbes cause temperature elevation indirectly by stimulating leukocytes to release substances he called ‘‘ferments.’’ In the 1940s, these ferments were isolated from monocytes and called endogenous pyrogen. During the 1970s and 1980s, Dinarello, Beutler, and Murphy defined

Fever

3

these pyrogens as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-␣), and interferon (INF). Galen may have been the first physician to devise a scale for measuring the qualities of heat and cold. For all intents and purposes, though, elevation of body temperature was guessed at by the use of the physician’s hand until the discovery of the air thermometer in the late 16th century by Galileo Galilei (1564–1642). Santorio Santorio (1561–1636) established the basic principles of medical thermometry by inventing a liquid based instrument with a temperature scale that showed that temperature changes were measurable and reproducible (see Figure 2). His thermometer was open at one end, thus exposing temperature recordings to barometric pressure. In 1654, Ferdinand II, grand duke of Tuscany, resolved this issue by sealing both ends of the instrument and is thus credited with the first liquid in glass thermometer. In 1665, Robert Hook, Robert Boyle, and Christian Huygens suggested that thermometers could be calibrated from a single fixed point. Gabriel Fahrenheit (1686–1736) was the

Figure 2 Oral thermometer of Santorio. The patient would place the end of the instrument (glass enclosed air) in his or her mouth. Wine within the glass column served as the marker. As the air became heated from the patient, the level of liquid in the tube dropped, showing the degrees of heat. Liquid not in the tube is held in an open reservoir at the bottom. The instrument had 110 divisions; the heat of the candle and cold of snow represented end points. (Adapted from McLaury 1983.)

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first to use mercury in a glass thermometer. He developed a scale for the thermometer marking the freezing point of water at 32⬚ and boiling water at 212⬚. Gradations of temperature were referred to as degrees of Fahrenheit (⬚F). Anders Celsius (1701–1744) developed a second scale of measurement with the freezing of water marked at 0⬚ and boiling at 100⬚. There were 100 gradations between these points measured as degrees Celsius (⬚C). Anton de Haen (1704–1776) of the Vienna Hospital noted in his voluminous Ratio Medendi that the temperatures of healthy and ill patients had diurnal variations. Antoine Cesar Becquerel and Gilbert Breschset established the mean ‘‘normal’’ body temperature as 98.6⬚F in 1835. Clinical thermometry did not become accepted practice until the publication of The Course of Temperature in Diseases: A Manual of Medical Thermometry by Carl Reinhold August Wunderlich (1815–1877) in 1868. Over an 18-year period he performed several million temperature recordings on 25,000 patients using an axillary thermometer. This feat of data collection is even more impressive when it is recognized that the patients had to hold the 22.5-cm-long instrument under an arm for 20 minutes for each reading. Although he reinforced the notion that the normal temperature was 98.6⬚F, Wunderlich emphasized that the normal temperature was better thought of as a range with the upper limit at 100.4⬚F. It was his work that helped demonstrate that fever was a sign of illness, not a disease in and of itself. A shortened, portable thermometer was introduced by T. Clifford Allbutt (1836–1925) in 1867. Edouard Sequin (1812–1880) helped introduce the thermometer to the United States in the 1860s and encouraged its use by the lay population to help reduce medical quackery. 3

NORMAL TEMPERATURE

The International Union Physiological Sciences Thermal Commission has defined fever as a ‘‘state of elevated core temperature, which is often, but not necessarily, part of the defensive responses of multicellular organisms to the invasion of microorganisms or inanimate matter recognized as pathogenic or alien by the host’’ (International Union Physiological Sciences Thermal Commission 1987). Although 37⬚C (98.6⬚F) is referred to as the ‘‘normal’’ human temperature, it is more accurate to think of the normal temperature as a range from 36⬚C (96.8⬚F) to 37.7⬚C (99.9⬚F). The mean temperature, derived from a study of 700 recordings from 148 persons was 36.8⬚C ⫾ 0.4⬚C. Other studies have shown that normal healthy adults can have oral temperatures as high as 38.2⬚C (100.8⬚F). Numerous studies, including those of Wunderlich, have shown that a person’s temperature is rarely 98.6⬚F. In addition, body temperature varies according to the site where it is measured. Rectal temperatures are, on average, 0.4⬚C (0.8⬚F) higher than oral readings and 0.8⬚C (1.6⬚F) greater than tympanic temperatures. Pulmonary artery (PA) temperatures are 0.4⬚C (0.7⬚F) higher than oral temperatures but 0.2⬚C (0.4⬚F) lower than rectal temperatures. Temperatures demonstrate a diurnal variation with maximal temperatures in the late afternoon to early evening and lowest temperatures in the early morning. This diurnal variation normally fluctuates by 1.0⬚C (1.8⬚F), and variation can be as high as 1.3⬚C (2.4⬚F) in some individuals. Recent studies have suggested that the late afternoon temperatures >37.7⬚C (99.9⬚F) and early morning temperatures >37.2⬚C (98.9⬚F) are above the normal range for young healthy adults. The normal diurnal variation is maintained during a febrile response but in an exaggerated manner. This drop in temperature (heat loss) during the night, mediated by the evaporation of sweat, is the cause of ‘‘night sweats’’ characteristic of most infections (see Figure 3).

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TEMPERATURE Normal temperature: Ranges from 36⬚C to 37.7⬚C (96.8⬚F–99.5⬚F), though healthy persons can have ‘‘normal’’ temperatures as high as 38.2⬚C (100.8⬚F). Rectal temperature is often higher than pulmonary artery temperature, which can be higher than simultaneous oral temperature. Diurnal variations are usually about 1⬚C (1.8⬚F) (see Figure 3). Febrile illness: Temperatures due to infection are rarely >41⬚C (106⬚F). Within this range temperatures do not cause thermal injury. Fever patterns or temperature height during illness rarely is helpful diagnostically. Hyperthermia: Excessive temperature is not mediated by the cytokine pathway. Heat stroke may result from excessive environmental temperature or physical exertion. Malignant hyperthermia may result from use of halothane, methoxyflurane, cyclopropane, or succinylcholine. Neuroleptic malignant syndrome may be due to haloperidol, thiothixene, or phenothiazine use. Thermometers: It is best to use electronic digital instruments rectally or orally. Ear thermometers have been inaccurate when compared to digital instruments and show significant variability from ear to ear.

Temperature differences have not been demonstrated between the young and old, Caucasian and non-Caucasian races, or smokers and nonsmokers. Women may show an increased temperature of 0.5⬚C during ovulation. Analysis of fever patterns as a diagnostic tool is a centuries old art. Temperatures have been described as sustained (elevated temperature throughout the entire 24 hours of a day with fluctuations of <1⬚C), intermittent (continuously above normal but with variations of >1⬚C), hectic (a type of intermittent fever with wide swings >1.4⬚C), and remittent (temperature that is normal during some part of the day). Wunderlich, as part of his treatise on temperature over 130 years ago, stressed the variety of fever patterns but also the lack of specificity and the fact that rarely do the patterns of fever help in making a clinical diagnosis. More recently Musher and associates (1979) prospectively and retrospectively studied approximately 300 febrile patients. They were unable to find a correlation between a specific infection and the pattern of fever. Occasionally temperature patterns may be helpful diagnostically such as with the cyclic tertian (every 48 hours with Plasmodium vivax or P. ovale) or quartan (every 72 hours with P. malariae) fevers of malaria. Patients who have Hodgkin’s lymphoma may demonstrate a relapsing fever lasting 3–10 days alternating with afebrile periods of 3–10 days (Pel Epstein fever). As part of the physiological response of temperature, the heart rate increases by 4 beats/min for each 1⬚C rise in temperature. Exceptions to this rule are illnesses that are associated with a pulse–temperature deficit such as typhoid fever, Legionella sp. infections, and drug fevers, wherein the temperature rise is out of proportion to the observed heart rate. In the author’s experience, fever patterns or the height of the temperature rarely if ever helps define the cause.

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Figure 3 Fever curves during febrile and afebrile conditions. The broken line represents the normal diurnal variation of temperature: peaking in the late afternoon and reaching a nadir in the early morning. The solid line is the temperature curve during a febrile illness. The diurnal variation is maintained but at a higher set point during infection. Heat is generated by shivering, causing chills (C). The temperature rises as a result of an increase in the hypothalamic set point (rising vertical dotted arrow) to a new, higher set point (40⬚C). Heat is lost by sweating (S) when the set point is lowered (falling vertical arrow) toward the ‘‘normal’’ set point. The solid arrow represents administration of an antipyretic, which artificially lowers the set point to a greater extent than would be expected during the normal diurnal variation of an infection, causing a marked fall in temperature. The patient experiences a ‘‘drenching’’ night sweat.

4

HYPERTHERMIA

Fever is a normal physiological response mediated by cytokines that ‘‘reset’’ the hypothalamic set point (discussed later). It represents a homeostatic mechanism balancing heat loss and generation. In response to infections, temperatures rarely rise above 41⬚C (106⬚F). Temperatures within this limit do not cause thermal injury to body tissues. The lethal limits of body temperature are as low as 26⬚C (78.8⬚F) and as high as 43⬚C (109.4⬚F). Hyperthermia, in contrast to fever, is a rise in body temperature not mediated by cytokines that represents a failure of thermoregulatory control to maintain body temperature within the normal physiological range. This failure of homeostasis may result from excessive ambient temperature, physical exertion, or an adverse reaction to certain drugs. Heat stroke is due to excessive environmental temperature. This is characteristically seen in the elderly during a heat wave associated with high humidity. These patients generally have underlying illnesses and exhibit headache, confusion, and prostration. Temperatures are often >41⬚C (106⬚F) and have reached as high as 44.4⬚C (112⬚F). In young individuals heat stroke may develop in response to excessive and prolonged exertion such

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as marathon running. These patients manifest rhabdomyalysis, renal failure, and disseminated intravascular coagulation (DIC). For patients with heat stroke, antipyretic agents are ineffectual and cooling must be done with external measures. Malignant hyperthermia is a rapid rise in temperature in response to certain inhalational anesthetic agents in genetically predisposed persons. These agents include halothane, methoxyflurane, cyclopropane, and ethyl ether or muscle relaxants such as succinylcholine. In addition to fever, patients have lessened relaxation during anesthetic induction and elevated creatinine phosphokinase (CPK) level. The neuroleptic malignant syndrome is brought on by neuroleptic agents such as haloperidol, thiothixene, or piperazine phenothiazines. Patients may demonstrate tachycardia, labile blood pressure, diaphoresis, catatonia, and muscular rigidity. Temperatures may exceed 41⬚C. 5

TEMPERATURE MEASUREMENT

The goal of temperature measurement is to record the core (abdomen, thorax, and cranium) body temperature. The goal standard is measurement of the pulmonary artery (PA) temperature. Since this is not practical during routine medical care, estimates of the core temperature are usually derived from the oval and rectal temperatures. Peripheral temperature measurements (skin or axilla) are not representative of the core temperature. For 200 years the standard tool for the measurement of temperature has been the mercury in glass thermometer (MIGT). The instrument must be left in place (mouth or rectum) for 5–8 minutes and may be uncomfortable or inconvenient for the patient. Recently environmental and health concerns have been raised about the accidental release of the mercury. Electronic instruments that use a heat sensing thermister coupled with a digital readout have come into greater use. They must be left in place (mouth or rectum) for 20–40 seconds and may also be inconvenient. More recently infrared ear thermometers (IETs) have become popular because of their ease of use. It is believed that this measurement represents core temperature since the external carotid artery supplies the tympanic membrane. The device measures heat radiation from the tympanic membrane and surrounding ear canal during a <1-second ‘‘snapshot’’ of the temperature. There is a large body of literature debating the accuracy of these IET devices. Several studies have raised serious doubts about the accuracy and reliability of these thermometers. A study by Modell and associates (1998) found that IET overestimated PA temperature on average by 0.36⬚C (range ⫺1.1⬚C to 1.8⬚C) and that variation between the left and right ears in an individual person could be >1⬚C and in a few persons >2.5⬚C. Irwin (1999) found oral temperatures were generally higher than tympanic measurements and that 58% of oral temperatures were 1⬚F higher than tympanic temperatures. In that study, 9/160 measurements were 2.2⬚F higher orally than by IET. Because of these concerns, many authorities (Jensen et al., 2000; Giuliano et al., 2000) continue to recommend the use of digital thermometers orally or preferably rectally. Others have gone so far as to characterize reliance on IET as potentially dangerous (Modell et al., 1998). 6

THERMOREGULATION

In warm-blooded animals, body temperature is controlled within a narrow range by balancing heat production and conservation with heat loss. This homeostatic control maintains the body at a ‘‘set point’’ by a coordinated effort involving autonomic, endocrinological,

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THERMOREGULATION AND ANTIPYRETICS Temperature is part of a complex physiological response to infection involving immunological, hormonal, and behavioral aspects (see Table 1 and Figure 4). The febrile response is believed to be beneficial (see Table 2). Endogenous pyrogens (IL-1, TNF, IL-6, and interferons) mediate temperature elevation by stimulating prostaglandin E2 production by COX. Aspirin and NSAIDs block COX-1 and COX-2 nonselectively, accounting for their antipyretic and anti-inflammatory actions. Acetaminophen may block a hypothesized third COX isoenzyme. The main concerns of antipyretics are their toxicities (see Table 3). Selective COX-2 inhibitors such as celecoxib and rofecoxib cause less gastrointestinal toxicity. Reducing a fever may make the patient more symptomatic by exacerbating the cyclic chills and sweats (see Figure 3). Temperatures should be lowered only to reduce the patient’s symptoms.

metabolic, and behavioral mechanisms. Heat is generated to maintain normal temperature or to raise it during a febrile illness. During normal afebrile times, heat arises from cellular metabolism, oxidation of nutrients, circulation of blood, and contraction of involuntary muscles. During febrile states, increased heat can be generated by skeletal muscle contraction (shivering). The heat generated in the core is distributed to the periphery by the circulation. In response to increased core temperature, cutaneous blood flow increases via the autonomic nervous system, causing heat loss by radiation and convection. Autonomic nerves also control sweating, causing heat loss by evaporation. Sweat loss of 1% of body weight can lower body temperature by 5⬚C. Decreased core temperature results in peripheral vasoconstriction, thus shunting blood centrally. A network of neurons extending from the hypothalamus to the spinal cord controls this heat distribution. The main component of this network is the preoptic region of the anterior hypothalamus. The neurons of this area are thermosensitive and receive input from receptors in the skin and core organs and via the mediators transported by the blood. When an invasive pathogen (the exogenous pyrogen) is phagocytized by white blood cells, endogenous pyrogens that mediate a complex inflammatory and immunological response to the infection are released (see Figure 4). In addition to microbial pathogens, endogenous pyrogen release can be stimulated by antigen–antibody complexes, complement, and bile acids. The endogenous pyrogens are cytokines, including IL-1, IL-6, TNF␣, and the interferons. These act locally and systemically, individually and in combinations, to trigger a large array of metabolic, physiological, and immunological responses. IL-1 (␣ and ␤) is a polypeptide secreted by mononuclear cells, pulmonary macrophages, keratinocytes, gingival and corneal epithelium, renal mesangial cells, cerebral astrocytes, and the reticuloendothelial system of the liver and spleen. It stimulates the bone marrow to increase neutrophils, polymorphonuclear (PMN) leukocytes to increase phagocytosis and bacterial killing, and fibroblasts to increase collagen synthesis. It induces IL2, cytotoxic T lymphocytes (CTLs), and acute phase reactant production. It increases secretion of IL-1, IL-6, and TNF. TNF-␣ is a polypeptide secreted by macrophages, monocytes, astrocytes, endothelial cells, kupffer cells, natural killer cells, and some tumors. It causes hemorrhagic necrosis

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Figure 4 Fever, immunity, and the inflammatory response. Exogenous pyrogen stimulates cytokine (endogenous pyrogen) release. IL-1, IL-6, TNF, and INF reset the hypothalamic set point via OVLT. The body temperature is raised. The inflammatory and immunological responses then control the exogenous pyrogen (dotted lines). WBC, white blood cell; IL-1, interleukin-1; IL-6, interleukin-6; TNF, tumor necrosis factor; ␦ INF, interferon; OVLT, organum vasculosum of the lamina terminalis.

of tumors in vitro, accounting for its primary name. It reduces lipoprotein lipase activity, resulting in decreased lipid uptake and clinical wasting, hence its other name, cachectic. It stimulates osteoclast, neutrophil, and CTL activity and B cell differentiation. It induces a procoagulant effect, leading to vascular thrombosis, and stimulates IL-1 release. It induces TNF-␣, IL-1, and IL-6. The interferons (␣, ␤, ␥) are glycoproteins produced by leukocytes that have been shown to have immune modulating, antitumor, antiviral, and antibacterial effects. Interferon-gamma (INF-␥) is secreted by T and natural killer (NK) cells. It stimulates B cell differentiation, antibody secretion, NK cell activity, and endothelium adhesion molecule expression. It increases secretion of TNF-␣ and IL-1. IL-6 is a potent cytokine secreted by monocytes, macrophages, fibroblasts, endothelial cells, keratinocytes, and bone marrow stromal cells. It induces acute phase proteins, CTL response, B cell proliferation, and antibody production and is a potent inducer of prostaglandin synthesis. Its secretion is under the control of TNF and IL-1, and therefore it has been described as a ‘‘downstream’’ mediator of fever, which is released after IL-1 and TNF-␣ are produced in response to infection. It decreases IL-1 and TNF-␣ secretion. Hormones affected by these cytokines include glucagon, growth hormone, cortisol, thyroid stimulating hormone, thyroxine, erythropoietin, and corticotrophin. These cause an increase in gluconeogenesis, muscle proteolysis, and increase in oxygen and caloric demand. There is increased synthesis of hepatic acute phase reactants such as C-reactive

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protein (CRP), haptoglobin, ceruloplasmin, fibrinogen, ferritin, complement, and serum amyloid A. There is a decrease in serum albumin, transferrin, hematocrit, zinc, and iron levels. Table 1 summarizes the effects of IL-1, the most potent of the endogenous pyrogens. In addition to immunological and hormonal changes, cytokines cause temperature elevation as part of the response to infection. These cytokines stimulate prostaglandin synthesis in the preoptic areas of the anterior hypothalamus. Endogenous pyrogens, however, are not able to reach the preoptic region of the anterior hypothalamus directly since they are unable to cross the blood–brain barrier (BBB). It is hypothesized that they mediate their effects via the organum vasculosum of the lamina terminalis (OVLT), a structure adjacent to the preoptic area with a ‘‘leaky’’ BBB that allows entry of the cytokines. Cytokines activate phospholipase A2, causing release of membrane bound arachidonic acid. They also increase synthesis of cylooxygenase (COX), which catalyzes arachidonic acid to prostaglandin G2 and H2, which are the intermediate precursors of prostaglandin E2 (PGE2) (see Figure 5). PGE2 decreases the firing rate of the preoptic ‘‘warm-sensitive’’ neurons in the preoptic region. The change in the firing rate of these neurons results in an upward resetting of the hypothalamic temperature set point. If the hypothalamic set point is raised (i.e., during an infection), the body is perceived to be cooler than the new set point. Physiological and behavioral changes are set in motion to raise the body temperature to match the higher set point. Shivering is initiated to generate heat, blood is shunted to the core to conserve heat, and sweating diminishes. The individual may seek warmth by covering up with blankets and raising the ambient temperature. The generated heat raises the body temperature to match the elevated set point. Anorexia, malaise, and somnolence are commonly experienced. When the hypothalamic set point is lowered, either as part of the normal diurnal fluctuations that occur during an infection or in response to antipyretic agents, the hypothalamus perceives the core temperature as higher than the set point and initiates heat loss by evaporation (sweating) and radiation (cutaneous vasodilation) (see Figure 3). The cyclic nature of the diurnal fluctuations is experienced by the patient as alternating chills and sweats. Recently (Boulant, 2000) it has been shown that these cytokines also stimulate the preoptic region via afferent vagal nerves that release norepinephrine, which in turn stimulates COX to produce PGE2. These two different mechanisms of cytokine activity (direct blood-borne and neural fiber–mediated) may account for the biphasic nature of the febrile response seen in experimental models.

Table 1 Direct and Indirect Effects of Interleukin 1 Metabolic • • • • • • • • •

↑ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑

Corticosteroids Insulin Zinc Iron Albumin Cytochrome P 450 Lipoprotein lipase Weight Acute phase reactants

Physiological • • • • •

↑ ↑ ↓ ↓ ↑

Temperature Sleep Appetite Blood pressure Sodium excretion

Immunological • • • • • •

↑ ↑ ↑ ↑ ↑ ↑

White blood cells T cell activation B cell activation Natural killer cell activation Interferon Procoagulants

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Figure 5 Prostaglandin E2 production. Prostaglandin E2 is synthesized from membrane bound phospholipid by phospholipase A2 and COX. Corticosteroids inhibit phospholipase A2, whereas aspirin and nonsteroidal anti-inflammatory drugs inhibit COX. Acetaminophen may also inhibit a hypothesized third COX isoenzyme. IL-1, interleukin 1; TNF, tumor necrosis factor; IL-6, interleukin 6; IFN, interferon; ASA, acetylsalicylic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; COX, cyclooxygenase.

As with all homeostatic processes, there are feedback mechanisms to control the rise in temperature. Endogenous antipyretics protect against the danger of unchecked temperature elevation. These substances include cortisone, cortisol, arginine vasopressin, adrenocorticotropin hormone (ACTH), ␣ melanocyte–stimulating hormone, ␦ melanocyte–stimulating hormone, IL-10, and perhaps TNF. When cytokines are released, there is also a release of soluble cytokine receptors that directly inhibit the cytokine effects. These mechanisms account for the potent antipyretic effect of corticosteroids when administered to patients who have fever.

7

IS FEVER GOOD OR BAD?

Fever is an adaptive mechanism that is part of the inflammatory and immunological response to microbial invasion. It should therefore be viewed as beneficial. The reasoning and data to support this idea fall into three categories (see Table 2).

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Table 2 Benefits of Fever Teleological • It is a phylogenetically old host response. • It evolved over 4 million years ago. • All vertebrates experience temperature elevation in response to infection. • Fever confirms a survival advantage in all vertebrates studied. • Fever is metabolically expensive. • If it were not beneficial, it should have been selected out. In vitro temperature elevation • ↑ Leukocyte mobility. • ↑ White blood cell bactericidal activity. • ↑ Immunoregulatory effects of IL-1. • ↑ Antibody production by B cells. In vivo studies in cold-blooded fish and lizards • Increasing the febrile state increased survival rate. • Antipyretics decreased survival rate.

7.1

Teleological

Fever has been documented in vertebrates, including mammals, birds, reptiles, amphibians, and fish, arthropods, including crabs, shrimps, and lobsters, and annelids, such as worms and leeches as a response to microbial infection. This suggests that fever as a host defense evolved over 4 million years ago. Fever is a metabolically expensive response. In mammals and birds, energy consumption must be increased by 20% to maintain a temperature 2⬚C– 3⬚C above the normal state. This energy expenditure also occurs in cold-blooded creatures that seek warmer environments when infected. If fever were not beneficial, this metabolically expensive response should have been eliminated by natural selection. 7.2

In Vitro Studies

Laboratory studies (Kluger, 1996) have shown that raising the temperature increases leukocyte motility and bactericidal activity, T lymphocyte transformation, and B cell antibody production. Human leukocytes heated to 38⬚C–40⬚C showed maximal phagocytic activity. Raising the temperature of the experimental environment increases the immunoregulatory effects of IL-1 and INF. The bacterial requirement for iron increases as the temperature is elevated. IL-1 causes PMN to release lactoferrin, which in turn decreases serum iron level, a vital nutrient for bacterial growth. Studies have shown that temperatures within the expected febrile range of a host interfere with microorganism growth and that antibiotics may work more effectively at higher temperatures. 7.3

In Vivo Studies

Studies in mammals and reptiles have demonstrated a survival benefit associated with elevation in body temperature. Similar studies have shown a survival disadvantage to artificially lowering temperature with antipyretics. The classic study was done in the 1970s by Kluger and colleagues (1975), who showed a relationship between the body temperature of an infected lizard, Dipsosaurus dorsalis, and survival. Lizards infected with Aeromonas hydrophilia were placed in incubators heated to different temperatures. All those lizards allowed to raise their body temperature in this manner survived. Those animals kept ar-

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tificially normothermic by blocking their movement into warmer areas had a 30% survival rate. An increasingly higher temperature correlated with increased survival rate. In a follow-up study, infected lizards treated with antipyretics had a poor survival rate if fever did not develop, a finding that suggests that artificially lowering body temperature with salicylates was harmful. Similar studies have been done in goldfish. Studies involving rabbits infected with Pasteurella multocida demonstrated better survival rates with increasing temperature within the normal range of the febrile response for these rabbits. Ferrets with influenza infection have less nasal viral shedding with increased temperatures than ferrets with lesser temperature elevations. Demonstration of a survival benefit from temperature elevation in humans has been more elusive. Hypothermia has been recognized as a poor prognostic marker during sepsis. In a retrospective study of patients with gram-negative bacteremia Bryant and associates (1971) found a positive correlation between the maximal temperature on the day of initial bacteremia and survival rate. Others (Weinstein et al., 1978) have noted a similar relationship between temperature elevation and survival rate in patients with spontaneous bacterial peritonitis. 8

ANTIPYRETIC THERAPY

Willow tree bark has been known for centuries for its fever reducing properties. Its use was first scientifically described in 1763 by the Reverend Edward Stone. In 1829 Henri Leroux isolated salicin from willow bark, and Raffaele Piria produced salicylic acid from the bark extract in 1838. By the late 19th century sodium salicylate was used as an antipyretic and anti-inflammatory drug, though poor taste and gastric irritation interfered with its use. In 1897 Felix Hoffman produced acetylsalicylic acid (subsequently named aspirin), which was effective and better tolerated. The Bayer Company also developed and produced phenacetin in 1887. Acetaminophen, the major metabolite of phenacetin, was shown to have fewer side effects and replaced it for use in the late 1940s. Indomethacin was produced in 1963. In 1971, John Vane showed that the antipyretic and anti-inflammatory activities of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) were due to blockade of COX involved in prostaglandin synthesis. Subsequently two isoenzymes, COX-1 and COX-2, have been identified. COX-2 plays the major role in the febrile and inflammatory response. Aspirin and older NSAIDs are nonselective COX inhibitors. Newer NSAIDs such as celecoxib (Celebrex, Searle) and rofecoxib (Vioxx, Merck) are selective COX-2 inhibitors. A third COX enzyme that may be blocked by acetaminophen, thus accounting for its antipyretic abilities, but negligible anti-inflammatory activity, has been hypothesized. Through most of recorded history, fever has been thought of as a disorder to be eradicated or an unpleasant or potentially dangerous symptom. In either case, most providers and patients feel that the febrile response should be suppressed. Although the studies discussed have demonstrated a survival disadvantage for those lizards, fish, and rabbits treated with antipyretics, extensive antipyretic use in humans during the last 30 years has not been shown to be obviously detrimental. Adding to the science and myth is a multibillion-dollar industry marketing antipyretic agents in hundreds of varied formulations to a worried and uncomfortable lay population. It needs to be reinforced that fever, even fever of 41⬚C, is not detrimental. Within the range of temperatures caused by most infections and noninfections alike, high temperatures do not cause thermal injury to the patient. Table 3 summarizes the pros and cons of antipyretic therapy. The major concerns related to antipyretic drug use involve toxicities. Gastrointestinal (GI) toxicities include

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Table 3 Advantages and Disadvantages of Antipyretic Therapy Advantagesa 1. ↓ Symptoms of fever 2. ↓ Metabolic demand in the elderly with cardiopulmonary disease 3. ↓ Metabolic demand in patients with central nervous system injury 4. ↓ Toxic encephalopathy in the elderly 5. ↓ Risk of febrile seizures in children Disadvantages 1. Fever potentially beneficial (see Table 2) 2. ↑ Chills and sweats 3. Toxicities of drugs • Gastrointestinalb • Renalb • Hepaticb,c • Antiplatelet activityb • Rashb • Reye’s syndromed a

Empirical only, no scientific proof of validity. Associated with aspirin and nonsteroidal anti-inflammatory drugs. c Associated with acetaminophen. d Aspirin use in children with influenza and varicella infection. b

dyspepsia (10%–20% of patients), ulcer formation, and bleeding. Those at most risk for GI adverse events include the elderly, those with preexisting peptic disease or bleeding, and those taking high doses of the drugs and taking concomitant steroids or anticoagulants. Acetaminophen can cause liver toxicity when used in cumulative doses of 4 g in a 24hour period. Nonselective COX inhibitors can cause fluid and electrolyte disorders, acute renal failure, and interstitial nephritis. Patients at increased risk for NSAID related acute renal failure include those with dehydration, congestive heart failure, and liver failure, all conditions associated with low intravascular volumes. Less commonly, hyperkalemia can be seen. Those at risk include insulin-dependent diabetics and those receiving ␤-blockers or potassium sparing diuretics. Long-term use of combinations of acetaminophen and NSAIDs can cause analgesia-induced nephropathy. NSAIDs are antiplatelet agents and thus may pose a bleeding risk to those undergoing surgery. Selective COX-2 inhibitors are reported to have reduced GI and renal toxicity; however, they are considerably more expensive (30 20-mg capsules for $70.00) than aspirin and acetaminophen. It has been suggested that fever should be treated to reduce the metabolic demand in patients with acute cardiopulmonary illness or with central nervous system injury. Although the reasoning behind this suggestion is sound, data supporting it are nonexistent. In addition, it should be noted that intravenous indomethacin has been shown to cause coronary vasoconstriction in patients with coronary artery disease. The use of antipyretics to reduce symptoms is a double-edged sword. Patients made uncomfortable by fever may feel transiently better after temperature reduction. For some patients, antipyretic therapy may exacerbate the cyclic chills and sweats that are part of a febrile illness and may in fact make them feel worse (see Figure 3). The decision, therefore, to use or not use an antipyretic agent is dependent on what makes the patient most com-

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fortable. Many patients are not particularly symptomatic or aware of their fever; treating the fever may only make them feel worse. If it is elected to treat a fever with an antipyretic drug, it should be given ‘‘around the clock’’ and not ‘‘as needed.’’ This continuous suppression of the hypothalamic set point may help alleviate the sharp peaks and valleys of the daily fever elevations and reductions, thus diminishing the associated chills and sweats. Aspirin, NSAIDs, and acetaminophen are equally efficacious in reducing temperatures. Sponge bathing with tepid water may improve heat evaporation while preventing peripheral vasoconstriction. Cooling blankets should be avoided. They may be very uncomfortable to the patient and counterproductive since the cold surface may cause shivering, increase metabolic rate, and actually raise core temperature. 9

SUMMARY

Fever is part of a complex metabolic, immunological, and behavioral response to infection and to noninfectious illness. This response has evolved over millions of years and is most likely beneficial to the host. Treatment with antipyretic agents should be limited to uncomfortably symptomatic patients or those with specific risks posed by the elevated metabolic rate that accompanies the fever. Toxicities from antipyretics need to be kept in mind. Fever, as a representation of infectious disease, has been a great enemy to humanity. It is also part of nature’s engine to control infection. Osler and Sydenham were both correct. BIBLIOGRAPHY Atkins E. Fever: Its history, cause and function. Yale J Biol Med 55:283–289, 1982. Boulant JA. Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin Infect Dis 31:S157–S161, 2000. Bryant RE, Hood AF, Hood CE, Koening MG. Factors affecting mortality of gram-negative rod bacteremia, Arch Intern Med 127:120–128, 1971. Giuliano KK, Giuliano AJ, Scott SS, MacLachlan E, Pysznik E, Elliot S, Woytowicz D. Temperature measurement in critically ill adults: A comparison of tympanic and oral methods. Am J Crit Care 9:254–261, 2000. Haller JS. Medical thermometry—a short history. West J Med 142:108–116, 1985. International Union Physiological Sciences Thermal Commission. Glossary of terms thermal physiology, 2nd ed. Pflugers Arch 78:567–587, 1987. Irwin S. Comparison of the oral thermometer versus the tympanic thermometer. Clin Nurse Spec 13:85–89, 1999. Jensen BN, Jensen FS, Madsen SN, Løssi K. Accuracy of digital tympants, oral, axillary and rectal thermometers compared with standard rectal mercury thermometers. Eur J Surg 166:848–851, 2000. Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D. The adaptive value of fever. Infect Dis Clin North Am 10(1):1–20, 1996. Kluger MJ, Ringler DH, Anver MR. Fever and survival. Science 188:166–168, 1975. Mackowiak PA, Worden G. Carl Reinhold August Wunderlich and the evolution of clinical thermometry. Clin Infect Dis 18:458–467, 1994. McLaury RL. A history of clinical thermometry. Oklahoma State Med Assoc. 76:420–426, 1983. Mettler CC. History of Medicine. Toronto: Blakiston, 1947. Modell JG, Katholi CR, Kumaramangalam SM, Hudson EC, Graham BS. Unreliability of infrared tympanic thermometer in clinical practice: A comparative study with oral mercury and electronic thermometers. South Med J 91(7):649–654, 1998.

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Musher DM, Fainstein V, Young EJ, Pruett TL. Fever patterns: Lack of clinical significance. Arch Intern Med 139(11):1225–2228, 1979. Netea MG, Kullberg BJ, Van der Meer JWM. Circulating cytokines as mediators of fever. Clin Infect Dis 21:S178–S184, 2000. Osler W. The study of fevers of the south. JAMA XXVI:999–1004, 1896. Paybe HF. Thomas Sydenham. London: T Fisher Unwinn, 1900. Simmons DL, Wagner D, Westover K. Nonsteroidal anti-inflammatory drugs, acetaminophen, cyclooxygenase 2, and fever. Clin Infect Dis 31:S211–S218, 2000. Weinstein MR, Jannini PB, Stafon CW, Eichoff TC. Spontaneous bacterial peritonitis: A review of 28 cases with emphasis on improved survival and factors influencing prognosis. Am J Med 64:592–598, 1978.

2 Infectious Disease Emergencies Recognition and Initial Management Robert E. Levitz University of Connecticut, Farmington, and Hartford Hospital, Hartford, Connecticut, U.S.A.

1

INTRODUCTION

Almost any infectious disease, under certain circumstances, may be considered to be a true emergency. This chapter discusses diseases that are often life threatening emergencies on presentation. These infections include bacterial meningitis, herpes simplex type 1 (HSVI) encephalitis, necrotizing soft tissue infections, tick-borne diseases, neutropenic fever, malaria, and septic shock. The purpose of this chapter is to aid the clinician in recognition and diagnosis of these conditions and initiation of the appropriate therapy. Patients with acute or fulminant illness due to bacterial endocarditis (Chapter 18), arthropod-borne encephalitis (Chapter 31), or intra-abdominal infection (Chapter 24); the ill human immunodeficiency virus (HIV) patient (Chapter 26); and other immunocompromised patients (Chapter 34) are reviewed in other sections of this book. Consultation of infectious disease experts is recommended when managing any of these acute life-threatening infections.

2

ACUTE BACTERIAL MENINGITIS

With the introduction of modern antibiotic therapy, the mortality rates for patients diagnosed with acute bacterial meningitis have fallen rapidly. Currently, 70% of all deaths of bacterial meningitis occur within the first 2 days of hospitalization. It is possible that many of these deaths could be prevented by earlier diagnosis and prompt pharmacological therapy. Besides reducing mortality rate, early treatment probably can decrease subsequent neurological deficits such as deafness and learning disabilities. 2.1

Clinical Presentation

The onset of bacterial meningitis is generally acute, with headache, fever, and neck stiffness. Confusion progressing to coma may occur over the initial 24–48 hours. Seizures can occur in up to 30% of patients. Palsies of cranial nerve (typically cranial nerves III, IV, VI, and VII) and focal neurological deficits may also occur. 17

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BACTERIAL MENINGITIS Clinical presentation Sudden onset of headache, fever, meningismus Seizures, focal neurological deficits Altered mental status progressing to coma over 24–48 hours Diagnosis CT/MRI prior to LP only if papilledema, seizure, focal neurological deficit, head and neck infection present CSF interpretation (see Table 1) Bacteriology (see Table 2) S. pneumoniae Most common Associated with skull fracture Concern for penicillin/cephalosporin resistance N. meningitidis Most rapidly fatal Petechial rash Need for isolation for initial 24 hours of therapy H. influenzae Less common because of HIB vaccine Antibiotic therapy (see Table 3) Steroids Consider if there is evidence of increased intracranial pressure Begin prior to antibiotics Meningococcal prophylaxis Close family contacts Health care workers involved in airway intubation, oral suctioning, and cardiopulmonary resuscitation Rifampin 600 mg qd, minocycline 100 mg bid for 2 days, or ciprofloxacin 500 mg X1

On physical examination, the patient appears acutely ill and may be confused and combative. Photophobia may be present; the neck is stiff. Other signs of meningismus such as Kerning’s sign (tightness and pain in the hamstring muscles when extending the knees) or Brusinski’s sign (retraction of the legs when flexing the neck) are present in only 50% of patients. Rash (discussed later) can be seen with meningococcemia. It is important to examine the mouth, sinuses, and ears to look for contiguous foci of infection that would raise concern of a brain abscess. If otitis media, sinusitis, or an odontogenic focus of infection is found, the patient should have a computed axial tomographic (CT) scan to rule out a brain abscess. 2.2

Diagnosis

The rapid diagnosis of bacterial meningitis requires that a lumbar puncture (LP) be performed in all patients with symptoms or signs of meningitis. Unfortunately, many physicians delay LP while awaiting CT or magnetic resonance imaging (MRI) scan results. This wait causes a delay in making a proper diagnosis and institution of therapy. If the patient’s physical examination findings are nonfocal, head and neck examination does not reveal a

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pyogenic focus, or evidence of papilledema and no history of seizure or skull fracture is obtained, then the clinician can proceed directly with the LP without prior neurological imaging. The risk of herniation after LP has been greatly overestimated and is certainly less than the risk of delayed therapy for meningitis. The one exception would be the presence of gross papilledema. After insertion of the LP needle, the opening pressure should be measured. In a LP, the cerebrospinal fluid (CSF) is usually withdrawn into three sterile tubes containing approximately 2 ml of fluid per tube. The first tube is for Gram stain and culture since it is least likely to be contaminated. The second tube may be used for protein and glucose measurements. The third tube is usually used for cell count and differential (see Table 1). In addition two sets of blood cultures should be performed. Over 90% of patients with bacterial meningitis have a cell count greater than 100 white blood cells (WBCs) per microliter, with a predominance of polymorphonuclear (PMN) leukocytes. In 75% of patients CSF glucose level less than 55 mg% and usually less than 50% of a simultaneously obtained blood glucose level. CSF protein levels are elevated in the vast majority of patients and are often above 100 mg%. Prior outpatient antibiotic therapy has no significant effect on the CSF cell count, differential, glucose, or protein finding. However, prior therapy reduces the sensitivity of the CSF Gram stain and culture. Antigen detection assays, including coagglutination and latex agglutination, may be used to detect bacterial antigens in CSF when culture findings may be negative as a result of prior antibiotic use. Polymerase chain reaction (PCR) may be useful in the future to detect bacterial deoxyribonucleic acid (DNA). It must be noted that several viral infections of the central nervous system, such as herpes simplex type 1 or mumps, can mimic acute bacterial meningitis both in symptoms

Table 1 Cerebrospinal Fluid Analysis CSF Parameter Opening pressure WBC count WBC differential

Glucose

Protein Lactate Gram stain

Culture Antigen detection H. influenzae N. meningitidis S. pneumoniae

Bacterial Meningitis >180 mm H2O >1000 cells/mm3 Range <100 to >10,000 >80% PMN

<40 mg% in 60% of patients CSF/serum ratio < 0.3 >100 mg% >35 mg% (⫹) in 60%–90%, though only 50% in L. monocytogenes (⫹) in 70%–85% 60%–100% sensitivity

Aseptic Meningitis <180 mm H2O 100–1000 cells/mm3 Possible early predominance with conversion to lymphocyte predominance in 24–48 hours >40 mg%

<150 mg% NA NA

NA If patient had been receiving antibiotics

PMN, polymorphonuclear leukocytes; WBC, white blood cell count; NA, not applicable; CSF, cerebrospinal fluid.

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and in CSF examination results, including the low glucose levels (hypoglycorrhachia). Aseptic meningitis, usually caused by enteroviral infections, can occasionally be confused with bacterial meningitis. In these patients, the mental status remains normal and there appears to be less toxicity. CSF analysis generally shows lymphocyte predominance with normal glucose levels. The bacteriological characteristics of purulent meningitis are summarized in Table 2. Streptococcus pneumoniae is the most common cause of bacterial meningitis, followed by Neisseria meningitidis. Listeria monocytogenes is a relatively uncommon cause of infection, though it occurs more frequently in persons with cirrhosis and cellular immune defects such as organ transplantation and those receiving high-dose prolonged corticosteroids. Aerobic gram-negative rods (GNRs) such as Escherichia coli, Klebsiella spp., and Enterobacter spp. are also uncommon causes but can be seen in the elderly and those who have undergone neurosurgical procedures. 2.3

Neisseria meningitidis

At any given time, the prevalence of nasopharyngeal colonization with N. meningitidis can range from 3.6% to 14.2% in normal healthy adults. Over an extended period of observation, up to 18% of people in a nonepidemic setting can become colonized. Epidemiological studies suggest that dissemination can occur in patients who acquire N. meningitidis from a colonized person. Why bacteremia or meningitis develops in some patients and others simply become colonized is unclear. There is a subgroup of patients with deficiencies in the late components of complement who appear to be particularly susceptible to disseminated disease. In other patients immunoglobulin A (IgA) antibodies appear to block an effective immune response and actually place patients at increased risk of disease. Intercurrent viral infections have also been implicated in the pathogenesis of meningococcal disease. There are at least eight different serogroups of N. meningitidis, which are based on differences in the polysaccharide capsule. Most sporadic cases are caused by group B, for which there is no effective vaccine. On the other hand, epidemics are often caused by

Table 2 Bacteriological Characteristics of Meningitis Pathogen Streptococcus pneumoniae Neisseria meningiditis Haemophilus influenzae type b (HIB) Aerobic gram-negative rod

Listeria monocytogenes Staphylococcus aureus Coagulase-negative staphylococcus Diphtheroids

Comment Most common Skull fractures Outbreaks in community settings such as colleges and military barracks Less common with use of HIB vaccine Rare Elderly Neurosurgical procedures Cell-mediated immune defect Alcoholic cirrhosis Previous neurosurgical procedures CSF shunt infections CSF shunt infections CSF shunt infections

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group A, C, or Y, for which a polyvalent vaccine is available. The institution of this vaccine for all college-bound students has now been recommended to decrease the number of epidemics on university campuses. Meningococcal meningitis is typically a disease of school age children and young adults. Patients sometimes have a history of an upper respiratory infection for several days followed by the abrupt onset of high fever, myalgias, headache, and nausea and vomiting. The clinical feature that distinguishes meningococcal meningitis is a rash that is present in at least half the cases. Early in the disease, a petechial rash appears. Ischemic necrosis of the purpuric area often occurs. In about one-third of patients meningitis without septicemia is seen and the typical rash is absent. Although pericarditis and aseptic synovitis can be seen in patients with meningococcal meningitis, these complications are generally not present on initial presentation but may occur during therapy. Meningococcal meningitis is the most rapidly fatal form of meningitis. Death may ensue only hours after the patient’s initial symptoms. Eradication of meningococcus from the blood and CSF is quite rapid: only 5 to 7 days of antibiotic therapy is usually required. Patients who succumb during the first 24 hours of therapy usually die of complications of their initial shock and disseminated intravascular coagulation. During the first 24 hours, patients should be placed in respiratory isolation to prevent the possibility of secondary cases. Thereafter there appears to be little risk of secondary spread although patients may remain colonized with meningococci. Remarkably, even patients who experience lethargy, coma, or seizures and survive meningococcal meningitis generally have no permanent neurological sequelae. 2.3.1

Prophylaxis of Meningococcal Disease

Individuals who have newly acquired N. meningitidis colonization are at risk for dissemination. Close contacts of patients with meningococcal disease have a risk of acquisition of 0.4% to 5.9%, depending on whether the disease is a sporadic or an epidemic case. Even the lower secondary attack rate gives close contacts a risk of disease hundreds of times greater than that of the general population. Since almost all secondary cases occur within 2 weeks of contact with the index case and usually within a few days, rapid institution of effective prophylaxis is desirable. Close contacts are defined as household members who eat or sleep in the same room as the patient. Medical personnel are considered at risk only if they resuscitated, intubated, or suctioned the patient prior to antibiotic therapy. Thus in most instances, medical personnel do not require postexposure prophylaxis against meningococcal disease. Although grade school or high school students are not at risk for secondary spread outside an epidemic setting, day care center contacts are at high risk and should receive prophylaxis. Historically, the drug of choice for prophylaxis has been rifampin given orally twice a day for 2 days. Adults should receive 600 mg/day and children 1–12 years old should receive 10 mg/kg/day. An alternative drug is minocycline at 100 mg, also administered twice a day for 2 days. Recent studies, however, have found that a single dose of ciprofloxacin 500 mg is easier to administer and is effective. 2.4

Streptococcus pneumoniae

With the remarkable fall in the numbers of cases of H. influenzae meningitis, S. pneumoniae is becoming the most common pathogen isolated in patients with meningitis. Patients with deficits in humerol immunity (multiple myeloma, acquired hypogammaglobulinemia, sickle cell disease patients and postsplenectomy patients) are particularly

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susceptible to severe pneumococcal disease including meningitis. In addition, S. pneumoniae is the leading cause of early posttraumatic meningitis in patients with skull fractures accompanied by cerebrospinal fluid leak and rhinorrhea. The clinician examining a patient with pneumococcal meningitis often finds evidence of a primary focus outside the central nervous system. Concomitant otitis media is present in up to 34% of patients. Evidence of pneumococcal pneumonia has been observed in 12%–25% of cases. In the preantibiotic era the combination of pneumonia, endocarditis, and meningitis was not uncommon, especially in alcoholic patients. Pneumococcal meningitis patients may appear severely ill, and mental status changes are common. Even with appropriate antibiotic therapy, the mortality rate in elderly patients is often above 50%. 2.5

Haemophilus influenzae

Haemophilus influenzae used to be the leading cause of meningitis in children from 2 months to 10 years of age. The institution of universal H. influenzae type b (HIB) vaccine has resulted in an extraordinary 94% fall in the incidence of this form of meningitis in children. H. influenzae meningitis is rarely seen in adults. The clinical presentation of H. influenzae meningitis is more insidious and less fulminant than that of either meningococcal or pneumococcal disease. A child may have a history of a nonspecific febrile illness or upper respiratory infection for days before the development of meningitis. Between 25% and 30% of patients have a prior history of otitis media but other primary foci of disease are uncommon. Adults with H. influenzae meningitis generally have a history of chronic sinusitis or head trauma. Over the past 20 years, the introduction of new broad-spectrum cephalosporins that cross the blood–brain barrier as well as the routine use of corticosteroids have improved survival and diminished neurological sequelae rates in children with this disease. 2.6

Therapy

Antibiotic therapy of bacterial meningitis should be guided by the results of CSF Gram stain (see Table 3). If the results are equivocal or no bacteria are seen on Gram stain, empirical therapy with high-dose ceftriaxone should be begun. The addition of vancomycin may be necessary because of the rapid rise of pneumococci that are either intermediately sensitive (MIC 0.1–1.0 ␮g/cm3) or resistant (MIC ⱖ 2.0 ␮g/cm3) to penicillin. For either meningococci or H. influenzae, ceftriaxone can be used. In patients with impaired cell mediated immunity when L. monocytogenes is suspected or if gram-positive rods are seen on CSF Gram stain, ampicillin must be added as cephalosporins do not provide adequate coverage of L. monocytogenes. Once sensitivities are known, antibiotics can be narrowed appropriately. If, for example, penicillin-sensitive (MIC < 0.1 ␮g/cm3) S. pneumoniae is grown from the CSF, the antibiotics can be changed to high-dose penicillin G at 4 million U every 4 hours. There is increasing evidence that early initiation of corticosteroid therapy improves neurological outcome and overall mortality rate. Most of this evidence is from studies of children with H. influenzae meningitis. However, it is clear to this author that corticosteroid administration before the initial antibiotic dose is associated with significant beneficial effects in patients with pneumococcal or meningococcal meningitis as well as those with H. influenzae. I recommend the use of dexamethasone at 0.4 mg/kg given twice a day for 2 days, with the first dose administered just prior to initiation of antibiotic therapy. Other authors have recommended steroid use only for those patients with evidence of increased CSF pressure such as with high opening pressure on LP, coma, altered mental status, or

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Table 3 Antibiotic Therapy for Bacterial Meningitisa Clinical presentation and Gram stain result

Antibiotic

Doseb

Gram stain result positive GPCc in pairs

Ceftriaxone and vancomycin

2 g q12h 15 mg/kg q12h 2 g q12h 4 million U q4h 2 g q12h 2 g q8h 2 g q4h

GNCd in pairs

Ceftriaxone or penicillin G

GNR

Ceftriaxone or ceftazidime

GPRe

Ampicillin

Gram stain result not available or negative Age < 50 yearsf Age > 50 yearsf

Ceftriaxone Ceftriaxone and ampicillin

Cell-mediated immune defect

Ceftazidime and ampicillin and vancomycin

CSF shunt Neurosurgery Basilar skull fracturef

Ceftazidime and vancomycin Ceftriaxone

2 g q12h 2 g q12h 2 g q4h 2 g q8h 2 g q4h 15 mg/kg q12h 2 g q8h 15 mg/kg q12h 2 g q12h

a

GNR, gram-negative rod, CSF, cerebrospinal fluid. Assuming normal renal function. c Gram-positive cocci, presumed S. pneumoniae. d Gram-negative cocci, presumed N. meningitidis. e Gram-positive rod, presumed L. monocytogenes. f Consider adding vancomycin if penicillin is intermediately resistant or resistant S. pneumoniae is present in the community. b

evidence of cerebral edema on CT or MRI imaging. It must be emphasized that clinical trials have not proved this point and the use of steroids in the treatment of adult patients remains controversial. Theoretical concerns about use of corticosteriods are tightening of the blood–brain barrier caused by the steroids and reduced penetration of vancomycin into the CSF. They could prove detrimental to patients with penicillin- and cephalosporinresistant pneumococcal meningitis. 3

HERPES SIMPLEX TYPE 1 ENCEPHALITIS

Herpes simplex virus type 1 (HSV-1) encephalitis is the most common sporadic type in the United States. It is also the only viral encephalitis amenable to treatment. It carries a high mortality rate, and for those who survive, a significant morbidity rate. Therefore, early recognition and treatment are essential. HSV is a double-strained DNA virus of the Herpesviridae family. These viruses, including varicella zoster virus and Epstein-Barr virus, have in common the ability to cause chronic lifelong infections and to reactivate. HSV-1 commonly reactivates in the form of orolabial blisters. On rare occasions, reactivation may take place along the trigeminal or autonomic nerve roots with extension into the brain parenchyma. This involve-

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HSV-1 ENCEPHALITIS Most common sporadic viral encephalitis Treatable but associated with high mortality and mobidity rates Clinical presentation Fever, headache Confusion, altered personality, seizures Stiff neck present or not present Diagnosis MRI scan most sensitive and specific imaging modality LP with lymphotic pleocytosis (see Table 1) CSF PCR for HSV-1 DNA Therapy Acyclovir 10 mg/kg q8h for 21 days

ment classically occurs in the frontal, temporal, or parietal lobes. Occasionally in adults, HSV-1 encephalitis can be due to newly acquired infection and not reactivation. 3.1

Clinical Presentation and Diagnosis

In contrast to bacterial meningitis that involves infection of the membranes surrounding the brain, HSV-1 encephalitis is a direct infection of the brain tissue parenchyma. Patients therefore have symptoms of altered brain function more often than headache or meningismus. The onset may be acute over several days to subacute over a week or more. In addition to fever and headache, the patient experiences confusion, altered personality, focal neurological deficits, and/or seizures. Confusion may progress to coma. The patient may not have a stiff neck. The presence or absence of concomitant orolabial HSV infection does not help establish the diagnosis. If the patient has had a seizure or has focal neurological signs, a CT scan should be performed to rule out a mass lesion prior to LP. It must be emphasized that the CT scan is an insensitive tool for demonstrating CNS abnormalities due to HSV-1 infection. A negative CT scan finding should not be interpreted as ruling out the diagnosis. Characteristically the LP shows a high opening pressure, a lymphocytic pleocytosis, and a normal glucose level but an elevated protein level. The Gram stain and bacterial culture results are negative. CSF results seen in HSV-1 encephalitis appear similar to those seen in viral meningitis and other viral encephalitides. However, an elevated red blood cell count in the CSF should suggest a diagnosis of HSV-1 encephalitis. The yield of growing HSV-1 from the CSF is very low. The determination of herpes simplex DNA in spinal fluid by PCR is sensitive and very specific. In contrast to the CT scan, the MRI scan is very sensitive for delineating changes due to HSV-1 encephalitis. Electroencephalograms may reveal a characteristic spike and dome pattern of HSV-1. 3.2

Therapy

The only available and tested therapy is high-dose intravenous acyclovir. Standard dose is 10 mg/kg every 8 hours if renal function is normal. The duration of therapy is 21 days.

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NECROTIZING SOFT TISSUE INFECTIONS Bacterial infection as a consequence of tissue hypoxia, trauma, or bacteremia involving the subcutaneous fat, fascia, muscle, and possibly skin Increased risk in patients with diabetes, hepatic cirrhosis, and immunocomprimise Approach to the recognition, diagnosis, and therapy (see Figure 1) Need for rapid recognition and surgical de´bridement Clinical presentation Fever, localized pain (may not be proportionate to clinical exam results) Crepitus, bullae, anesthetic skin, areas of skin necrosis Syndromes and bacteriology (see Table 4) Diagnosis Clinical examination CT/MRI scan Surgical exploration Therapy Urgent de´bridement Antibiotic therapy (see Table 4)

Even with early acyclovir therapy, HSV-1 encephalitis has a mortality rate of more than 50%. In those surviving, the majority have permanent neurological sequelae. 4

NECROTIZING SOFT TISSUE INFECTIONS

Recognition and treatment of necrotizing or gangrenous soft tissue infection are true medical emergencies. These infections stem from a variety of different pathogens and often have different clinical manifestations. The nomenclature and taxonomy of necrotizing soft tissue infections are confusing. Bacteria such as Clostridium perfringens or Streptococcus pyogenes can cause necrotizing infections of the skin, subcutaneous tissue, and muscle. Often more than one tissue compartment (skin, subcutaneous tissue, fascia, or muscle) is involved simultaneously. Different bacteria can cause clinical syndromes that appear identical. Often these infections are polymicrobic. Types of soft-tissue necrotizing infections have historically been called clostridium cellulitis, nonclostridium crepitant cellulitis, necrotizing fasciitis, clostridial myonecrosis, anaerobic streptococcal myonecrosis, and synergistic nonclostridial anaerobic myonecrosis. More important than assigning a specific name to an infection are prompt recognition and urgent surgical exploration and de´bridement of involved tissue. 4.1

Pathophysiological Characteristics

Any condition that can cause tissue trauma or hypoxia can lead to the development of a necrotizing subcutaneous infection. Therefore, necrotizing soft tissue infections often originate in areas of trauma and crush injury, burns, and gastrointestinal malignancy. Rare cases of clostridial myositis (gas gangrene) have been reported after intramuscular injections. It should also be emphasized that, on occasion, severe clostridial infections may appear spontaneously. These cases seem to be associated with clinically silent malignancies, especially those in the large bowel. Patients with diabetes mellitus are predisposed to necrotizing soft tissue infections. This predisposition is most likely related to accelerated atherosclerosis and vascular insufficiency and diminished WBC function.

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Gas in infected tissue is produced by bacteria in an anaerobic environment as the end product of fermentation. Gases are primarily hydrogen and nitrogen. GNRs such as Escherichia coli and Klebsiella spp. and gram-positive cocci such as Staphylococcus aureus and S. pyogenes are facultative bacteria and may utilize anaerobic (and thus produce gas) or aerobic metabolism. The subcutaneous gas produced can increase tissue pressure and lead to hypoxic damage to the tissue. Tissue necrosis can also be caused by vascular thrombosis or bacterial toxin production. Thrombosis of vessels is common in anaerobic infections because of the production of heparinase. In the case of Clostridium perfringens, another toxin, called lecithinase, is produced by the organism and may be responsible for some of the extensive necrosis. Clostridium spp. also produce exotoxin, which destroys PMN. This explains the typical Gram stain finding of clostridial myonecrosis, which reveals many gram-positive rods but only few PMNs. 4.2

Clinical Syndromes

The approach to the patient with suspected necrotizing soft tissue infection is summarized in Figure 1. The presence of palpable crepitus or radiological evidence of gas in the soft tissue, the formation of blisters or bullae in an area of cellulitis, areas of anesthesia in the midst of cellulitis, and extreme pain disproportionate to the physical examination findings are hallmarks of necrotizing infections. When any of these signs is present, urgent surgical exploration is indicated to confirm the clinical suspicion, evaluate the extent and depth of tissue involvement, and begin surgical de´bridement. If there is doubt about the diagnosis prior to surgical exploration, imaging of the involved area with CT or MRI scan may help demonstrate gas in the soft tissue and delineate the extent of tissue necrosis. 4.2.1 Clostridial Cellulitis Clostridium spp. are gram-positive obligate anaerobes that normally inhabit the human gastrointestinal and genital tracts. Clostridial cellulitis is a necrotizing infection of devitalized subcutaneous tissue without involvement of the fascia or muscle. Gas formation is common and extensive; in fact, more gas is seen in this infection than in clostridial myositis. Infection is generally due to C. perfringens that has been introduced into inadequately de´brided traumatic wounds. Clostridial cellulitis can also arise from infections in the perineum, abdominal wall, or lower extremities contaminated with fecal flora. The incubation period is usually several days. There is little local pain or systemic toxicity. Surgical exploration is necessary to determine the extent of tissue involvement. The large amount of gas present, the lack of extreme pain, and the minimal systemic toxicity make clostridium cellulitis more likely than clostridium myositis. Occasionally S. aureus or anaerobic streptococci can also cause crepitant cellulitis, especially in the diabetic patient. 4.2.2

Necrotizing Fasciitis

Necrotizing fasciitis is an acute infection characterized by rapid progression and prominent systemic toxicity. Minor trauma or prior surgery is the usual predisposing factor. There is an increased risk in diabetes mellitus, alcoholism, and cirrhosis patients. When necrotizing fasciitis is caused by S. pyogenes, the syndrome is referred to as streptococcal gangrene or type II necrotizing fasciitis. Crepitus is rarely present. Anesthesia of the skin is common because of thrombosis of small blood vessels and destruction of the superficial nerves in the necrotic subcutaneous tissue. The skin appearance gradually changes from erythema to the formation of large cutaneous bullae. Aspiration of these bullae usually yields strep-

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Figure 1 Approach to the patient with suspected necrotizing skin or subcutaneous infection. High suspicion is required to diagnose and treat necrotizing soft tissue infections rapidly. Risk factors should be determined, and clinical examination should seek hallmarks of a necrotizing infection. CT or MRI imaging may be helpful. Differentiating types of subcutaneous necrotizing infections (horizontal arrows) can be difficult. All patients need urgent surgical exploration and de´bridement. If the microbiological characteristics are not clear, broad-spectrum antibiotics should be instituted until culture results are available.

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tococci by Gram stain and S. pyogenes by culture. Later, patchy skin necrosis resembling that of a full-thickness burn develops. Laboratory evaluation reveals leukocytosis, thrombocytopenia, and renal insufficiency. Blood cultures in streptococcal gangrene often have positive results and metastatic infections may be seen. Type I necrotizing fasciitis is caused by a mixture of non–group A streptococcus, aerobic GNRs such as E. coli, Klebsiella spp. and occasionally Pseudomonas aeruginosa; and anaerobic bacilli such as Bacteroides spp. Aside from the difference in Gram stain morphological features, this mixed infection emits a foul smell at surgery, whereas a group A streptococcal infection has little odor. Mixed necrotizing fasciitis of the male genitalia is referred to as Fournier’s gangrene. Despite antibiotic therapy and surgical removal of necrotic soft tissue and fascia, the mortality rate in necrotizing fasciitis remains 30% to 35%. 4.2.3

Clostridium Myonecrosis

Classical gas gangrene secondary to C. perfringens generally originates in contaminated wounds. The incubation period may range from a few hours to several days. Severe pain at the initial site of injury is the earliest symptom. Gas in the tissue, on the other hand, is often a later sign of infection. The lack of tissue gas does not exclude clostridial gangrene. The patient’s condition appears toxic with tachycardia, fever (generally low-grade), and leukocytosis. Disseminated intravascular coagulopathy as well as renal insufficiency can be seen. Creatinine phosphokinase (CPK) level may be elevated. Symptoms of advanced clostridial myonecrosis are diffuse bronzing of the skin, formation of bullae containing hemorrhagic fluid, cutaneous gangrene, and finally crepitus. C. septicum can also cause myonecrosis, although this infection is classically seen in neutropenic patients. Muscle involvement usually begins spontaneously without antecedent trauma. As with C. perfringens infection, the onset is acute and progression rapid. Mortality rate approaches 67%–100%. 4.2.4

Nonclostridial Myonecrosis

Myonecrosis can be caused by bacteria other than Clostridium spp. Anaerobic streptococci such as Peptostreptococcus are most commonly implicated. There is more extensive cutaneous erythema in anaerobic streptococcal myositis than there is in clostridial disease. Early on, pain is less prominent than in clostridial gangrene. Gram stain is also helpful in differentiating the two syndromes as PMNs are present in the tissue fluid of anaerobic streptococcal gangrene. S. pyogenes can also cause acute myositis. It may occur spontaneously or after trauma. The onset is acute and progression rapid. The patient is toxic and the pain can be intense. The muscle is swollen and tense, and a compartment syndrome may develop. Eventually the skin may become involved with bullae formation and cutaneous necrosis. Synergistic nonclostridial anaerobic myonecrosis is another life-threatening soft-tissue infection involving muscle as well as fascia and soft tissue. Obese diabetic patients are at particularly high risk for this infection. Infection generally begins on the leg or the perineum especially if a perirectal abscess is present. The patient appears toxic and is in severe pain. The skin shows patchy necrosis, and ulcers draining foul-smelling pus are common. Gas is present in the tissue in approximately one-quarter of cases. A combination of anaerobic bacteria such as Bacteroides spp. or Peptostreptococcus spp. and aerobic GNRs are usually isolated. Thus, this syndrome may be considered an extension of a type I necrotizing fasciitis caused by similar pathogens.

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29

Initial Management

Extensive surgical de´bridement is the key to success. Antibiotics are also important but are not effective without concomitant surgical intervention. Because of the variety of bacteria involved in these infections, a Gram stain may be useful to guide the initial antibiotic therapy. Gram-positive cocci in pairs would suggest S. pyogenes; large grampositive bacilli are indicative of Clostridium spp; GNRs alone or a mixture of GNRs and gram-positive cocci would suggest a synergistic infection. If infection due to S. pyogenes is suspected, high-dose penicillin G (4 million U q4h) and clindamycin (900 mg intravenously [IV] q8h) should be started. If a mixed infection is suspected or Gram stain results are not available, a broad spectrum of antibiotics should be initiated to cover aerobic and anaerobic GNRs, streptococci, and staphylococci (see Table 4). The antibiotic regimen can be narrowed on the basis of culture results. Patients generally require repeated surgical exploration and de´bridement over the initial 48 hours of therapy. The use of hyperbaric oxygen has been advocated in the treatment of clostridial myositis as a means of limiting the amount of tissue excision required. There are a number of case reports documenting clinical improvement of patients treated with hyperbaric oxygen. However, no controlled studies have been performed, and the consensus of opinion is that immediate surgical de´bridement coupled with antibiotic therapy is still the initial treatment of choice. Hyperbaric oxygen may be useful as an adjuvant therapy after extensive surgery has been performed. 5

ARTHROPOD-BORNE DISEASES

Arthropod borne diseases (also see Chapter 30) often appear with nonspecific symptoms and may be difficult to differentiate from viral influenza or a typical bacterial infection. Failure to recognize and diagnose these diseases can lead to a severe or even fatal outcome. 5.1

Rocky Mountain Spotted Fever

Rocky Mountain spotted fever (RMSF) is a tick-borne disease caused by Rickettsia rickettsii. The two most important ticks transmitting this disease are Dermacentor andersoni, the wood tick, which is the principal vector in the western United States, and Dermacentor variabilis, the dog tick, the common vector in the eastern United States. In the South, the Lone Star Tick, Amblyomma americanum, is also implicated. Despite the name, 82% of recently reported cases occurred in the southern Atlantic coast and south central regions of the United States and less than 2% in the mountain states. Since untreated the disease has a case fatality rate of 25%, it is exceedingly important that this diagnosis not be overlooked. As might be expected in a tick-borne disease, most cases occur during the summer months, when tick activity is at its peak. People who are frequently outdoors and have high tick exposure are at highest risk for disease. After the bite of the infected tick the rickettsiae multiply in the vascular endothelium. Damage to the vessels appears to account for the most prominent clinical manifestations such as rash, headache, mental confusion, myocarditis, and renal disease. 5.1.1

Clinical Manifestations

Although many patients may recall a history of tick bites, a substantial minority does not. The disease should be considered for all patients with possible tick exposure. The onset

Mix of GNR, GPC

Necrotizing fasciitis Type I

GPR GPC GNR

C. perfringens Peptostreptococci, E. coli, Klebsiella spp., Pseudomonas spp., Bacteroides spp., streptococci

S. pyogenes

E. coli, Klebsiella spp., Pseudomonas spp., Bacteroides spp., streptococci

C. perfringens

Bacteriological characteristics

b

GPR, gram-positive rod; GNR, gram-negative rod; GPC, gram-positive coccus. Assuming normal renal function. c Or ciprofloxacin 400 mg q8h.

a

Myonecrosis Clostridial Nonclostridial, synergistic

GPC in chains

GPR

Clostridial cellulitis

Type II

Gram stain resulta

Clinical syndrome

Table 4 Necrotizing Soft Tissue Infections

Penicillin G Ceftazidimec Vancomycin Metronidazole

Ceftazidime Vancomycin Metronidazole Penicillin G and clindamycin

Penicillin G

Antibiotic(s)

4 million U q4h 2 g q8h 15 mg/kg q12h 500 mg q8h

2 g q8h 15 mg/kg q12h 500 mg q8h 4 million U q4h 900 mg q8h

4 million U q4h

Doseb

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ARTHROPOD-BORNE INFECTIONS Rocky Mountain Spotted fever Mostly in south Atlantic and south central US Onset 2–7 days after tick bite Abrupt onset of headache, fever Rash after fever begins Periphery → central Possible palm and sole involvement Maculopapular, progressing to petechial/hemorrhagic Diagnosis Leukopenia, thrombocytopenia IFA of skin biopsy PCR of rickettsial DNA in blood Fourfold rise in IgG Therapy: doxycycline 100 mg bid Ehrlichiosis Transmitted by Ixodes scapularis, as are Lyme disease and babesiosis Onset ⬃7 days after tick bite Headache, fever, myalgia Rash in 10% (sparing of palms and soles) Diagnosis Morulae in WBC (see Chapter 30, Figure 6) Leukopenia, thrombocytopenia Fourfold rise in IgG Therapy: doxycycline 100 mg bid

of the disease is generally about 2 to 7 days after the bite of an infected tick. Although the onset may be gradual, in most patients it is abrupt, with fever up to 39⬚C–41⬚C. Most importantly patients complain of severe headache, which is often the chief complaint. The headache is excruciating and intense in the frontal area and is generally unresponsive to acetaminophen or nonsteroidal anti-inflammatory agents. There may be accompanying myalgias, and nausea and vomiting. The characteristic rash usually appears several days after the fever has begun. The lesions are generally pink and appear at first in the periphery on the wrists and ankles. The rash then spreads to the trunk. Importantly the rash is present on the palms and soles, quite a rare location for any other diseases of infectious cause outside secondary syphilis. The rash becomes maculopapular and then may become petechial or hemorrhagic. Only half of patients have the rash within the first 3 days of therapy. A not uncommon clinical scenario is that these undiagnosed patients are placed on an antibiotic empirically and when the rash appears it is ascribed to an allergic reaction. Most allergic reactions except true erythema multiforme do not affect the palms and soles. Also to be emphasized is that multiple studies of RMSF suggest that the characteristic rash may never appear in a substantial minority of patients, who thus have ‘‘spotless’’ fever. The mortality rate in this group is often higher as a result of delayed diagnosis. If it is untreated, organ failure is common and often associated with hypotension, circulatory failure, adult respiratory distress syndrome, and arrhythmia. Severe neurological disease including meningoencephalitis and coma may ensue. Fortunately, in recovered patients permanent neurological damage is uncommon.

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5.1.2

Diagnosis and Treatment

There is no existing rapid diagnostic test for RMSF. Currently the Centers for Disease Control and Prevention use an indirect immunofluorescence assay (IFA) to detect IgG antibodies to R. rickettsii. A confirmed case of RMSF generally shows a fourfold or greater rise in the IFA titers in two serum specimens. Acute laboratory data are not very helpful, although leukopenia and thrombocytopenia are present in most cases. The usual treatment of RMSF is doxycycline 100 mg twice a day orally or intravenously for 7 days. Parenteral chloramphenicol therapy is also quite effective. Even with antibiotic therapy the mortality rate of this disease remains around 5%–7%; generally it is related to diagnostic delays. 5.2

Ehrlichiosis

Human monocytotrophic ehrlichiosis caused by Ehrlichia chaffeensis and human granulocytic ehrlichiosis caused by E. phagocytophilia represent another class of tick-borne zoonoses that can have a clinically similar presentation to that of Rocky Mountain spotted fever. The peak incidence is in the summertime. Cases have been reported in over 30 states, particularly in the northeastern, south central, and southeastern United States. In the Northeast, the tick vectors are Ixodes scapularis (deer tick), which also spreads Borrelia burgdorferi, the agent of Lyme disease, and Babesia microti. Human monocytotrophic ehrlichiosis in the South is most likely spread by the Lone Star tick, Amblyomma americanum. After entry into the bloodstream via tick bite, the Ehrlichiae invade either monocytes or PMNs, depending on the species. 5.2.1

Clinical Manifestations

After an incubation period of about 1 week there is an acute onset of headache, fever, myalgias, and malaise. A maculopapular rash is present in about a third of patients with human monocytotrophic ehrlichiosis but only about 10% of patients with human granulocytic ehrlichiosis. The rash characteristically does not involve the palms and soles and therefore helps differentiate the disease from RMSF. Nausea, vomiting, and diarrhea are common. Severe manifestations include rhabdomyolysis, renal failure, hemolysis, and thrombocytopenia. The disease has been mistaken for thrombotic thrombocytopenic purpura. About 40% of patients with human monocytic ehrlichiosis require hospitalization. Numerous deaths have been reported for both types of ehrlichiosis. Laboratory features common to both types of ehrlichiosis include leukopenia, thrombocytopenia, anemia, and elevated hepatic transaminase level. 5.2.2.

Diagnosis and Treatment

Human granulocytic ehrlichiosis can often be diagnosed by the finding of morulae in the peripheral blood smear (see Figure 6, Chapter 30). Diagnosis is generally made by an IFA finding that demonstrates a fourfold or greater rise in antibody titers. Doxycycline 100 mg twice daily has been quite effective in rapidly relieving the symptoms of this disease and preventing severe morbidity and mortality. Chloramphenicol has not been shown to be effective in this disease and should generally not be used. The quinolones have excellent activity against Ehrlichia spp., but there are limited clinical data to support their use. Since Lyme disease, ehrlichiosis, and RMSF all respond to doxycycline therapy, this antibiotic should be strongly considered when a patient has a febrile illness after a tick bite.

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FALCIPARUM MALARIA Importance of taking a travel history in febrile patients Transmitted by Anopheles mosquito in Asia, Central Africa, South America Can have high parasite loads with rapid progression of hemolytic anemia, renal failure, circulatory collapse, and coma Presentation Fever, headache Altered consciousness Anemia and thrombocytopenia Leukopenia or leukocytosis Diagnosis: thick/thin Giemsa stained blood smear Therapy Hospitalization Quinine sulfate and doxycycline (see Chapter 39, Table 11)

6

MALARIA

Malaria (also see chapter 39) is caused by one of four protozoan species of the genus Plasmodia: P. falciparum, P. vivax, P. ovale, and P. malariae. The disease is transmitted by infection of the sporozoite form through the bite of the female Anopheles sp. mosquito. Whereas all species of malaria can cause significant disease, only P. falciparum is typically life-threatening. 6.1

Pathophysiological Characteristics

After transmission to blood by a mosquito bite, the sporozoite invades the liver parenchymal cells. After 2 weeks merozoites are released into the bloodstream, where they invade erythrocytes and develop into a trophozoite. The trophozoite then can produce more merozoites, thus continuing the cycle of erythrocyte parasitism, or produce gametocytes. The male and female gametocytes are then taken up by mosquitoes on a subsequent bite and continue the cycle of infection to other humans. The symptoms of malaria are related to the changes in the red blood cell rheological features caused by parasitic infections. The parasitized erythrocytes become lodged in the microvasculature, causing tissue ischemia and hypoxic damage. The lysis of infected red cells with the release of merozoites is often associated with a paroxysm of chills, fever, myalgias, headache, nausea, and vomiting. Parasitized red cells are also filtered and destroyed in the spleen, resulting in hemolytic anemia. Since P. falciparum can invade red cells at any point in their development, very high levels of parasitemia can be seen. Blockage of cerebral arteries secondary to parasitized red cells causes cerebral malaria with alteration of consciousness or coma. 6.2

Clinical Presentation

Symptoms begin with shaking chills and temperatures up to 40⬚C. Headache, myalgias, abdominal pain, vomiting, and diarrhea are all common. In severe falciparum malaria, altered consciousness can be followed by coma. The paroxysm usually ends with severe diaphoresis and resolution of fever until the next paroxysm begins. Renal failure can occur

34

Levitz

with P. falciparum as a result of hemolysis and hemoglobinuria. Such patients have jaundice and dark urine (blackwater fever). Surprisingly, sometimes the chief complaint of malaria patients is that they have the disease. This generally occurs in immigrants from countries where malaria is indigenous and common and they are able to recognize their symptoms. The malaria paroxysm of fevers is related to the lysis of red cells with release of the new infectious merozoites. This event occurs continuously or irregularly with P. falciparum, as opposed to the every48-hour, or tertian pattern, with P. vivax. Patients who are at risk for falciparum malaria are those who have traveled to endemic areas such as Asia, Central Africa, or South America. In the author’s experience, failure to ascertain a travel history is the leading cause of missed diagnosis and the resultant increased morbidity and mortality rates for malaria. 6.3

Diagnosis

The diagnosis is made from review of a thin or thick Giemsa stained blood smear. Typically all sizes of red blood cells are infected. Often 5% or more of the circulating erythrocytes are infected. Multiple ring forms can be seen in a single red blood cell. Multiple smears may be needed before the diagnosis is confirmed. Patients may be anemic and thrombocytopenic with either leukocytosis or leukopenia. Since the level of parasitemia and hemolysis can be extensive, the patient may rapidly become severely anemic and hemodynamically unstable. 6.4

Treatment

P. falciparum is assumed to be resistant to chloroquine. The most common recommended treatment is quinine sulfate plus doxycycline administered for 1 week (see Chapter 39, Table 11). If the patient has severe nausea and vomiting or cannot take oral medications, treatment is begun with intravenous quinadine in a setting with cardiac monitoring. Highdose mefloquine and halofantrine are second-line agents. Unfortunately high doses of mefloquine are associated with severe neurological and gastrointestinal side effects. Halofantrine can prolong the q-t interval and thus must be administered in a setting with cardiac monitoring. In severely ill patients when parasitemia is greater than 15%, exchange transfusion may be considered to decrease the parasite burden rapidly. Corticosteroids have not been shown to be helpful in severe malaria, including cerebral malaria. 7

NEUTROPENIC FEVER

Recognition and rapid institution of antibiotic therapy have reduced the mortality rate of neutropenic fever from >50% to <10%. Neutropenia may develop within 7–10 days after administration of many chemotherapeutic agents. It has been shown that an absolute neutrophil count (ANC) < 500 cells/mm3 correlates with a great increase in the number of both infections and infection-related deaths. When the ANC falls to below 100/mm3, there is even more substantial increase in serious infection and mortality rates. 7.1

Presentation and Assessment

Patients experience fever, chills, and generalized weakness. Localizing symptoms are uncommon (see Table 5). A thorough physical examination needs to be performed with special attention to indwelling intravenous catheters and the gastrointestinal tract, especially the oral cavity,

Infectious Disease Emergencies

35

NEUTROPENIC FEVER Increased risk when ANC < 500 cells/mm3 Presentation (see Table 5) Special attention to oropharynx, central catheters, skin, perirectal area, abdomen Two sets of blood cultures and urine culture prior to antibiotics Therapy (see Table 6) Antipseudomonas ␤-lactum plus aminoglycoside Monotherapy with ceftazidime, imipenem Vancomycin added for cellulitis or catheter infection Outpatient management Potential candidates: patients with nonhematological malignancies, expected short duration of neutropenia, and no comorbidities Oral ciprofloxacin plus amoxicillin-clavulanate Parenteral once daily ceftriaxone plus aminoglycoside

Table 5 The Febrile Neutropenic Patient Clinical assessment Clinical presentation ANC < 500 cells/mm3 Fever, chill, sweats Physical examination Central catheters Erythema at exit site, along tunnel or entrance site Inability to flush or draw blood Oral cavity Candida spp. Herpes simplex Mucositis Skin Drug rashes Icthyma gangrenosum Perirectal Tenderness, hemorrhoids, fissure, cellulitis Abdomen a

Comment Increased risk of infection when ANC below 500 cells/mm3; greater risk of bacteremia when ANC < 100 cells/mm3

Raise concern for staphylococcal or streptococcal infection

Oral streptococci and mouth anaerobes

Diffuse pruritic, maculopapular Anesthetic black eschar suggestive of GNR bacteremia Polymicrobic infection with aerobic and anaerobic GNR, enterococci Typhilitis characterized by cecal distention and polymicrobic sepsis

ANC, absolute neutrophil count; GNR, gram-negative rod.

36

Levitz

abdomen, and perirectal region. Typhilitis is a bacterial infection of the large intestine characterized by marked dilatation of the cecum. Patients have fever and right lower quadrant pain. Aside from the complete blood count (CBC), blood and urine cultures should be performed and a chest radiograph obtained. 7.2

Treatment

Because of the high mortality rate associated with neutropenic fever, all patients should receive immediate empirical antibiotic therapy. Empirical combination antibiotic therapy should generally be used to treat aerobic GNRs such as Escherichia coli, Klebsiella spp., and P. aeruginosa (see Table 6). Commonly used combinations include an extended-spectrum cephalosporin such as cefipime or ceftazidime or a ureidopenicillin such as ticarcillin or piperacillin given in combination with an aminoglycoside such as gentamicin, tobramycin, or amikacin. Broad-spectrum carbapenems such as imipenem-cilastatin sodium (Primaxin) or meropenem have also been successfully used. Antibiotics with activity against S. aureus and coagulase-negative Staphylococcus spp. such as vancomycin are generally not indicated unless there is evidence of cellulitis or catheter infection. The use of granulocyte colony-stimulating factor (G-CSF) has been demonstrated to shorten the duration of neutropenia, hospitalization, and antibiotic therapy of patients with high-risk febrile neutropenia. In many institutions, monotherapy for febrile neutropenia has been successfully employed. Ceftazadime, cefopime, meropenem, and imipenem-cilastatin sodium have all been used. These agents should be used as monotherapy only in institutions where the prevalence of GNR resistance is low and resistant gram-positive infections are unlikely. Finally, there is much current interest in risk-based therapy for febrile patients with neutropenia. It has become clear that morbidity and mortality risks differ, depending on the underlying malignancy and the duration of expected neutropenia. In hemodynamically stable patients who have nonhematological malignancies and no concurrent morbidity, the risk of fatal infection during febrile neutropenia is actually quite low. Multiple studies have demonstrated the safety of treating these patients in the outpatient setting with either high-dose oral regimens such as ciprofloxacin plus amoxicillin-clavulanate (Augmentin) or once-a-day IV therapy with ceftriaxone plus an aminoglycoside. 8

SEPTIC SHOCK

Septicemia is generally defined as fever (rarely hypothermia), tachycardia, and tachypnea in association with bacteremia. The sepsis syndrome is septicemia associated with organ malfunction such as oliguria, confusion, or shortness of breath. If hypotension ensues and is refractory to fluid resuscitation (500 cm3 of normal saline solution), a diagnosis of septic SEPTIC SHOCK Differential diagnosis to include pancreatitis, trauma, burns, myocardial infarction, and pulmonary emboli BP < 90 mm Hg or 40 mm Hg fall of BP Fever, tachypnea, orthostasis, confusion Search for primary infection Empirical therapy (see Table 7)

Infectious Disease Emergencies

37

Table 6 Initial Empirical Therapy for the Febrile Neutropenic Host Dosea

Antibiotic Combination therapy Ceftazidime

2 g q8h

or Cefipime

Comment Therapy for suspected bacteremia caused by aerobic GNR including Pseudomonas aeruginosa

2 g q8h

or Piperacillin

4 g q6h

and Gentamicinb or tobramycinb

7 mg/kg/d

or Amikacinb Monotherapy Ceftazidime Imipenem-cilastatin sodium Meropenem

7.5 mg/kg q12h 2 g q8h 500 mg q6h 1 g q8h

Aerobic GNR only Good coverage for aerobic and anaerobic GNR and most gram-positive cocci though not methicillin-resistant staphylococci

Coverage of staphylococci or streptococci Vancomycin

15 mg/kg q12h

Cellulitis, catheter infections

Coverage of anaerobic infections add Metronidazole Clindamycin

500 mg q8h 900 mg q8h

Perirectal or oral infections

Home therapy Ciprofloxacin

750 mg PO bid

Consultation of oncology or infectious disease specialists suggested prior to initiating therapy Patients with solid organ malignancies Short duration of neutropenia expected Limited comorbidities

and Amoxicillinclavulanate

875 mg PO bid

or Ceftriaxone

1 g q24h

and Gentamicin a

7 mg/kg q24h

Assuming normal renal function. Must monitor renal function carefully.

b

38

Levitz

shock can be made. About 1.5 million cases of septicemia occur each year in the United States, where septicemia is the 10th leading cause of death. Sepsis and septic shock can be community- or hospital-acquired. Most commonly the microbiological causes are aerobic GNRs such as E. coli, Klebsiella spp., Enterobacter spp., Proteus spp., and Pseudomonas aeruginosa and gram-positive bacteria such as staphylococci, enterococci, and streptococci. Septic shock can also be caused by mycobacteria, yeast, and, less commonly, parasitic infection. It is important to remember that noninfectious causes can produce a septic shock–like clinical illness, including severe pancreatitis, large pulmonary emboli, burns, severe trauma, and extensive myocardial infarction. 8.1

Pathophysiological Characteristics

Lipopolysaccharide (LPS) present in the cell walls of gram-negative bacteria plays a key role in starting a cascade of endogenous mediators of shock by stimulating the release of interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-␣), and interferon gamma. TNF-␣ is perhaps the most important mediator of septic shock. These cytokines increase capillary permeability with subsequent fluid release into the third space, organ dysfunction, and cardiac depression. Shock can also be caused by gram-positive bacteria as a result of release of teichoic acid, which stimulates the cytokine cascade. 8.2

Clinical Presentation

The hallmark of septic shock is hypotension, defined as systolic blood pressure of <90 mm Hg or a drop in systolic blood pressure of >40 mm Hg. Initially this hypotension may be manifested, as orthostatic blood pressure changes, dizziness, or syncope. In addition, patients often have sweats, pallor, fever, and disorientation. Organ dysfunction may be present with pulmonary edema and oliguria. A diffuse erythroderma may be seen with staphylococcal or streptococcal toxic shock. Ecthyma gangrenosum can be seen with GNRs, especially P. aeruginosa. Bleeding secondary to coagulopathy and thrombocytopenia can also be seen. A focus of infection such as pneumonia, cellulitis, urinary tract infection, intraabdominal abscess, or central venous catheter erythema should be sought. Laboratory evaluation should include a complete blood count with differential, hepatic and renal function tests, and prothrombin and partial thromboplastin times. Other tests that may help in making the diagnosis include D-dimer, fibrinogen levels, and arterial blood gas evaluations. Cultures of blood and urine should be obtained. Chest radiography and other imaging studies should be performed as indicated. Leukocytosis and thrombocytopenia are generally seen. Leukopenia with a large number of band forms may be a harbinger of fulminant septic shock. 8.3

Treatment

Management of patients with septic shock should occur in the intensive care unit. Initial management includes volume resuscitation and antibiotic therapy. Pulmonary artery catheterization and monitoring should be performed as indicated and vasopressor support started if fluid resuscitation does not maintain adequate blood pressure. Initial antibiotic therapy is summarized in Table 7. The initial selection of antibiotic is necessarily broad to cover the most common bacterial pathogens. Antibiotics can be adjusted on the basis of results of blood and other culture results. If the suspected source is urinary, combination therapy with a third-generation cephalosporin or ureidopenicillin and an aminoglycoside would be prudent. A similar regimen

Infectious Disease Emergencies

39

Table 7 Initial Antibiotic Management for Community Acquired Septic Shock Clinical syndrome suspected Urinary tract infection (UTI)

Antibiotic Ceftazidime

Dosea 2 g q8h

or ciprofloxacin

400 mg q8h

Comment If there is concern for enterocccus because of recent hospital admissions or recurrent UTI add vancomycin

and

Pneumonia

gentamicin or tobramycin

7 mg/kg q24h

Ceftriaxone

1 g q12h

and

Neutropenia Skin or catheter Unknown source

azithromycin

500 mg q24h

Ceftazidime

As above

or ciprofloxacin

As above

and gentamicin or tobramycin

As above

and

Intra-abdominal

vancomycin

15 mg/kg q12h

Piperacillintazobactam

3.375 g q6h

or meropenum

1 g q8h

and gentamicin or tobramicin

As above

or ciprofloxacin

As above

and vancomycin

As above

and metronidazole a

Assuming normal renal function.

500 mg q8h

Addition of vancomycin when penicillin-resistant pneumococci in community Coverage for atypical pathogens through macrolide addition Need to differentiate cellulitis from toxin mediated diffuse erythroderma; ecthyma gangrenosum suggestive of GNR If central venous catheter cause of sepsis, strong consideration of removing it, especially if tunnel or entrance involved Surgical consultation needed; drainage of abscess or removal of necrotic tissue essential

40

Levitz

could be employed for sepsis of intra-abdominal origin. In sepsis of pulmonary origin, a third-generation cephalosporin plus vancomycin should be considered to cover resistant gram-positive organisms as well. In patients with a history of significant allergy to penicillin, a parenteral quinolone may be employed. In vitro, Enterobacteriaceae release lower quantities of endotoxin and cytokines when treated with aminoglycosides, quinolones, or imipenen. Aminoglycosides and quinolones are also more rapidly bactericidal than ␤lactam antibiotics. However, no studies have demonstrated that these in vitro properties lead to improved patient outcomes when these antibiotics are employed for therapy of septic shock. Despite the advancements in antimicrobial therapy and hemodynamic support and monitoring, the death rate of septic shock remains unacceptably high. Numerous attempts to block bacterial pathogenesis and cytokine cascade, including use of antisera against the J5 mutant of E. coli, intravenous IgG, human or murine IgM against LPS, recombinant IL-I receptor antagonist, monoclonal antibodies against TNF-␣ and TNF-␣ receptors, platelet activating factor antagonists, bradykinin, and nitric oxide synthetase inhibitors, have failed to improve the mortality rate. In 2001 the use of recombinant human activated protein C (Drotrecogin alfa) showed promise in reducing the mortality rate of patients with severe sepsis. BIBLIOGRAPHY Bodey GP, Rolston KV. Management of fever in neutropenic patients. J Infect Chemother 1:1–9, 2001. Brandt NM, Copron CA, Wahl WL. Necrotizing soft tissue infections: a surgical disease. Am Surg 66(1):967–970, 2000. Drage LA. Life-threatening rashes: Dermatologic signs of four infectious diseases. Mayo Clin Proc 74(1):68–72, 1999. Elliott D, Kufera JA, Myers RA. The microbiology of necrotizing soft tissue infection. Am J Surg 179(5):361–366, 2000. Gordon RB, Vincent JL, Laterrre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Eng J Med 344:699–709, 2001. Kwitkowski VE, Demko SG. Infectious disease emergencies in primary care. Lippincott Prim Care Pract 3(1):108–125, 1999. Levitz RE. Herpes simplex encephalitis: A review. Heart Lung 27(3):209–212, 1998. Looareesuwan S, Chulay JD, Canfield CJ, Hutchinson DB. Malarone (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group. Am J Trop Med Hyg 60(4):533–541, 1999. Newton P, White N. Malaria: New developments in treatment and prevention. Annu Rev Med 50: 170–192, 1999. Roos JI. Acute bacterial meningitis. Semin Neurol 20(3):293–306, 2000.

3 Commonly Used Oral Antibiotics Thomas Lamarre Infectious Diseases Consultants of Cincinnati, Cincinnati, Ohio, U.S.A.

William Maher and Robert Fass† The Ohio State University, Columbus, Ohio, U.S.A.

1

INTRODUCTION

In recent years, there has been an increase in both the number and the spectra of available oral antimicrobial agents. In addition to their use in treating common relatively non-lifethreatening outpatient infections, some oral antibiotics are now indicated for the treatment of more serious infections and in many cases as substitutes for parenteral therapy. Effective oral antimicrobial therapy can reduce drug costs as well as the complications and costs of prolonged intravenous infusion therapy while increasing patient comfort and convenience. The emergence of resistant bacteria has become a major problem, accounting for antibiotic failures of older agents and the need for newer drugs. The overuse of antibiotics has contributed greatly to this growing problem. This chapter focuses on commonly used oral antibiotics, including how they are best selected and utilized in addition to when oral antibiotic therapy may be an appropriate substitute for intravenous therapy. Outpatient parenteral antibiotic therapy is reviewed in Chapter 6. 2 ␤-LACTAMS Since the commercial introduction of penicillin in the late 1940s, ␤-lactams have remained popular despite the emergence of penicillin-resistant organisms and the prolific expansion of available antimicrobials (Table 1). This use has been, in large part, due to their continued and unparalleled efficacy against specific organisms, an adequately broad spectrum of activity, and the general good tolerance and low toxicity encountered with their administration. 2.1

Chemical Properties, Mechanism of Action, and Bacterial Resistance

The antimicrobial action of ␤-lactam antibiotics is dependent on the ␤-lactam nucleus (thiazolidine ring) and the adjacent heterocyclic ring. The structure of the heterocyclic ring can be varied somewhat, giving rise to the various classes of ␤-lactams (penicillins, cephalosporins, carbapenems, and monobactams). The addition of side chains to the ␤-lactam nucleus results in the multiple drugs in each class with differing antimicrobial spectra, resistance patterns, pharmacological characteristics, pharmacokinetics, and adverse reac-

†Deceased.

41

b

a

Beepen-VK, Betapen-VK, Pen-Vee K, V-Cillin K, Veetids, Ledercillin VK, Robicillin VK Bactocill, Prostaphlin Cloxapen, Tegopen Dynapen, Dycill, Pathocil Amoxil, Polymox, Trimox, Wymox Augmentin (fixed dose combination product) Geocillin Cefanex, Keflex, Keflet Keftab Velosef Duricef, Ultracef Ceclor Cefzil Ceftin, Zinnat Lorabid Suprax Vantin Cedax Omnicef

Proprietary name(s)

Cost based on average wholesale cost for a 10-day prescription (2000 Drug Topics Red Book). Cost ranges from lowest to highest dose.

Oxacillin sodium Cloxacillin sodium Dicloxacillin sodium Amoxicillin Amoxicillin ⫹ clavulanate potassium Carbenicillin indanyl sodium Cephalexin Cephalexin hydrochloride Cephradine Cefadroxil Cefaclor Cefprozil Cefuroxime axetil Loracarbef Cefixime Cefpodoxime proxetil Ceftibutin Cefdinir

Penicillin V potassium

Antibiotic

Table 1 Standard Dosages, Proprietary Names, and Costs of Oral ␤-Lactams

0.5 to 1 g every 4 to 6 hr 0.25 to 1 g every 6 hr 0.250 to 0.5 g every 6 hr 0.25 to 0.5 g every 8 hr 0.25 to 0.5 g every 8 hr or 0.875 g every 12 hr 0.382 to 0.764 g every 6 hr 0.25 to 1 g every 6 hr 0.25 to 1 g every 6 hr 0.25 to 1 g every 6 hr 0.5 to 1 g every 12 to 24 hr 0.25 to 0.5 g every 8 hr 0.25 to 0.5 g every 12 to 24 hr 0.125 to 0.5 g every 12 hr 0.2 to 0.4 g every 12 to 24 hr 0.4 g every 24 hr 0.1 to 0.4 g every 12 hr 0.4 g every 12 to 24 hr 0.3 to 0.6 every 12 to 24 hr

0.25 to 0.5 g every 6 hr

Standard dose (for adults)

$7.60–$22.80 $6.00–$40.00 $14.80–$29.60 $6.00–$12.00 $66.00–$106.00 $97.00 $80.00–$160.00 $66.00–$248.00 $118.00–$236.00 $38.00–$84.00 $184.00–$368.00 $70.00–$145.00 $57.00–$115.00 $42.00–$148.00 $39.00–$100.00 $62.00 $52.00–$146.00 $75.00–$150.00 $35.00–$140.00

$2.80–$5.60

Costa,b

42 Lamarre et al.

Commonly Used Oral Antibiotics

43

tions. The ␤-lactams bind to penicillin binding proteins (PBPs) of bacteria, interfere with cell wall synthesis, and cause bacterial cellular death. They are bactericidal drugs. Bacteria may become resistant to ␤-lactam antibiotics by one or more of three mechanisms: (1) production of ␤-lactamases, which hydrolyze the ␤-lactam ring, rendering it inactive; (2) failure of the antibiotic to reach its site of action (i.e., alteration of bacterial cell wall permeability such that ␤-lactam antibiotic cannot reach its PBP target); and (3) production of altered PBPs that have a low affinity for ␤-lactam antibiotics. 2.2

Clinical Pharmacological Properties

In general, oral absorption of ␤-lactams yields peak serum levels in 1 to 2 hours (Table 2). Absorption is generally delayed 2–3 hours with food ingestion with lower peak levels, with the exception of penicillin V, amoxicillin, cephalexin, cefadroxil, cefprozil, and cefixime. Also, food seems to increase absorption of the esterified ␤-lactams such as cefuroxime axetil and cefpodoxime proxetil. Peak serum levels of oral ␤-lactams are usually quite modest when compared to those of parenteral counterparts. ␤-lactams are time-dependent antibiotics. The time the antibiotic spends above the minimal inhibitory concentration (MIC) is more important than the amount or concentration above the MIC; see Chapter 4. Therefore, serum levels of oral ␤-lactam antibiotics are more than adequate for treating most community-acquired infections. Excretion is rapid, and consequently these agents have short half-lives. Excretion of penicillins, but not cephalosporins, can be blocked by probenecid with prolongation of their serum half-life. Because of the short half-lives of elimination, dosage is usually three or four times a day. Protein binding is variable and probably not clinically important except for those drugs in which it exceeds 95%, as with the penicillinase-resistant penicillins (e.g., nafcillin). ␤-lactams are well distributed to most areas of the body, although penetration of penicillins into eye, prostate, brain, and cerebrospinal fluid (CSF) is low in the absence of inflammation. Cefuroxime and the parenteral third- and fourth-generation cephalosporins have significant penetration into eye and CSF, but oral ␤-lactams would not be expected to produce therapeutically useful eye or CSF levels despite favorable in vitro susceptibilities. In the presence of normal renal function urine concentrations of ␤-lactams are high but may not reach therapeutic concentrations in the urine with severe renal dysfunction. Most oral ␤-lactams are metabolized to a minor degree and then excreted in the urine (Table 3). In the setting of modest or severe renal dysfunction dosage adjustment is required for penicillin G, penicillin V, the aminopenicillins, and all oral cephalosporins. Hemodialysis generally requires an additional ‘‘replacement’’ dose after dialysis. Peritoneal dialysis removes variable amounts of ␤-lactams, but only the cephalosporins need further adjustment of dosage in this setting. The use of indanyl carbenicillin should be avoided in the presence of renal disease (discussed later). In contrast, the excretion of the penicillinase-resistant penicillins is primarily via the biliary route, and these agents do not require dosage changes even with severe renal disease or dialysis. 2.3 2.3.1

Oral Penicillins Oral Natural Penicillins (Penicillin G and Penicillin V)

The natural penicillins are the drugs of choice for susceptible gram-positive bacteria and are traditionally used to treat infections caused by streptococci (including penicillin-sen-

50 35–76 75–92 30 90–100 52–95 30–52 90 30–50 41–64

Penicillin V

Cloxacillin Dicloxacillin Amoxicillin (⫾ clavulanate) Indanyl carbenicillin Cephalexin Cefaclor Cefuroxime (axetil) Loracarbef Cefixime Cefpodoxime (proxetil)

Yes Yes No Noa No Yes Noa Yes No Noa

No

Absorption decreased by food

Absorption of esterified ␤-lactams is increased when taken with food.

60–73

Antibiotic

a

Oral absorption (%)

94 97 17–25 50 10–19 20–25 33–50 25 48–69 40

75–89

Protein binding (%)

Biliary Biliary Renal Renal Renal Renal Renal Renal Renal 50% Renal

Renal

Route of excretion

Table 2 Pharmacokinetic Properties of Selected Oral ␤-Lactams (Agents Representative of Each Class)

0.5 0.5 1 1.1 0.9 0.8 1.3 1.1 3.7 2.2

1

Serum half-life (normal renal function) (hours)

⫹⫹ (with renal failure) ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫺ ⫺ ⫹ ⫺ ? ⫺

Serum half-life increased by liver impairment

44 Lamarre et al.

NC NC NC NC NC

Cefaclor

Cefuroxime axetil

Loracarbef

Cefixime

Cefpodoxime proxetil

a

Avoidance Dosage every 8–12 hr

NC NC

50% Dosage every 24 hr

Dosage every 48 hrs

Dosage every 24–48 hr Dosage every 72 hr

Dosage every 12 hr

NC NC 50%–100% Dosage every 12–24 hr Avoidance Dosage every 12 hr

NC

<10 ml/min Dosage every 6 hr and additional dose AD NC NC 50%–100% Dosage every 12–24 hr with 250 mg AD Avoidance Dosage every 12 hr with 250 mg AD Dosage every 12 hr with 250500 mg AD Dosage every 24 hr with 500 mg AD Dosage every 72 hr with dose AD 50%–75% Dosage every 24 hr (no dose necessary AD) 50% Dosage every 24 hr with dose AD

Hemodialysis

Change during dialysis

CAPD, chronic ambulatory peritoneal dialysis; NC, no change; AD, after dialysis; PD, peritoneal dialysis.

50%–75% Dosage every 24 hr Dosage every 24 hr

50%–100% Dosage every 8 hr Dosage every 12–24 hr Dosage every 24 hr

NC NC Dosage every 8–12 hr

NC NC NC

Cloxacillin Dicloxacillin Amoxicillin (⫾ clavulanate) Indanyl carbenicillin Cephalexin

NC

NC

Penicillin V

Antibiotic

Creatinine Clearance 50–90 ml/min 10–50 ml/min

Dosage/schedule change in renal failure

Table 3 Oral ␤-Lactam Dosage and Schedule Change in Renal Disease and During Dialysisa

50% Dosage every 24 hr

50% Dosage every 24 hr

Dosage every 24 hr

50%–100% Dosage every 8–12 hr Dosage every 12–24 hr

Avoidance 50% Dosage every 8 hr

NC NC Dosage every 12 hr

NC

CAPD

Commonly Used Oral Antibiotics 45

46

Lamarre et al.

sitive S. pneumoniae and virtually all strains of Streptococcus pyogenes), non-␤-lactamaseproducing gonococci, meningococci, spirochetes, non-␤-lactamase-producing staphylococci, and oral anaerobes (Table 4). They are also active against susceptible strains of Bacillus, Corynebacterium, Erysipelothrix, and Streptobacillus species. Appropriate clinical indications for the oral natural penicillins include pharyngitis and mild to moderate skin and soft tissue infections unlikely to be caused by ␤-lactamaseproducing staphylococci, oral infections, and actinomycosis. Successful prophylactic uses of penicillin include the reduction of recurrences of rheumatic fever (a low dose of penicillin given twice a day) and the termination of outbreaks of S. pyogenes (penicillin V given twice a day for 5 days prophylactically). Penicillin V is the preferred oral penicillin and is usually given four times a day. Penicillin G is poorly absorbed and should not be used orally. Penicillin V achieves a peak serum concentration approximately 50% that of intravenous penicillin G and in general is not thought to be therapeutically equivalent to penicillin G. Although the natural penicillins as a group have similar antimicrobial spectra, penicillin V is less active than penicillin G against Haemophilus and Neisseria species as well as gram-negative enteric organisms. 2.3.2

Oral Penicillinase-Resistant Penicillins (Nafcillin, Oxacillin, Cloxacillin, and Dicloxacillin)

The penicillinase-resistant penicillins nafcillin, oxacillin, cloxacillin, and dicloxacillin are active against gram-positive organisms, including staphyloccoci, streptococci, and anaerobic gram-positive cocci and bacilli (Table 4). They are not active against enterococci, Listeria monocytogenes, gram-negative organisms, or methicillin-resistant staphylococci. This class was intended to treat infections caused by penicillin-resistant staphylococci that are not methicillin-resistant. Methicillin resistance is a historical term used to designate resistance to all ␤-lactams (not just methicillin), and this resistance is mediated by the production of a unique low-affinity PBP, not a ␤-lactamase. Cloxacillin and dicloxacillin are the preferred drugs in this class as absorption is more predictable (oral absorption of nafcillin is erratic and should not be used) and serum concentrations are higher relative to those of similar oral agents (e.g., oral cephalosporins) (Table 2). Peak oral serum levels are much lower than levels achieved by intravenous administration so oral cloxacillin and dicloxacillin were not intended to be used as primary therapy for serious staphylococcal infections. Cloxacillin and dicloxacillin are given four times a day and the absorption of both is affected by food. 2.3.3

Oral Aminopenicillins (Ampicillin, Amoxicillin, Amoxicillin with Clavulanate)

The aminopenicillins, ampicillin and amoxicillin, possess the same spectrum as penicillin G and as such remain active against enterococci and Listeria monocytogenes (Table 4). They are also active against some gram-negative rods (GNRs), including Escherichia coli, Proteus mirabilis, and Salmonella and Shigella species, although emerging drug resistance has significantly limited their effectiveness against many of these strains. The addition of a ␤-lactamase inhibitor such as clavulanate (amoxicillin-clavulanate potassium [Augmentin]) extends antimicrobial activity to include ␤-lactamase-producing organisms, most importantly S. aureus (non-methicillin-resistant strains only), Bacteroides species, H. influenzae, Klebsiella pneumoniae, and some resistant E. coli. Clinically, this class has been used with great success in the oral treatment of otitis media, pharyngitis, sinusitis, bronchitis, pneumonia, gonorrhea, typhoid, and cystitis. Amoxicillin may be the preferred oral penicillin for treatment of S. pneumoniae infections because of its more reliable absorption, longer half-life, and slightly more favorable MICs,

⫹⫹⫹f ⫹⫹⫹ ⫹⫹ ⫹ ⫹⫹⫹ j ⫹⫹⫹ ⫹⫹ ⫹q

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹

⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹p 0 0 0 0

⫹⫹⫹ 0 ⫹⫹⫹ ⫹⫹ 0 0 0 0

⫹⫹⫹ 0 ⫹⫹⫹ ⫹⫹ ⫹k ⫹⫹m ⫹⫹⫹ ⫹⫹⫹

0 0 ⫹⫹h ⫹⫹

Staphylococcus Enterococcus Listeria Enterospp.c spp. spp. bacteriaceaed

⫹ 0 ⫹⫹o ⫹⫹

0 0 0 ⫹⫹ ⫹l ⫹⫹n ⫹⫹⫹ ⫹⫹⫹

⫹g 0 ⫹⫹⫹h ⫹⫹ 0 0 0 0

0 0 0 ⫹⫹

Pseudomonas spp.

⫹⫹ ⫹ ⫹ ⫹

⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹⫹

Oral

0 0 0 0

⫹ 0 ⫹⫹h ⫹

Fecal

Anaerobese

a

⫹⫹⫹, ideal activity against most strains or organisms; ⫹⫹, good activity for many strains or organisms; ⫹, limited activity for most strains or organisms; 0, little or no clinically useful activity. See text for details. b Highly penicillin-resistant Streptococcus pneumoniae are resistant to all oral ␤-lactams. Mild to moderately penicillin-resistant S. pneumoniae may be slightly more susceptible to amoxicillin and some oral third-generation cephalosporins. c Methicillin-sensitive organisms only. Methicillin-resistant Staphylococcus species are resistant to all ␤-lactam antibiotics. d The family of Enterobacteriaceae includes genera such as Escherichia, Proteus, Klebsiella, Salmonella, Shigella, and Yersinia. The genera Citrobacter, Enterobacter, and Serratia are also in this family but are listed separately because of resistance patterns. e Oral anaerobes include anaerobic gram-positive cocci and bacilli and gram-negative cocci. Fecal anaerobes further include anaerobic gram-negative bacilli, notably Bacteroides fragilis and Prevotella melaninogenica, many of which produce ␤-lactamases. f Penicillin-sensitive strains are rare. g Neisseria gonorrhoeae is rarely penicillin-sensitive because of ␤-lactamase production. Neisseria meningitidis remains sensitive to penicillin, but this infection is inappropriate for oral formulations. Haemophilus and Moraxella species commonly produce ␤-lactamases. h Active against ␤-lactamase-producing organisms with the addition of clavulanate. i Useful for genitourinary infections only. j Penicillin-resistant (not methicillin-resistant) organisms are susceptible. k Activity includes E. coli, K. pneumonia, and indole-negative Proteus mirabilis only. l Activity against Moraxella catarrhalis only. m Increased activity against E. coli, K. pneumoniae and indole-negative P. mirabilis only. n Agent destroyed by ␤-lactamase-producing strains. o Agent not active against Serratia species. p Ceftibutin lacks activity against S. pneumoniae. q Cefixime and ceftibutin have very poor activity against staphylococci.

Penicillin V Cloxacillin Amoxicillin Indanyl Carbenicillin i Cephalexin Cefaclor Cefuroxime Cefixime

Antibiotic

Stretococcus spp.b

Serratia, Neisseria, citrobacter, moraxella, enterobacter haemophilus spp. spp.

Table 4 Clinical Spectrum of Activity of Selected Oral ␤-Lactams (Agents Representative of Their Class)a

Commonly Used Oral Antibiotics 47

48

Lamarre et al.

even against some relatively resistant S. pneumoniae strains. With the addition of a ␤lactamase inhibitor such as clavulanic acid, animal and human bite wounds, skin-structure infections, and diabetic foot infections may be addressed as well. Amoxicillin and ampicillin are both available in the United States (Table 1). Amoxicillin dosage is usually three times a day and ampicillin is given four times a day. Amoxicillin with clavulanate is available as a fixed-dose preparation and is given two to three times a day. Intravenous administration of ampicillin/sulbactam produces peak serum ampicillin levels that are approximately 10 times higher than those achieved with oral dosing of ampicillin or amoxicillin. 2.3.4

Oral Carboxypenicillins (Indanyl Carbenicillin)

The drug indanyl carbenicillin is an ester of carbenicillin that allows its oral absorption. Absorption is increased by concomitant food intake. Although slightly less active against gram-positive organisms than penicillin G, it has a spectrum that includes susceptible GNRs, including Pseudomonas, Enterobacter, Serratia, Morganella, and Providencia species (Table 4). Oral administration of indanyl carbenicillin, however, does not provide serum or tissue levels adequate for treating systemic infections (Table 2). Thus, clinical indications are confined to cystitis and prostatitis. Because of frequency of dosing (it is given four times a day) and because the requirement of large doses, this drug should not be the first choice for genitourinary infections. Further, indanyl carbenicillin is contraindicated in the presence of renal disease as urine levels may be subtherapeutic. 2.4 2.4.1

Oral Cephalosporins Oral First-Generation Cephalosporins (Cephalexin, Cephradine, and Cefadroxil)

The agents cephalexin, cephradine, and cefadroxil have a similar spectrum to that of penicillin G but also are active against ␤-lactamase-producing staphylococci, Moraxella catarrhalis, and many, but not all, strains of E. coli, K. pneumoniae, P. mirabilis, Citrobacter koseri, and Salmonella and Shigella species (Table 4). As with all cephalosporins, they are not active against enterococci or L. monocytogenes. Clinical indications include the treatment of staphylococcal or streptococcal infections when it is desirable to avoid penicillin use. Appropriate scenarios include mild to moderate skin and soft tissue infections, streptococcal pharyngitis, and uncomplicated cystitis. This class is not ideal for otitis media, sinusitis, or most lower respiratory tract infections because of inconsistent activity against H. influenzae. The lack of activity against Pasturella multocida makes first-generation oral cephalosporins unsuitable for animal bite or scratch wounds. Relatively low serum levels with oral administration and a less than comprehensive spectrum should discourage empirical use of first-generation oral cephalosporins for infections thought likely to be due to gram-negative organisms; though, if sensitive, these drugs can be used. All agents in this class are well absorbed, but oral peak serum levels are only a small fraction of the peak serum levels achieved with intravenous administration of an equivalent parenteral cephalosporin. Cephalexin dosage is usually four times a day. Cefadroxil may be administered one to two times a day because of its more prolonged halflife, though it is more expensive (Table 1). This generation does not adequately cross the blood–brain barrier.

Commonly Used Oral Antibiotics

2.4.2

49

Oral Second-Generation Cephalosporins (Cefuroxime Axetil, Cefaclor, Cefprozil, and Loracarbef)

The second-generation cephalosporin group has a similar spectrum to that of first-generation agents but provides significantly improved activity against H. influenzae, M. catarrhalis, and Neisseria species (Table 4). Activity remains good against susceptible staphylococci, streptococci, and selected E. coli and Klebsiella and Proteus species. As a group, they (along with first-generation agents) lack activity against penicillin-resistant pneumococci and Enterobacter, Serratia, and Pseudomonas species. Clinically, this group has demonstrated success in the treatment of otitis media, sinusitis, mild to moderate skin and soft tissue infections, and uncomplicated cystitis. Traditionally, they have been used for the treatment of upper and lower respiratory system infections. Because of the cost and broader spectrum of this class, agents that are less expensive and/or have a more narrow spectrum of activity (first-generation cephalosporins and penicillins) should be considered first. On the basis of pharmacokinetic considerations, cefuroxime axetil may be the best agent in this class for oral therapy (Table 2). Absorption of cefuroxime axetil is enhanced with food and dosage can be two times a day because of relatively long half-life. However, all agents in this class have excellent absorption, with the caveat that oral cephalosporin preparations achieve only a fraction of the levels achieved by their intravenous counterparts. They do not adequately cross the blood–brain barrier. 2.4.3

Oral Third-Generation Cephalosporins (Cefixime, Cefpodoxime Proxetil, Ceftibutin, and Cefdinir)

The third-generation cephalosporins were developed to provide activity against gram-negative bacteria (Table 4). Their spectrum includes H. influenzae, Neisseria species, M. catarrhalis, and most Enterobacteriaceae, including E. coli and Klebsiella, Proteus, Providencia, Aeromonas, Morganella, and Serratia species. There is no antipseudomonal activity. Further, most drugs in this class provide excellent coverage against most Streptococcus species, including moderately penicillin-resistant pneumococci and methicillinsensitive S. aureus. As mentioned, oral cephalosporins lack activity against Pseudomonas species, highly penicillin-resistant S. pneumoniae, Enterococcus species, L. monocytogenes, and Stenotrophomonas species. Cefixime has poor activity against staphylococci, and ceftibutin lacks activity against staphylococci and pneumococci. The oral third-generation agents have been used primarily in the treatment of respiratory, sinus, and urinary tract infections, including uncomplicated pyelonephritis, as well as in single-dose oral therapy for anogenital gonorrhea (including penicillin-resistant strains). However, because of their relatively high cost, the availability of less expensive narrower-spectrum agents, and the relative rarity of resistant GNRs in community-acquired infections, these agents should not be used routinely. All the agents in this class are well absorbed. Oral peak serum levels are not comparable with those of intravenous third-generation preparations. 2.5 2.5.1

Adverse Reactions to ␤-Lactams Hypersensitivity Reactions

Hypersensitivity reactions are the most common and potentially the most severe adverse events associated with ␤-lactam use (see Table 5). They include rash or urticarial reactions, serum sickness, or allergic vasculitis and anaphylaxis. Exfoliative dermatitis and Stevens-

50

Lamarre et al.

Table 5 Adverse Reactions to Oral ␤-Lactams Allergic IgE antibody Anaphylaxis Early urticaria (<72 hr) Cytotoxic antibody Hemolytic anemia Antigen–antibody complex disease Serum sickness Delayed hypersensitivity Contact dermatitis Idiopathic Skin rash Fever Late urticaria (>72 hr) Gastrointestinal Nausea, dyspepsia Diarrhea Enterocolitis Hematological Hemolytic anemia Neutropenia Eosinophilia Platelet dysfunction Thrombocytopenia Thrombocytosis Hepatic Elevated aminotransferase levels Biliary sludge Electrolyte Hypokalemia Neurological Seizure Nonspecific (e.g., paresthesias, altered taste) Renal Interstitial nephritis Hemorrhagic cystitis Superinfection (e.g., vaginitis, colitis)

Johnson syndrome are also possible. Fortunately, serious events are rare. Skin testing for penicillins may predict anaphylaxis but fails to predict other rashlike reactions. Skin testing for cephalosporins is unreliable and not recommended. Cephalosporin cross-reactions occur in 1%–7% of patients with a history of penicillin allergy, so some care is advised in the case of a known severe penicillin hypersensitivity. 2.5.2

Hematological Reactions

Clinically significant hematological reactions are uncommon. Reversible neutropenia can occur with any ␤-lactam, particularly with large doses. Isolated eosinophilia can be seen

Commonly Used Oral Antibiotics

51

as well but is more common with the cephalosporins. Coombs-positive hemolytic anemia has been reported but is rare. Platelet inhibition can also be seen with any ␤-lactam; however, thrombocytopenia is generally associated with penicillins. Thrombocytosis can occur with cephalosporin use. 2.5.3

Renal Reactions

Interstitial nephritis is the most common form of toxicity associated with the ␤-lactams but is uncommon (especially with cephalosporins). Hypokalemia can be seen with very large doses of any penicillin, mainly carbenicillin. Renal toxicity may also result from allergic angiitis. 2.5.4

Central Nervous System Reactions

Accumulation of any penicillin, either from massive doses or from renal failure, can result in myoclonic seizures. This reaction has not been seen with cephalosporins. 2.5.5

Gastrointestinal Reactions

Gastrointestinal disturbances are common with oral ␤-lactams. Diarrhea is also common and Clostridium difficile colitis has been reported after the use of all ␤-lactams. Abnormalities of hepatic enzymes have also been reported but are decidedly less common. Mild elevations of aminotransferase and alkaline phosphatase levels in most instances do not necessitate discontinuation of the agent. Major hepatic injury is rare and levels usually return to baseline with discontinuation of the offending ␤-lactam. 2.5.6

Superinfection

All ␤-lactams can result in bacterial and/or fungal superinfections, including candidal vaginitis, C. difficile colitis, and enterococcal infections. 3

MACROLIDES AND LINCOSAMIDES

3.1

Macrolides

Erythromycin was discovered in 1952 and was quickly embraced by clinicians because of its broad and somewhat unique spectrum of activity and its suitability as an oral therapeutic option for the penicillin-allergic patient. Its therapeutic application has always been limited by a relatively short serum half-life and the rather frequent occurrence of gastrointestinal intolerance (nausea and vomiting). Recently developed macrolides, azithromycin and clarithromycin, offer improved gastrointestinal toleration and superior pharmacokinetic and tissue penetration characteristics, as well as broader antibacterial spectra, but at an increased cost. Erythromycin and clarithromycin act as motilin receptor agonists in the gut and gallbladder, thus stimulating gastrointestinal motility. There is some suggestion that macrolides have anti-inflammatory activity, though the role these drugs play as anti-inflammatory agents is not clear. 3.1.1

Chemical Properties, Mechanism of Action, and Bacterial Resistance

The structure and action of the macrolides are based on a 14-member macrocyclic lactone ring that reversibly binds the bacterial 50S ribosomal subunit to interfere with bacterial protein synthesis and cell growth. Azithromycin is slightly different as it has a 15-member ring with an amino-methyl group insertion. Azithromycin is therefore an azalide rather than a macrolide. Typically all of these drugs are bacteriostatic at therapeutic concentra-

52

Lamarre et al.

tions, but they may be bactericidal for certain organisms, including Streptococcus species and H. influenzae. Bacterial resistance is mediated by one or more of four mechanisms: (1) decreased penetration into the cell due to decreased permeability of the cell envelope, (2) active efflux of the drug, (3) alteration of the ribosomal binding site, and less commonly (4) enzymatic inactivation of the macrolide. Resistance to one member of this class implies resistance to all. 3.1.2

Clinical Pharmacological Properties

Oral erythromycin dosage is confusing as there are several different preparations currently available (Table 6). Erythromycin base is inherently acid labile and must be administered in another formulation: 1.

2. 3. 4.

Enteric coated base a. Tablets: E-Mycin, Ery-Tab b. Pellets: Eryc c. Film coated tablets: Filmtabs Erythromycin stearate a. Erythrocin Stearate Filmtabs Erythromycin ethylsuccinate a. EryPed, E.E.S. Erythromicin estolate a. Ilosone

The stearate, ethylsuccinate, and the estolate formulations are less acid labile. Absorption of these various preparations is comparable in the fasting state, but only the absorption of the estolate form is unaffected when taken with food. Estolate preparations of erythromycin, however, should be avoided by adults because of an increased incidence of cholestatic hepatitis. This cholestatic reaction is less frequent in children, for whom the estolate may be the most bioavailable and most clinically efficacious oral formulation of erythromycin. Clarithromycin is absorbed equally well with or without food. Early capsule preparations of azithromycin had to be taken on an empty stomach. However, more recent film tab preparations and the oral suspension of azithromycin may be taken with food. Substances containing magnesium or aluminum decrease the absorption of macrolides. Oral azithromycin and clarithromycin are better tolerated from a gastrointestinal standpoint than oral erythromycin. Peak serum levels of intravenous erythromycin are appreciably higher than those attainable by oral administration, but oral peak serum levels of azithromycin compare more favorably with levels attained from intravenous administration. In general, macrolides have high levels of tissue penetration and persist longer in tissues than in blood. This is especially true of azithromycin and clarithromycin. Drug is concentrated in the biliary tree. Tissue levels are adequate for treatment of the upper respiratory tree, sinuses, lung, pleural fluid, and middle ear infections. Central nervous system (CNS), eye, prostate, and synovial and ascitic fluid levels are just a fraction of serum levels. Urine levels after dosing can be high but are variable to the point that these agents are not used for treatment of urinary tract infections. High concentrations of erythromycin are attained intracellularly in alveolar macrophages and polymorphonuclear neutrophils as compared to serum levels. Erythromycin and azithromycin do not require dosage modification regardless of the degree of renal insufficiency (Table 7). Dose adjustment is required when using clarith-

Oral absorption (%)

>90 With food >90 With food 18–45 (Varies on salt of drug used) 37 55 90

65–85 99 90 96 70–90

80

Antibiotic

Tetracycline Doxycycline Erythromycin

Azithromycin Clarithromycin Clindamycin

Ciprofloxacin Levofloxacin Moxifloxacin Gatifloxacin Co-trimoxazole

Metronidazole

No

No Slightly No No No

Yes No No

Slightly Slightly Yes

Absorption decreased by food

65–85 24–38 50 20 44 (Trimethoprim) 70 (Sulfamethoxazole) <20

7–50 42–70 94

65 93 65–90

Protein binding (%)

Biliary ⫹ renal

Renal 40% Renal Biliary Renal Renal

Biliary Renal Biliary

Renal Renal ⫹ fecal Biliary

Route of excretion

3.5–6 6–8 9–16 7–14 8–11 (Trimethoprim) 10–13 (Sulfamethoxazole) 5–10

35–72 4.3–7 2–3

8 18 1.5–3

Serum half-life (normal renal function) (hr)

Table 6 Pharmacokinetic Properties of Selected Oral Antibiotics (Selected Agents Representative of Their Class)

⫹⫹

⫺ ⫺ ⫹⫹ (With renal failure) ⫺ ⫺ ⫺ ⫺ ⫺

⫺ ⫺ ⫺

Serum half-life increased by liver impairment

Commonly Used Oral Antibiotics 53

NC NC NC NC NC NC

NC

Clindamycin Ciprofloxacin

Levofloxacin

Moxifloxacin Gatifloxacin

Co-trimoxazole

Metronidazole

NC 75% Dosage every 12 hr NC 50%–75% Dosage every 12 hr 50% Dosage every 24 hr NC 50% Dosage every 24 hr 50% Dosage every 12 hr (CrCl of 30 ml/min only) NC

Avoidance NC NC

Avoidance NC 50%–75% Dosage every 6–8 hr NC 50%–75% Dosage every 12 hr NC 50% Dosage every 12 hr 25%–50% Dosage every 24 hr NC 50% Dosage every 24 hr Not recommended, but 30%–50% Dosage every 12 hr 50%–100% Dosage every 8 hr Normal dosage AD

25%–50% Dosage every 24 hr No data 50% Dosage every 24 hr AD 30%–50% Dosage every 24 to 48 hr AD

NC 50%–75% Dosage every 12 hr with dose AD NC 250 mg Every 12 hr

Avoidance NC NC

CAPD, chronic ambulatory peritoneal dialysis; NC, no change; AD, after dialysis; PD, peritoneal dialysis.

NC NC

Azithromycin Clarithromycin

a

NC NC NC

Hemodialysis

<10 ml/min

Creatinine clearance 50–90 ml/min 10–50 ml/min

Tetracycline Doxycycline Erythromycin

Antibiotic

Change during dialysis

Dosage/schedule change in renal failure

Table 7 Selected Oral Antibiotic Dosage and Schedule Change in Renal Disease and During Dialysisa

50%–100% Dosage every 8 hr

No data 50% Dosage every 24 hr 30%–50% Dosage every 12 hr

250 mg Every 48 hr

NC 50%–75% Dosage every 12 hr NC 250 mg Every 8 hr

Avoidance NC NC

CAPD

54 Lamarre et al.

Commonly Used Oral Antibiotics

55

romycin in the setting of moderate to severe renal insufficiency. Since erythromycin and clarithromycin are both metabolized by the cytochrome P-450 system, these drugs inhibit the metabolism of other drugs that also utilize this system. Drugs such as carbamazepine, warfarin, cyclosporine, theophyline, quinidine, digoxin, cisapride, and tacrolimus (to name a few) may have elevated levels when administered with erythromycin or clarithromycin. The patient’s drug list should be reviewed for possible interacting medications before prescribing these antibiotics (see Chapter 4, Table 4). Azithromycin, on the other hand, is not metabolized by the cytochrome P-450 system and drug–drug interactions are generally not an issue. The active metabolite of clarithromycin, 14-hydroxyclarithromycin, has additive antimicrobial activity. The newer macrolides (azithromycin and clarithromycin) have longer half-lives relative to that of erythromycin and penetrate tissue better. Azithromycin quickly distributes to body tissues and takes a relatively long time to wash out of this compartment. Thus, 5 days of therapy with azithromycin may be equivalent to 7 to 10 days of treatment with erythromycin or clarithromycin (Table 8). 3.1.3

Spectrum of Activity and Clinical Indications (Erythromycin, Azithromycin, and Clarithromycin)

The macrolides share broad-spectrum activity against a wide variety of organisms (Table 10). They have good clinical activity against Streptococcus species, but up to 15% of S. pneumoniae isolates may be resistant. Penicillin-sensitive strains of S. pneumoniae tend to remain sensitive to macrolides, but macrolide resistance seems to parallel penicillin resistance for unclear reasons. Activity against Staphylococcus aureus is good in vitro, but methicillin-resistant isolates are typically macrolide-resistant. Overall, clinical outcomes in treatment of staphylococcal infections with macrolides have generally been worse than initial in vitro testing would have predicted. There is a propensity for staphylococcal strains to acquire resistance to erythromycin during therapy. In general, when considering infections likely to be staphylococcal one should think of clindamycin or ␤-lactam antibiotics rather than macrolides. Gram-positive activity extends to L. monocytogenes and Enterococcus species, but the clinical relevance of this is questionable. Azithromycin is generally less active against gram-positive organisms than other macrolides, whereas clarithromycin is the most active agent against gram-positive agents in this class. As a class, macrolides are active against Neisseria species (however, N. gonorrhoeae is increasingly resistant), Moraxella catarrhalis, Bordetella species, and Campylobacter species. More consistent activity against H. influenzae is seen with azithromycin. Clarithromycin has been useful against H. influenzae strains but less so than azithromycin. Macrolides are very active against intracellular organisms such as Chlamydia, Mycoplasma, and some Rickettsia species and especially Legionella spp. They are not clinically useful for the treatment of anaerobic infections. Clinically, the macrolides are first choice in the treatment of Mycoplasma and Legionella species and Chlamydia trachomatis infections as well as pertussis, bacillary angiomatosis due to Bartonella henselae in human immunodeficiency virus (HIV) infected patients, diphtheria, and Campylobacter jejuni gastroenteritis. Traditionally, they have been used for pharyngitis, sinusitis, otitis media, bronchitis, community-acquired pneumonia, and mild to moderate soft tissue infections. Their use also includes alternative therapy for early Lyme disease and combination therapy for Helicobacter pylori. In most situations, the newer drugs clarithromycin and azithromycin offer simpler, better tolerated therapy rather than any major therapeutic advance. This is not the case when considering the use of clarithromycin for treatment of mycobacterial infections.

Doxy Caps, Vibra-Tabs, Doryx, Doxy Vibramycin, Monodox Minocin ERYC, PCE, E-Mycin, Ery-Tab, Robimycin, E-Base Ilosone EryPed, E.E.S. Erythrocin, Wyamycin Zithromax, Z-PAK, Sumamed Biaxin, Biclar, Klacid LA, Klaricid XL, Zeclar Cleocin NegGram Cinobac Cipro Penetrex Maxaquin Noroxin Floxin Levaquin Tequin Avelox Zagam Bactrim, Septra, Cotrim, Sulfatrim, Sulfoxaprim, Uroplus Flagyl, Metric, Protostat, Metro

Doxycycline hyclate Doxycycline monohydrate Minocycline hydrochloride Erythromycin base

Erythromycin estolate Erythromycin ethylsuccinate Erythromycin stearate Azithromycin Clarithromycin Clindamycin hydrochloride Nalidixic acid Cinoxacin Ciprofloxacin Enoxacin Lomefloxacin hydrochloride Norfloxacin Ofloxacin Levofloxacin Gatifloxacin Moxifloxacin Sparfloxacin Co-trimoxazole DS Metronidazole

b

Standard dosage (adults) 0.5 g every 6 hr 0.3 g every 12 hr 0.1 to 0.2 g every 12 hr first day, then 0.1 every 24 hr As for doxycycline calcium As for doxycycline calcium 0.2 g, then 0.1 g every 12 hr 0.25 to 0.5 g every 6 hr (Ery-Tab 0.333 g every 8 hr) 0.25 to 0.5 g every 6 hr 0.4 g every 6 hr 0.25 to 0.5 g every 6 hr 0.25 to 0.5 g every 24 hr 0.25 to 0.5 g every 12 hr 0.15 to 0.3 g every 6 hr 1 g every 6 hr 0.5 g every 12 hr 0.25 to 0.75 g every 12 hr 0.4 g every 12 hr 0.4 g every 12 hr 0.4 g every 12 hr 0.2 to 0.4 g every 12 hr 0.25 to 0.5 g every 24 hr 0.4 to 0.6 g every 24 hr 0.4 g every 24 hr 0.4 g on day 1, then 0.2 g every 24 hr 0.16/0.8 g every 12 to 24 hr 0.25 to 0.75 g every 8 hr

Cost based on average wholesale pharmacy cost for a 10-day prescription (2000 Drug Topics Redbook). Cost range from lowest to highest dose. c Cost for a Z-pack (500 mg on day 1, then 250 mg every day on days 2–5).

a

Achromycin V, Panmycin, Robitet, Sumycin, Tetralan Declomycin Vibramycin

Proprietary name(s)

Tetracycline hydrochloride Demeclocycline hydrochloride Doxycycline calcium

Antibiotic

Table 8 Standard Dosage, Proprietary Names, and Costs of Selected Oral Antibiotics

$27.00–$53.00 $43.00 $6.00–$8.80 $39.00c $70.00–$140.00 $76.00–$152.00 $88.00 $48.00 $70.00–$83.00 $68.00 $138.00 $80.00 $78.00–$98.00 $73.00–$85.00 $140.00–$210.00 $87.00 $74.00 $13.00–$26.00 $51.00–$153.00

$68.00–$136.00 $66.00–$136.00 $ 37.00 $10.00–$21.00

$3.60 $170.00 $68.00–$136.00

Costa,b

56 Lamarre et al.

Commonly Used Oral Antibiotics

57

Clarithromycin is uniquely active against many of the atypical mycobacteria and has become one of the first-line agents in the treatment of infections due to Mycobacterium avium-intracellulare, M. kansasii, M. chelonei, and M. fortuitum. Both clarithromycin and azithromycin have been shown to be useful for primary prophylaxis of Mycobacterium avium-intracellulare infections in HIV infected patients with low CD4 counts. Azithromycin is generally preferred because of its lower pill burden (two 600-mg pills/wk), lower incidence of drug interactions, and possibly lower likelihood of macrolide resistance with failure of prophylaxis. 3.1.4

Adverse Reactions to Macrolides (Table 9)

Cardiovascular. QT interval prolongation with ventricular tachycardia has rarely been reported with both erythromycin and clarithromycin. Hypersensitivity Reactions. Hypersensitivity reactions are very uncommon, but fixed drug eruptions, morbilliform rashes, fever, and eosinophilia have been reported. Gastrointestinal. All agents in this class can cause nausea, vomiting, cramps, dyspepsia, and diarrhea. Symptoms are especially common with erythromycin as this agent is an enteric motilin receptor agonist. Enteric-coated erythromycin does not ameliorate these effects. Patients taking clarithromycin may experience an unpleasant metallic taste.

Table 9 Adverse Reactions to Oral Macrolides and Clindamycin Cardiovascular QT prolongation with ventricular tachycardia (clarithromycin, erythromycin) Hypersensitivity reactions Anaphylaxis Fixed drug eruptions Morbilliform rashes Fever Erythema multiforme Gastrointestinal Nausea, dyspepsia Diarrhea Hematological Eosinophilia Neutropenia, rarely agranulocytosis (clindamycin only) Thrombocytopenia (clindamycin only) Hepatic Autoimmune, hepatotoxic Cholestatic hepatitis (particularly erythromycin) Elevated aminotransferase levels Neurological Hearing loss and tinnitis (macrolides only) Headaches and dizziness (macrolides only) Acute psychosis and mania (clarithromycin only) Superinfection Vaginitis Colitis

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Hepatic. Autoimmune, hepatotoxic, and cholestatic hepatitis all have been reported and may be accompanied with rash, fever, leukocytosis, and eosinophilia. Generally, all are reversible with discontinuation of the offending agent. Cholestatic hepatitis is especially common with estolate preparations of erythromycin, which should not be used if possible. Actual and false-positive aminotransferase level elevations also can occur with macrolides. Central Nervous System. Transient hearing loss, tinnitis, headaches, and dizziness have been reported with all the macrolides and appear associated with large doses, particularly in the presence of renal insufficiency in elderly patients. Acute psychosis and mania have been associated with clarithromycin. Superinfection. Although all macrolides can result in bacterial and/or fungal superinfections, including candidal vaginitis and C. difficile colitis, superinfection occurrence is decidedly less common when compared to that in other classes of antibiotics. 3.2

Lincosamides

Lincomycin was isolated in Lincoln, Nebraska, in 1962, and its antibacterial action was found to be very similar to that of the macrolides, but these two classes of antimicrobials are chemically unrelated. Clindamycin is modified from lincomycin and remains the preferred agent because of its greater antimicrobial potency and better oral absorption (Table 8). 3.2.1

Chemical Properties, Mechanism of Action, and Bacterial Resistance

Clindamycin is basically an amino acid linked to an amino sugar. Similarly to the macrolides, it binds the 50s ribosomal subunit, interfering with protein synthesis and cell growth. Although clindamycin is chemically unrelated to the macrolides, it could theoretically compete for binding to the 50S ribosomal subunit. Thus, coadministration of these drugs should be prevented. Generally bacteriostatic in action, clindamycin may be bactericidal for Streptococcus species and S. aureus. Bacterial resistance is mediated by one or more of three mechanisms: (1) alteration of the ribosomal binding site, (2) chemical alteration of clindamycin to an inactive form, and (3) intrinsic resistance (e.g., aerobic gram-negative bacilli) due to poor permeability of the cell membrane to the drug. 3.2.2

Clinical Pharmacological Properties

Oral absorption is excellent and yields peak serum levels in 1 hour (Table 6). Concomitant food intake slightly delays but does not decrease absorption. Clindamycin is highly protein bound. Peak oral serum levels are approximately 50% of those achieved with parenteral dosing. Tissue distribution is excellent, with the exception of poor penetration into the CNS even in the presence of meningitis. Antibiotic concentration is especially high in bone and abscesses, and high levels are achieved in the urine and feces as well. The liver and biliary tree metabolize clindamycin primarily; hence dosing modification is unnecessary in the presence of renal insufficiency alone (Table 7). However, substantial dose reduction should be considered when both hepatic and severe renal disease are present. 3.2.3

Spectrum of Activity and Clinical Indications (Clindamycin)

Clindamycin has very good activity against most gram-positive bacteria, including Streptococcus species, and remains active against the majority of S. aureus strains (Table 10).

⫹ ⫹h ⫹⫹⫹ ⫹j ⫹ ⫹⫹ 0

⫹⫹e ⫹⫹g ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ ⫹⫹l 0

⫹ ⫹ 0 ⫹ ⫹ ⫹ 0

Enterococcus spp. ⫹⫹ ⫹⫹⫹ 0 ⫹⫹⫹ ⫹⫹⫹ ⫹m 0

Atypicalsb ⫹⫹ ⫹ 0 ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ 0

Enterobacteriaceaec 0 0 0 ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ 0

⫹⫹f ⫹⫹⫹i 0 ⫹⫹⫹ ⫹⫹ ⫹⫹⫹ 0

Neisseria, moraxella, haemophilus spp. 0 0 0 ⫹⫹ ⫹ 0 0

Pseudomonas spp.

⫹⫹ ⫹ ⫹⫹⫹ 0 ⫹⫹ 0 ⫹⫹⫹

Oral

⫹⫹ ⫹ ⫹⫹⫹ 0 ⫹⫹k 0 ⫹⫹⫹

Fecal

Anaerobesd

a

⫹⫹⫹, ideal activity against most strains or organisms; ⫹⫹, good activity for many strains or organisms; ⫹, limited activity for most strains or organisms; 0, little or no clinically useful activity. See text for details. b The category of atypical organisms generally refers to Mycoplasma and Chlamydia spp. but may include Legionella or Rickettsia spp. or spirochetes, depending on the specific agent. See text for further detail. c The family Enterobacteriaceae includes genera such as Escherichia, Proteus, Klebsiella, Salmonella, Shigella, and Yersinia. The genera Citrobacter, Enterobacter, and Serratia are also in this family but are listed separately because of resistance patterns. d Oral anaerobes include anaerobic gram-positive cocci and bacilli and gram-negative cocci. Fecal anaerobes further include anaerobic gram-negative bacilli, notably Bacteroides fragilis and Prevotella melaninogenica. e Penicillin-resistant strains, including S. pneumoniae, are often tetracycline-resistant as well. f Penicillin-resistant strains, especially N. gonorrhoeae, are often tetracycline-resistant as well. g Resistance is increasing; up to 15% of S. pneumoniae may be macrolide-resistant. h Methicillin-resistant strains are often macrolide-resistant as well. i Azithromycin has more gram-negative activity and less gram-positive activity than other macrolides. j Methicillin-resistant strains are often fluoroquinolone-resistant as well. k Bacteroides species may be susceptible to moxifloxacin and can be resistant to gatifloxacin. l S. pneumoniae resistance is common. m Chlamydia species are sensitive to sulfonamides.

Tetracycline Erythromycin Clindamycin Ciprofloxacin Gatifloxacin Co-trimoxazole Metronidazole

Antibiotic

Staphylococcus spp.

Streptococcus spp.

Serratia, citrobacter, enterobacter spp.

Table 10 Clinical Spectrum of Activity of Selected Oral Antibiotics (Agents Representative of Their Class)a

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Despite clindamycin’s good activity against ‘‘the majority’’ of staphylococcal strains, it must be kept in mind that its activity against staphylococci is not universal. In fact, 15% of methicillin-susceptible strains may be resistant, and a considerably larger proportion of methicillin-resistant staphylococci are also resistant to clindamycin. Reliance on clindamycin for treatment of potentially serious staphylococcal infections or for prolonged therapy (e.g., osteomyelitis) must be guided by results of susceptibility testing. Empirical use for treatment of staphylococcal infections may be unduly risky in certain clinical situations. Clindamycin has excellent activity against gram-positive and gram-negative anaerobes, including B. fragilis. However, these agents are generally inactive against Enterococcus species, L. monocytogenes, and aerobic gram-negative cocci and bacilli. Clindamycin is indicated for infections involving B. fragilis and/or penicillin-resistant anaerobic organisms, including anaerobic pulmonary infections (aspiration pneumonia or lung abscess) and intra-abdominal/pelvic infections (in combination with a GNR agent). It is also useful in the management of staphylococcal infections (discussed earlier), particularly osteomyelitis, as well as bacterial vaginosis. Clindamycin is an alternate therapy for Pneumocystis carinii pneumonia (in combination with primaquine) and Toxoplasma gondii (in combination with pyrimethamine). There have been cases of acquired resistance to clindamycin during therapy of staphylococcal infections. They are unusual but have been seen when there is coexisting resistance to erythromycin. Curiously, clindamycin has been used with some success in the treatment of babesiosis and in some cases of highly drug-resistant falciparum malaria (in combination with quinine). 3.2.4

Adverse Reactions to Clindamycin (Table 9)

Hypersensitivity Reactions. The most common hypersensitivity reaction to clindamycin is rash. Less common reactions include fever, anaphylaxis, and erythema multiforme. Gastrointestinal Reactions. Although dyspepsia, nausea, and vomiting can occur, diarrhea is by far the most frequent reaction, occurring in up to 20% of patients. It is more common with oral administration and is dose related. The incidence of C. difficile is also increased by the persistence of the drug in feces for days to weeks. Hematological Reactions. Neutropenia and thrombocytopenia have been reported but are reversible upon drug discontinuation. Agranulocytosis can also occur but is very rare. Hepatic Reactions. While hepatotoxicity has been reported, more common are minor are reversible elevations of aminotransferases. Superinfection. Lincosamides can result in bacterial and/or fungal superinfection, including candidal vaginitis and particularly C. difficile colitis (discussed previously). 4

TETRACYCLINES

Tetracyclines were discovered in 1949 by screening soil organisms for antimicrobial properties. Although considerable antimicrobial resistance has evolved against tetracyclines, they remain active against a wide range of typical and atypical organisms. They are inexpensive and have convenient dosage schedules. 4.1

Chemical Properties, Mechanism of Action, and Bacterial Resistance

The basic structure and action of the tetracyclines consist of a nucleus of four fused benzene rings that reversibly binds the 30S ribosomal subunit, interfering with protein

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synthesis and cell growth. Derivatives of this basic structure account for differences in pharmacological properties. Tetracyclines are bacteriostatic at therapeutic concentrations. They are classically divided according to their serum half-lives (see Table 8): Short-acting: tetracycline, oxytetracycline Intermediate-acting: demeclocycline Long-acting: minocycline, doxycycline Bacterial resistance is most commonly mediated by one or more of three mechanisms: (1) alteration of the ribosomal binding site, (2) decreased intracellular accumulation caused by either decreased uptake or active efflux, and (3) chemical alteration to an inactive form. Resistance to one member of this class implies resistance to all. 4.2

Clinical Pharmacological Properties

Oral absorption of tetracyclines yields peak serum levels in 1 to 3 hours (Table 6). Food slightly decreases absorption but not to a clinically significant extent. Absorption is markedly decreased when they are taken with substances that contain calcium, magnesium, or aluminum (e.g., antacids, multivitamins, dairy products, or iron), as tetracyclines form complexes with divalent cations. Oral absorption of all tetracyclines is excellent but is better with doxycycline and minocycline. In general, tetracyclines are highly protein bound, but the clinical significance of this characteristic remains unclear. Peak levels of oral tetracyclines compare favorably with those of intravenous dosage as serum levels are almost identical once tissue distribution occurs, especially for doxycycline and minocycline. Tetracyclines are lipophilic and have a large volume of distribution with sequestration in tissues. Detectable levels are found in liver, lung, kidney, tears, sinuses and mucosal fluid, synovial fluid, and unobstructed bile. CNS levels are only a fraction of serum levels. With the exception of minocycline concentrations, therapeutic concentrations are achieved in urine. In general, tetracyclines should not be used in the setting of renal insufficiency (Table 7). Doxycycline is a notable exception and can be used regardless of the degree of renal impairment as it is excreted in the gastrointestinal tract under these circumstances. These agents should be used with caution in the setting of hepatic disease. 4.3

Spectrum of Activity and Clinical Indications (Tetracycline, Oxytetracycline, Demeclocycline, Doxycycline, and Minocycline)

The tetracyclines share an almost identical broad spectrum of activity but the longer-acting, more lipophilic agents (i.e., doxycycline and minocycline) are two- to fourfold more active than their shorter-acting counterparts (e.g., tetracycline) (Table 10). Doxycycline is the preferred oral agent in this class. Tetracyclines are clinically active against gram-positive cocci in general (excluding Staphylococcus species), N. meningitidis and N. gonorrhoeae, and selected communityacquired gram-negative bacilli, including H. influenzae, E. coli, and Salmonella, Shigella, and Campylobacter species (although resistance is rapidly increasing). If an isolate is penicillin-resistant, including the pneumococcus and gonococcus, it is usually tetracyclineresistant as well, although these classes are chemically unrelated and the mechanisms of resistance are not related. Tetracyclines are particularly useful in treatment of Mycoplasma, Chlamydia, and Rickettsia species infections, as therapy for early Borrelia burgdorferi infection; as alternate therapy for Treponema pallidum; and in combination therapy for

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Helicobacter pylori. This class also possesses activity against many anaerobes, including B. fragilis. Traditionally, tetracyclines have been used to treat upper respiratory infections, exacerbations of bronchitis, uncomplicated cystitis, mild to moderate soft tissue infections, pelvic inflammatory disease, Lyme disease, actinomycosis, and infections caused by atypical organisms. They are not recommended for routine treatment of food-borne diarrheal illness because of increasing resistance. 4.4 4.4.1

Adverse Reactions to Tetracyclines (Table 11) Hypersensitivity Reactions

Hypersensitivity reactions, which are uncommon, include urticaria, anaphylaxis, angioedema, fixed drug eruptions, and morbilliform rashes. A reaction to one member of the class implies an allergy to all. Further, minocycline has been associated with a lupuslike syndrome and autoimmune hepatitis, which are reversible with drug discontinuation.

Table 11 Adverse Reactions to Oral Tetracyclines Allergic Urticaria Angioedema Anaphylaxis Fixed drug eruptions Rash Bones and teeth Permanent discoloration (children <8 years of age) Black discoloration (minocycline only; occurs at any age) Gastrointestinal Nausea, dyspepsia Diarrhea Esophageal ulceration Pancreatitis (reported with tetracycline) Hepatic Hepatitis Idiopathic Autoimmune Neurological Benign intracranial hypertension Vertigo, lightheadedness, tinnitis (minocycline only) Renal Fanconi-like syndrome (with outdated tetracycline only; very rare) Nephrogenic diabetes insipidus (demeclocycline only) Azotemia Skin Phototoxicity Black discoloration (minocycline only) Superinfection Vaginitis Colitis

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63

Skin Reactions

Phototoxicity occurs with all tetracyclines; it is demonstrated by a red rash on areas exposed to sunlight and is frequently associated with onycholysis. Prolonged minocycline use can rarely produce black discoloration of skin, nails, and sclera that is slowly reversible on drug discontinuation. 4.4.3

Bone and Tooth Reactions

Permanent discoloration of teeth occurs in children taking tetracyclines as a result of enamel hypoplasia. This event appears related to total dose of therapy and is less pronounced with doxycycline. Tetracyclines should not be used by pregnant women or by children less than eight years of age. Minocycline also may cause permanent black discoloration of teeth (visible through gums) with prolonged use. 4.4.4

Gastrointestinal Reactions

All agents in this class can cause nausea, vomiting, and dyspepsia, which may be ameliorated with concomitant food intake. Esophageal ulceration has been reported with swallowing pills with little or no water or just before lying flat (e.g., going to bed). Pancreatitis has been reported with tetracycline. Hepatotoxicity is more common in pregnant women or in patients with excessive serum levels (e.g., in renal failure) and carries a high mortality rate. Diarrhea is less common with doxycycline and minocycline. 4.4.5

Renal Reactions

Older preparations of tetracycline that were outdated have been associated with a Fanconilike syndrome but it is not likely with current preparations. Demeclocycline induces nephrogenic diabetes insipidus and has been used to treat the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). All agents may aggravate preexisting azotemia. 4.4.6

Central Nervous System Reactions

Benign intracranial hypertension has been described with the tetracyclines and is reversible with drug discontinuation. Minocycline is commonly associated with vertigo, lightheadedness, dizziness and tinnitis and is reversible as well. 4.4.7

Superinfection

All tetracyclines can cause bacterial and/or fungal superinfection, including candidal vaginitis and less commonly C. difficile colitis.

5

QUINOLONES

Nalidixic acid, the first quinolone, was identified in 1962 among by-products of chloroquine synthesis. Rapid expansion of this class, however, did not occur until the 1980s with the addition of a fluorine group (hence the name fluoroquinolones) at the 6 position, as well as piperzinyl at C-7 to the 4-quinolone nucleus. These changes not only conferred an increased antibacterial spectrum but significantly enhanced the antimicrobial potency of this class of drugs. Quinolones have convenient dosages and are well tolerated but remain expensive (see Table 8). Related to the widespread use of the quinolones, resistance, especially to Pseudomonas and Staphylococcus species, has developed and is worsening.

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Chemical Properties, Mechanism of Action, and Bacterial Resistance

The basic structure of quinolones is a dual ring; derivatives of this structure account for the microbiological and pharmacokinetic differences between individual agents. Quinolones are bactericidal and initiate cell death by inhibition of bacterial deoxyribonucleic acid (DNA) synthesis. Specifically, they interfere with bacterial DNA gyrase that is responsible for twisting the DNA helix and topoisomerase IV, which separates daughter molecules of DNA after replication. These agents are concentration dependent with a modest postantibiotic effect. Bacterial resistance is mediated by one or more of three mechanisms: (1) alteration of the antibiotic target site (mutations of the DNA gyrase enzyme), (2) decreased permeability of the cell membrane to the drug, and (3) active efflux of the drug. Resistance to one member of the class usually, but not necessarily, implies resistance to all. 5.2

Clinical Pharmacological Properties

Oral absorption of quinolones yields peak serum levels in 1 to 3 hours (Table 6). All are well absorbed with bioavailability exceeding 50% for all agents in this class (and approaching 100% for several agents). Food does not significantly alter absorption; however, coadministration with aluminum-, magnesium-, or calcium-containing substances (antacids, zinc, iron, or vitamins with minerals) markedly reduces bioavailability, as does coadministration of sucralfate. Enteral feedings may also reduce absorption. Serum levels obtained through oral administration approximate those obtained with intravenous dosage. Drug binding to serum proteins is generally low, but the significance for clinical practice is unclear. In general, quinolones have a high volume of distribution with probably some drug accumulation in tissue. Concentrations in prostate, stool, lung, bile and neutrophils and macrophages exceed serum concentrations. Concentrations in urine and kidney are generally high as well. Saliva, prostatic fluid, and bone levels are lower than serum levels but remain adequate for effective therapy. Penetration into the CNS is variable, with concentrations potentially much lower than those of serum. Penetration into ascitic fluid (in the setting of hepatic failure) has been documented for ofloxacin. Nalidixic acid and moxifloxacin do not require dosage modification in renal insufficiency, but the rest of the agents in this class generally do require some dosage changes in this setting (Table 7). 5.3

5.3.1

Spectrum of Activity and Clinical Indications (Nalidixic Acid, Cinoxacin, Ciprofloxacin, Enoxacin, Norfloxacin, Ofloxacin, Levofloxacin, Gatifloxacin, Moxifloxacin) First- and Second-Generation Quinolones

The nonfluorinated so-called first- and second-generation quinolones include nalidixic acid and cinoxacin. These drugs share activity against Enterobacteriaceae, particularly against E. coli, Proteus species, and Klebsiella species and other selected gram-negative organisms, including H. influenzae, M. catarrhalis, and Neisseria species. These agents lack activity against gram-positive and anaerobic organisms as well as P. aeruginosa. Traditionally used for urinary tract and N. gonorrhoeae infections, they hold no advantage over other antibiotic classes, and because of increasing antimicrobial resistance and an increased incidence of adverse effects, they should not be a first choice for genitourinary infections.

Commonly Used Oral Antibiotics

5.3.2

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Fluoroquinolones

The fluoroquinolones encompass the remaining agents of this class and generally have an enhanced spectrum of activity against gram-negative organisms, particularly Enterobacteriaceae, Haemophilus species, and gram-negative cocci, when compared to the nonfluorinated quinolones (Table 10). Activity against atypical organisms, including Chlamydia, Mycoplasma, and Legionella species, is also very good. Gram-positive activity is variable and dependent on the specific agent. Characteristically, penicillin-resistant pneumococci may remain susceptible to the fluoroquinolones, but methicillin-resistant staphylococci are almost uniformly fluoroquinolone-resistant. The First Wave of Fluoroquinolones. Ciprofloxacin, enoxacin, lomefloxacin, and norfloxacin, including ofloxacin and levofloxacin, have excellent gram-negative organism activity and moderate activity against gram-positive organisms (variable activity against streptococci) but lack activity against anaerobes. Ciprofloxacin is the most active fluoroquinolone against gram-negative organisms (including P. aeruginosa); ofloxacin has somewhat better gram-positive activity than other agents in this group. Levofloxacin is the L-enantiomer of ofloxacin, which possesses all of the useful antibacterial activity of the racemic mixture. Levofloxacin offers increased gram-positive activity, particularly against streptococci, including penicillin-resistant S. pneumoniae, and some enterococci, with preserved gram-negative activity. However, activity against P. aeruginosa and anaerobes is still not enhanced enough to make this agent clinically useful in treatment of these infections. The Advanced-Generation Fluoroquinolones. The advanced-generation fluoroquinolones include gatifloxacin, moxifloxacin, temefloxacin, trovafloxacin, grepafloxacin, and sparfloxacin. They possess enhanced gram-positive activity, preserved gram-negative activity, clinically significant anaerobic activity, and perhaps enhanced activity against atypical organisms as well (Table 10). Rare, but serious toxicities have caused several of these drugs to be removed from the market or have seriously limited their clinical use: sparfloxacin (phototoxicity), trovafloxacin (hepatotoxicity), grepafloxacin (cardiac arrhythmias), and temefloxacin (hemolytic-uremic syndrome). The remaining and newest agents are 8-methoxy quinolones, gatifloxacin and moxifloxacin. It is hoped that these agents will be as well tolerated as they appear to be therapeutically useful. Moxifloxacin and gatifloxacin are active against anaerobes, including most Bacteroides species; moxifloxacin does not have activity against B. uniformis and B. thetaiotamicrons. They are not as active as ciprofloxacin (and similar fluoroquinolones) against gram-negative organisms, especially in regard to P. aeruginosa. Activity against S. pneumoniae, including penicillin-resistant strains, is excellent and superior to that of the older quinolones, including levofloxacin. Activity is retained against atypical agents such as Legionella, Chlamydia, and Mycoplasma species, as well as the Enterobacteriaceae. There is enhanced activity against methicillin-sensitive S. aureus strains, though they remain fairly resistant. Traditionally, quinolones have demonstrated great success in the treatment of genitourinary infections, including pyelonephritis, prostatitis, and sexually transmitted diseases (N. gonorrhoeae, C. trachomatis, and H. ducreyi but no activity against T. pallidum), bacterial gastrointestinal infections (Shigella and Salmonella species, enterotoxigenic E. coli, C. jejuni), peritonitis, respiratory tract infections, and uncomplicated skin, soft tissue, and bone and joint infections. Gatifloxacin may be preferred for urinary tract infections because of its higher degree of urinary excretion and the availability of an intravenous

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preparation. Norfloxacin is indicated only for uncomplicated urinary tract infections as it does not achieve serum levels adequate to treat systemic infections. For empirical gramnegative coverage ciprofloxacin is likely the most appropriate choice (often in combination with another agent), especially when P. aeruginosa infection is suspected. For empirical therapy of suspected penicillin-resistant S. pneumoniae, polymicrobic and/or anaerobic organisms, or atypical pathogens, particularly in the setting of community-acquired pneumonia, the newer 8-methoxy quinolones (gatifloxacin and moxifloxacin) may be ideal. It should be noted, however, that because of their cost and the availability of less expensive and more narrow-spectrum agents, these agents should be carefully selected on the basis of the suspected pathogen(s), the site of infection, and the results of a thorough diagnostic evaluation. Similarly, one may want to consider the trade-offs of enhanced in vitro activity of the newer quinolones versus unknown safety issues. Drugs with known track records of safety (oral penicillins, cephalosporins, and even ciprofloxacin) may be preferred until more information is available. 5.4 5.4.1

Adverse Reactions (Table 12) Hypersensitivity Reactions

Allergic reactions have been reported with all quinolones but are uncommon. Unspecified rashes appear to be most common. Drug fever, angioedema, vasculitis-like syndromes, serum sicknesslike syndromes, and anaphylactoid reactions have been reported. 5.4.2

Bone and Joint Reactions

Juvenile animal studies have documented arthropathy with cartilage erosions and noninflammatory effusions in weight bearing joints. The human adult experience has been limited to rare occurrences of tendinitis with tendon rupture in association with quinolone use. Quinolones are generally not recommended for children less than 8 years of age. Limited use of quinolones in special populations (e.g., cystic fibrosis patients) has been uncommonly associated with reversible joint symptoms. 5.4.3

Cardiovascular Reactions

Prolongation of the QT interval has been observed with moxifloxacin but not with gatifloxacin. Serious arrhythmias have not been encountered, but it is recommended that class IA (quinadine, procainamide, and disopyramide) and III (amiodarone and sotolol) antiarrhythmic agents not be used (or be used with extreme caution) for patients receiving quinolones. 5.4.4

Gastrointestinal Reactions

Gastrointestinal disturbances, including anorexia, nausea, vomiting, abdominal discomfort, and an unpleasant taste, are commonly reported. Adverse effects are often associated with increasing dosages and duration of therapy. Diarrhea does occur but with much less frequency than with other antimicrobials. 5.4.5

Hematological Reactions

Leukopenia, thrombocytopenia, and pancytopenia have been reported but are rare, as is eosinophilia. Cases of hemolytic anemia have also been associated with quinolone use, with renal failure, and with coagulopathy but are extremely rare.

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Table 12 Adverse Reactions to Oral Quinolones Allergic Anaphylactoid reactions Angioedema Drug fever Rash Serum sickness–like reactions Vasculitis-like reactions Bone and joint Tendonitis or tendon rupture (rare) Cardiovascular QT prolongation with ventricular tachycardia (moxifloxacin) Gastrointestinal Nausea, dyspepsia Diarrhea Hematological Hemolytic anemia Leukopenia Pancytopenia Thrombocytopenia Neurological Dizziness Headaches Insomnia Mood alterations Seizures Renal Interstitial nephritis Skin Photosensitivity Superinfection Vaginitis Colitis

5.4.6

Central Nervous System Reactions

Mild headaches, dizziness, insomnia, and mood alterations have been reported in up to 11% of patients receiving quinolones. Hallucinations, delirium, and seizures have been reported, but are rare. The risk of seizures is increased in the setting of theophylline accumulation (except lomefloxacin) and the concomitant use of nonsteroidal antiinflammatory agents. 5.4.7

Renal Reactions

Renal toxicity from quinolone use is uncommon, but acute interstitial nephritis (allergic in origin) has been reported. Associated eosinophilia with urine eosinophils is sometimes seen, but crystalluria is rare. 5.4.8

Skin Reactions

Photosensitivity reactions have been reported with all quinolones but appear more common in patients receiving lomefloxacin and sparfloxacin.

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SULFONAMIDES AND TRIMETHOPRIM

The sulfonamides were the first antimicrobials available for clinical use in the United States, used as far back as 1935. Today, sulfonamides are infrequently used alone, because of the emergence of resistance and availability of more efficacious and better tolerated antibiotics. Trimethoprim was first studied in the 1950s and was found to be synergistic with sulfonamides in 1968. Efficacious for genitourinary infections when used alone, trimethoprim is now most commonly used as part of a fixed dose combination with sulfamethoxazole in a preparation called co-trimoxazole. 6.1

Chemical Properties, Mechanism of Action, and Bacterial Resistance

Sulfonamides are similar in structure to para-aminobenzoic acid (PABA), whereas trimethoprim is a diaminopyrimidine. Both inhibit microbial folic acid synthesis, and the combination synergistically inhibits bacterial purine, thymidine, and DNA biosynthesis. Bacterial resistance is mediated by one of four mechanisms: (1) microbial overproduction of PABA, (2) structural change of the target enzyme(s) that results in decreased affinity for the antibiotic, (3) decreased cell permeability to the antibiotic, and (4) rarely, development of mutants (auxotrophs) that can utilize exogenous thymidine. 6.2

Clinical Pharmacological Properties

Sulfamethoxazole and trimethoprim are absorbed readily and almost completely from the upper gastrointestinal tract with peak levels in 1 to 4 hours (Table 6). Coadministration (as co-trimoxazole) does not affect the absorption of either drug; it is prepared as a fixed dose combination in a ratio of one part trimethoprim to five parts sulfamethoxazole. For purposes of bacterial synergy, the fixed dose 1:5 ratio of trimethoprim/sulfamethoxazole is designed to affect a 1:20 ratio in the serum after intravenous or oral administration. Cotrimoxazole may be taken with or without food, and serum levels achieved with oral administration compare very favorably with those achieved with intravenous dosing. Protein binding is moderate (actually may vary) but is reversible. Importantly, protein binding of co-trimoxazole may displace other compounds, notably bilirubin, and may lead to toxic levels in newborns. Co-trimoxazole is widely distributed in tissue with concentrations exceeding those of plasma in lung, kidney, and sputum. Genitourinary levels, including prostate levels, may approach two to three times those of serum; however, lower levels are seen in chronic prostatitis. Good levels are also seen in bile, human breast milk, seminal fluid, and synovial, pleural, and peritoneal fluids. CSF penetration is adequate, with levels approximately 40% those of serum. Excretion is primarily via renal tubular secretion with some excretion in the bile (Table 7). Dosage modification is necessary in the presence of moderate to severe renal insufficiency. Co-trimoxazole should be avoided by patients with a creatinine clearance of 15 ml/minute or less. 6.3

Oral Co-trimoxazole: Spectrum of Activity and Clinical Indications

Co-trimoxazole has a broad spectrum of activity but lacks clinically significant activity against gram-positive and gram-negative anaerobes as well as P. aeruginosa (Table 10). It remains active against many gram-positive organisms, including streptococci, L. monocytogenes, and methicillin-sensitive and a number of methicillin-resistant staphylo-

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cocci. Activity also extends to S. pneumoniae, but up to 40% of isolates may be resistant. Activity against enterococci may vary and is clinically unpredictable. Co-trimoxazole has activity against gram-negative organisms, including gram-negative cocci and most Enterobacteriaceae, including Salmonella and Shigella species, but susceptibility testing should be used to guide therapy whenever possible as resistance is widespread, may vary from year to year, and is highly dependent on geographical location. Co-trimoxazole is active against Stenotrophomonas maltophilia and Burkholderia species but not against most Pseudomonas species. A number of atypical organisms, including Chlamydia, Actinomyces, and Nocardia species, as well as P. carinii, are also susceptible to co-trimoxazole. Clinically, co-trimoxazole has traditionally been used for the treatment of genitourinary tract infections and is efficacious for cystitis, pyelonephritis, prostatitis, orchitis, and epididymitis (for susceptible organisms) (Table 10). Although either sulfamethoxazole or trimethoprim may also be used alone in the treatment of cystitis, trimethoprim remains the preferred agent of the two because of its lower incidence of adverse events when compared to that of sulfa containing regimens. In addition, co-trimoxazole has been found to be beneficial in the treatment of recurrent and chronic urinary tract infections in adults. Co-trimoxazole can also be used for episodes of otitis media and externa, sinusitis, acute bronchitis, exacerbations of chronic bronchitis, and pneumonia, although it is not the first choice for any single respiratory pathogen. Its diminished activity against S. pneumoniae makes it a poor choice for empirical therapy of community-acquired pneumonia. Other indications have included bacterial diarrhea and uncomplicated gonorrhea, chlamydia, and chancroid, but empirical therapy for these pathogens with co-trimoxazole should be undertaken with caution as resistance is increasing. Co-trimoxazole can be useful for acute and chronic osteomyelitis, but again, such therapy must be guided by antimicrobial susceptibilities. Co-trimoxazole is also useful in the treatment of P. carinii pneumonia and nocardiosis and in combination therapy for brucellosis, biliary tract infections, and periodontal infections. It is very effective prophylaxis for P. carinii pneumonia in HIV infected patients and in other patients undergoing therapeutic immunosuppression. Curiously, it may cause prolonged disease-free remissions in selected patients with Wegener’s granulomatosis. 6.4 6.4.1

Adverse Reactions to Co-trimoxazole (Table 13) Allergic Reactions

Fever, hypersensitivity syndromes, drug eruptions, and rash remain the most significant and common adverse reactions and may complicate therapy in up to one-third of patients. In immunocompromised patients such as HIV-infected individuals, their occurrence may even be greater. More severe reactions have also been reported, including anaphylaxis, erythema nodosum, erythema multiforme, and vasculitis-like syndromes. Fortunately, most syndromes are reversible on drug discontinuation. 6.4.2

Central Nervous System Reactions

Uncommonly, headaches and depressive and psychotic symptoms have been reported. Cotrimoxazole is a well-known cause of aseptic meningitis. Associated peripheral neuropathy has been reported. 6.4.3

Gastrointestinal Reactions

Nausea, vomiting, dyspepsia, altered taste, and diarrhea are not uncommon. Pancreatitis has been associated with co-trimoxazole but is rare.

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Table 13 Adverse Reactions to Oral Cotrimoxazole Hypersensitivity syndromes Erythema nodosum Fever Rash (very common) Serum sickness–like syndrome Vasculitis-like syndrome Gastrointestinal Altered taste Diarrhea Nausea, dyspepsia Pancreatitis Hematological Agranulocytosis Aplastic anemia Hemolytic anemia Megaloblastic anemia Leukopenia Pancytopenia Thrombocytopenia Hepatic Elevated aminotransferase levels Hepatic necrosis Hyperbilirubinemia Kernicterus Neurological Aseptic meningitis Depression Headaches Peripheral neuropathy Psychosis Renal Artifactual serum creatinine level elevation Crystalluria (very rare) Hyperkalemia Interstitial nephritis Tubular necrosis Skin Photosensitivity Superinfection Vaginitis Colitis

6.4.4

Hematological Reactions

Leukopenia is common but reversible on drug discontinuation. Megaloblastic anemia, thrombocytopenia, and rarely agranulocytosis and aplastic anemia can also occur. Hemolytic anemia can be precipitated more commonly in the setting of glucose 6-phosphate dehydrogenase deficiency.

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Hepatic Reactions

The spectrum of adverse effects includes isolated elevation of aminotransferase levels to hyperbilirubinemia to hepatic necrosis. Further, co-trimoxazole should not be used in the third trimester of pregnancy as competition for bilirubin binding sites on albumin may precipitate kernicterus. 6.4.6

Renal Reactions

Acute interstitial nephritis, tubular necrosis, and necrotizing angiitis can all occur, but tubular deposits of sulfonamide crystals (resulting in crystalluria) are generally not seen with newer preparations (except in the setting of hemodialysis). As a result of tubular secretion of co-trimoxazole, artifactual elevation of serum creatinine level may also occur. Hyperkalemia may occur with increasing dosage, as trimethoprim may inhibit distal tubular potassium excretion. 6.4.7

Superinfection

Co-trimoxazole can result in bacterial and/or fungal superinfection, including candidal vaginitis and C. difficile colitis.

7

METRONIDAZOLE

Introduced in 1959, metronidazole is the most active drug available against anaerobic organisms and selected parasites. It has no activity against aerobic organisms. It is bactericidal with excellent tissue penetration. In general metronidazole is well tolerated. 7.1

Chemical Properties, Mechanism of Action, and Bacterial Resistance

Metronidazole is a nitroimidazole. Intracellularly, this drug is converted to toxic metabolites and free radicals that result in bacterial killing. The generation of toxic intermediates from metronidazole requires a low redox potential, hence its exclusive activity against anaerobic organisms. Bacterial resistance is mediated by one of three mechanisms: (1) intrinsic resistance (i.e., aerobic organisms), (2) decreased uptake into the cell, and (3) decreased intracellular reduction of the drug. 7.2

Clinical Pharmocological Properties

Oral absorption is excellent and rapid, yielding peak serum levels in 1 to 2 hours (Table 6). Concomitant food intake delays but does not decrease absorption. Metronidazole has very little protein binding. Peak serum levels after oral dosage are similar to those achieved with parenteral dosage. Rectal absorption is also very good. Tissue distribution is excellent with therapeutic levels achieved intracellularly and in most tissues and fluids, including bone, cerebrospinal fluid, biliary tree, peritoneal fluid, pelvic tissues and fluids, colonic mucosa, and saliva. Abscess penetration is excellent. Intraocular levels are about 50% of serum levels. Although the metabolites of metronidazole are primarily eliminated in the urine, dosage modification is unnecessary in the presence of renal disease or in the setting of chronic ambulatory peritoneal dialysis (Table 7). Metronidazole is rapidly removed with hemodialysis. Dosage modification, however, is required in the presence of hepatic disease.

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Oral Metronidazole: Spectrum of Activity and Clinical Indications

Metronidazole is active against most anaerobic gram-positive and -negative bacteria and has slightly less activity against anaerobic gram-positive cocci (Table 10). Most Actinomyces and Propionibacterium species are not susceptible to metronidazole. It lacks clinically significant activity against most aerobic organisms. It is as active as oral vancomycin against Clostridium difficile and useful against Helicobacter pylori in combination therapy. The parasites Trichomonas vaginalis, Giardia lamblia, and Entamoeba histolytica are also susceptible to metronidazole. Metronidazole is indicated for most anaerobic infections, including those of the gastrointestinal tract (used in combination with a GNR agent) bone, joints, central nervous system (although oral administration may not be appropriate as initial therapy), oral cavity, head and neck, and soft tissues (Table 8). It is very effective in the treatment of C. difficile colitis and bacterial overgrowth syndromes as well. Because of its variable activity against gram-positive anaerobes, metronidazole is not ideal for anaerobic infections of the lower respiratory tree. It remains the treatment of choice for trichomoniasis, giardiasis, and amebiasis. 7.4 7.4.1

Adverse Reactions to Metronidazole (Table 14) Central Nervous System Reactions

The most serious reactions to metronidazole include seizures and encephalopathy, necessitating cautious use in seizure or other central nervous system disorders. Peripheral neuropathy is generally seen with prolonged use and, although reversible, may persist for prolonged periods. Other CNS reactions include cerebellar dysfunction and ataxia, mood disorders (including depression), dizziness, psychotic reactions, insomnia, headache, and confusion. Patients should be warned about the potential for a disulfiram-like reaction if metronidazole is used concurrently with ethanol. 7.4.2

Endocrine Reactions

Gynecomastia has rarely been associated with metronidazole. 7.4.3

Gastrointestinal Reactions

Nausea, vomiting, metallic taste, anorexia, dry mouth, and dyspepsia are by far the most common adverse reactions. Diarrhea is not uncommon. Furring tongue, glossitis, stomatitis, and pancreatitis have also uncommonly been reported. 7.4.4

Hematological Reactions

Neutropenia has been uncommonly reported but is reversible on drug discontinuation. 7.4.5

Hypersensitivity Reactions

A variety of reactions have been reported but are generally uncommon. Maculopapular and fixed drug rashes are most common; urticaria, pustular eruptions, and fever are known to occur. 7.4.6

Superinfection

Metronidazole can result in bacterial and/or fungal superinfection, including candidal vaginitis, and, very rarely, C. difficile colitis.

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Table 14 Adverse Reactions to Oral Metronidazole Central nervous system Ataxia Confusion Disulfiram-like reaction Dizziness Encephalopathy Headache Insomnia Mood disorders Seizures Psychotic reaction Endocrine Gynecomastia (rare) Gastrointestinal Altered/metallic taste Anorexia Diarrhea Glossitis/stomatitis Nonspecific (e.g., nausea, dyspepsia) Pancreatitis Hematological Neutropenia Hypersensitivity Fever Rash (multiple types) Urticaria

8

OXAZOLIDINONES

First reported in 1987, the oxazolidinones are a new, completely synthetic class of antibiotics that includes just one available agent, linezolid, which was approved for use in the fall of 2000. It was designed in response to the emergence of multidrug-resistant grampositive organisms, including S. aureus, S. epidermidis, S. pneumoniae, and Enterococcus species. Linezolid is a bacteriostatic agent (excepting streptococci, for which it is bactericidal) that acts uniquely through the inhibition of the formation of the ribosomal initiation complex of bacterial protein synthesis. Because of this novel mechanism of action, there is no cross-resistance with other antimicrobial classes. In fact, it has been difficult to generate linezolid-resistant strains in the laboratory, and clinical resistance has arisen only rarely and only in the most difficult clinical situations (unremoved joint prostheses, infection with enterococci). 8.1

Clinical Pharmacological Properties

Available for oral administration, linezolid is rapidly absorbed and its bioavailability approaches 100% with serum levels similar to those achieved with parenteral dosage. Food may delay but does not decrease absorption. In addition, the oral and parenteral dose and schedule are identical (i.e., 600 mg bid). Tissue distribution is excellent and there is little

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protein binding. Elimination is primarily nonrenal, and dosage modification is not required in the presence of renal insufficiency or dialysis. 8.2

Spectrum of Activity and Clinical Indications

Designed for the treatment of infections due to multidrug-resistant gram-positive organisms, linezolid remains active against methicillin-resistant staphylococci, penicillin/cephalosporin-resistant pneumococci, and vancomycin-resistant enterococci, as well as antibiotic-susceptible gram-positive aerobic and anaerobic organisms. It lacks clinically significant activity against gram-negative organisms. Although linezolid has been shown to be efficacious in the setting of pneumonia, bacteremia, and skin and soft tissue infections, its exact place in therapy is not yet clear. It is extremely expensive. A 10-day course would cost approximately $800.00, priced near the cost of a intravenous vancomycin. As it is a recently introduced agent, clinical experience is limited. Its use should be reserved for infections due to multidrug-resistant grampositive organisms when there is a lack of other viable treatment options or there are major problems with or complications due to prolonged vascular access. 8.3

Adverse Reactions

Clinically, linezolid appears well tolerated and safe. The most serious adverse effects appear to be reversible thrombocytopenia and treatment-related hypertension. Headache, nausea and diarrhea, dyspepsia, tongue discoloration, and abdominal pain are not uncommon. Elevation of hepatic enzyme levels and rash have been reported. Superinfection, including candida vaginitis or C. difficile colitis, may also occur. Linezolid is a mild monoamine oxidase inhibitor. Patients should avoid eating large quantities of foods that contain tyramine (alcohol, anchovies, avocados, bananas, bean curd, cheese, fava beans, ginseng, liver, peanuts, raisins, sardines, sauerkraut, snails, sour cream, soy sauce, yogurt) and concomitant administration of adrenergic or serotonergic agents (clomipramine, cyclobenzaprine, desipramine, imipramine, amitriptyline, doxepin, ephedrine, maprotiline, methyldopa, pargyline, pergolide, perphenazine, trazadone, and trimipramine). Caution should be observed in administration of meperidine, other narcotics, and over-the-counter cold remedies as increases in blood pressure have been associated with coadministration of linezolid and phenylpropanolamine. BIBLIOGRAPHY Oral Antibiotics and Resistance Carrie AG, Zhanel GG. Antibacterial use in community practice: Assessing quantity, indications, and appropriateness and relationship to the development of antibacterial resistance. Drugs 57(6):871, 1999. The choice of antimicrobial drugs. Med Lett Drugs Ther 41:95, 1999. MacGregor RR, Graziani AL. Oral administration of antibiotics: A rational alternative to the parenteral route. Clin Infect Dis 24:457, 1997. Virk A, Butler CC. Clinical aspects of antimicrobial resistance. Mayo Clin Proc 75:200, 2000. Penicillins and Cephalosporins Holten KB, Onusko EM. Appropriate prescribing of oral beta-lactam antibiotics. Am Fam Physician 62(3):611, 2000. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc 74:187, 1999.

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O’Leary MR, Smith MS. Penicillin anaphylaxis. Am J Emerg Med 4(3):241, 1986. Wright AJ. The penicillins. Mayo Clin Proc 74(3):290, 1999. Tetracyclines Joshi N, Miller DQ. Doxycycline revisited. Arch Intern Med 157:1421, 1997. Smilack JD. The tetracyclines. Mayo Clin Proc 74:727, 1999. Macrolides Alvarez-Elcoro S, Enzler MJ. The macrolides: Erythromycin, clarithromycin, and azithromycin. Mayo Clin Proc 74:613, 1999. Clarithromycin and azithromycin. Med Lett Drugs Ther 34:45, 1992. Piscitelli SC, Danziger LH, Rodvold KA. Clarithromycin and azithromycin: New macrolide antibiotics. Clin Pharmacokinet 11:137, 1992. Fluoroquinolones Gatifloxacin and moxifloxacin: two new fluoroquinolones. Med Lett Drugs Ther 42:1, 2000. Hooper DC. New uses for new and old quinolones and the challenge of resistance. Clin Infect Dis 30:243, 2000. Walker RC. The fluoroquinolones. Mayo Clin Proc 74:1030, 1999. Clindamycin and Metronidazole Falagas ME, Gorbach SL. Clindamycin and metronidazole. Med Clin North Am 79(4):845, 1995. Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc 74:825, 1999. Trimethoprim and Sulfamethoxazole Clark AJL, Mauchizadeh J, Faunch R, et al. Trimethoprim alone. Lancet 1:1030, 1980. Cockerill FR III, Edson RS. Trimethoprim-sulfamethoxazole. Mayo Clin Proc 66:1260, 1991. Oxazolidinones Chien JW, Kucia ML, Salata RA. Use of linezolid, an oxazolidinone, in the treatment of multi-drug resistant Gram-positive bacterial infections. Clin Infect Dis 30:146, 2000. Clement D, Markham A. Linezolid. Drugs 59(4):815, 2000. Diekema DJ, Jones RN. Oxazolidinones—a review. Drugs 59(1):7, 2000. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

4 Pharmacokinetics and Dynamics John W. Ahern Fletcher Allen Health Care, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Pharmacokinetics and pharmacodynamics are two subdivisions of pharmacology that are utilized to design drug dosage regimens. Pharmacokinetics describes how drug concentrations change as a function of time. Pharmacokinetics serves as a tool that enables the clinician to develop a dosage regimen of a given magnitude and frequency that will produce a desired biological fluid concentration. Pharmacodynamics examines the relationship between antimicrobial concentrations in biological fluids and the resulting effect on microorganisms. Pharmacodynamic principles guide the clinician in determining desired biological fluid concentrations. Pharmacokinetics can then be applied to achieve these desired concentrations. An understanding of pharmacokinetic and pharmacodynamic principles provides the clinician with a rational approach to the antimicrobial dosage. PHARMACOKINETICS AND PHARMACODYNAMICS Pharmacokinetics Determines how drug concentrations change with time Drug volume of distribution (Vd), clearance (CL), and half-life (T1/2) determine how much drug should be given and how often Pharmacodynamics Determines the relationship between antimicrobial concentration and biological effect on the microorganism Determines desired biological fluid concentration Steady state Drug concentration at which the rate of drug administration equals the rate of elimination Concetrations reached after approximately 4–5 half-lives of drug (see Figure 1) Antibiotics can be concentration-dependent (see Figure 2A, 2C) Higher peak levels above minimal inhibitory concentration yield higher drug activity Aminoglycosides, fluoroquinolones (see Figure 3) Antibiotics can be concentration-independent (see Figure 2B, 2C) The more time the antibiotic is above the MIC the greater the effect ␤-Lactams, vancomycin, macrolides, clindamycin (see Figure 4)

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PHARMACOKINETICS

When a dose of a drug is administered to a patient, a serum concentration is produced. This serum concentration does not remain static but decreases over time as the drug is eliminated from the body. If it is desired to maintain the serum drug concentration within a specified range, a subsequent dose must be administered to replace the drug that has been eliminated. To know when to administer a subsequent dose, it is important to understand the magnitude of the serum concentrations that are obtained after the dose as well as the rapidity with which these concentrations decline over time. Pharmacokinetic parameters such as volume of distribution (Vd), clearance (CL), and half-life (T1/2) are used together to determine how much drug should be given and how frequently it should be administered. 2.1

Volume of Distribution

The volume of distribution (Vd) is the apparent volume into which a particular dose of a drug appears to dissolve. It is referred to as apparent because the Vd is not a real physiological volume but rather a tool to compare drug concentration to the total amount of drug in the patient. Mathematically, the apparent Vd can be expressed as follows: Vd =

Dose Cp

In the expression, dose represents the amount of drug that is present in the body. Cp represents the plasma concentration obtained immediately after the dose. For example, if a 100-mg dose of gentamicin produces a plasma concentration of 5 mg/L, the apparent volume of distribution is 20 L: 20 L = 100 mg ⫼ 5 mg/L. The apparent volume of 20 L does not represent an actual anatomical volume, but the apparent fluid volume that is necessary to contain the entire drug dose at the same concentration as is found in the plasma. The apparent Vd is used to characterize the extent of drug distribution throughout the body. A drug with a small Vd may remain primarily confined to the vascular space. In contrast, a drug with a large Vd may leave the vascular space and undergo extensive tissue distribution. In clinical practice the apparent Vd is used to calculate the magnitude of drug doses. 2.2

Clearance

Clearance (CL) represents the volume of plasma from which drug can be cleared or removed per unit of time. Clearance is expressed in units of volume/time (L/hr or ml/min). Clearance represents the intrinsic capacity of an organ (kidney or liver) to remove drug from plasma. Total body clearance represents a summation of the individual clearances of eliminating organs. This is expressed as follows: CLtotal body = CLrenal ⫹ CLhepatic ⫹ CLother CLother refers to all other routes (i.e., lungs, sweat, bile) of clearance. As an example, the total body clearance of gentamicin is nearly 100% renal. As a result, CLtotal body of gentamicin can be expressed as CLtotal body = CLrenal, where renal clearance represents creatinine clearance. Thus, in renal impairment, the clearance of gentamicin is reduced, with the potential to cause accumulation of the drug. In clinical practice, clearance is used to determine the frequency of drug administration. This is applied to the calculation of maintenance dosing.

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Half-Life

The half-life (T1/2) represents the time required for a drug concentration to decrease by 50%. For example, if the concentration of a drug declines from 20 mg/L to 10 mg/L over 2 hours, then the drug half-life is 2 hours. In clinical practice, T1/2 is used to calculate when steady state will be achieved during a drug dosage regimen. Steady state occurs when the rate of drug administration equals the rate of drug elimination. When this occurs, the drug is no longer accumulating within the body. (see Figure 1). The time required to reach steady state on a drug dosage regimen is dependent on the T1/2 of the drug. A steady state is considered to occur after 4–5 half-lives of the drug. In general, plasma drug concentrations should be obtained after the steady state is achieved. If plasma drug concentrations are obtained prior to the steady state, the clinician must be aware that the drug concentrations will continue to rise until steady state is achieved. The T1/2 may also be used to calculate the time required to eliminate the entire dose of a drug from the body. This is considered to occur after 5–7 half-lives. 2.4

Relationships Among Vd, CL, and T1/2

The relationships among T1/2, clearance, and volume of distribution can be expressed by using the following equation for any drug that is eliminated by a first-order process: T1/2 =

0.693 ⫻ Vd CL

In first-order elimination the rate of drug elimination is proportional to the amount of drug that is present within the body. Antibiotics are generally eliminated by first-order kinetics. From the preceding equation it can be seen that Vd and CL determine the T1/2 of a drug. If Vd increases but CL

Figure 1 Steady state. A concentration versus time profile that represents drug administration by multiple intravenous doses. Peak concentrations occur after the antibiotic dose. Trough concentrations result from drug elimination that occurs before the next antibiotic dose. The initial upward slope of the curve represents increasing drug concentrations as a result of accumulation from repeated drug doses. This process continues until the rate of drug elimination equals the rate of drug administration. When this occurs, drug concentrations plateau, resulting in steady state. The steady state takes 4–5 half-lives of the drug.

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remains the same, T1/2 increases. Conversely, if CL increases but Vd remains the same, T1/2 decreases. 2.5

Application of Pharmacokinetic Concepts to Antibiotic Dosage

The dosage regimens that are recommended for antimicrobials are based on the plasma concentration of the antibiotic compared with the minimal concentration of the antimicrobial that is needed to inhibit bacterial growth. This is known as the minimal inhibitory concentration (MIC). To understand how this information can be applied to the design of an antibiotic dosage regimen, consider the following example using cefazolin, a first-generation cephalosporin, administered intravenously. After a 1-gram intravenous dose, the usual peak plasma concentration for cefazolin is 180 ␮g/ml. If a pathogen has a cefazolin MIC of 8 ␮g/ml, what is the longest frequency that the cefazolin could be administered to ensure that plasma concentrations remain above the MIC for an entire dosage interval? With a half-life of 2 hours, the peak level of 180 ␮g/ml decreases by 50% every 2 hours. At the end of 4 half-lives or 8 hours, the concentration is 11 ␮g/ml. Thus, for this pathogen with a cefazolin MIC of 8 ␮g/ml, a cefazolin dosage regimen of 1 gram q8h maintains concentrations above the MIC for the entire dosage interval. For antimicrobials such as aminoglycosides and vancomycin an appropriate dosage interval is important to prevent high drug concentrations that increase the risk of toxicities. For example, usual peak plasma concentrations achieved with multiple daily doses of gentamicin (1.5 mg/kg) are 5–10 ␮g/ml. It is generally recommended that trough concentrations be maintained at less than 2 ␮g/ml. The usual T1/2 for gentamicin in patients with normal renal function is 2–4 hours. If a gentamicin dosage regimen is producing a peak level of 6 ␮g/ml, at least 2 T1/2 (4–8 hours) is required before the trough concentration decreases to <2 ␮g/ml. If the gentamicin T1/2 is 4 hours, a dosage interval of at least 8 hours (2 half-lives) is needed to produce a trough of <2 ␮g/ml; the calculated trough is 1.5 ␮g/ml. For vancomycin, trough levels of 5–20 ␮g/ml are generally considered adequate for the management of infections due to gram-positive microorganisms. For adult patients with normal renal function, a vancomycin dosage regimen of 15 mg/kg every 12 hours is frequently recommended. The basis for this recommendation can be seen when the pharmacokinetics of vancomycin are considered. A 15-mg/kg dose typically produces vancomycin peak levels in the range of 30–40 ␮g/ml. The half-life of vancomycin in adults with normal renal function is approximately 8 hours. If a peak level of 30 ␮g/ml is obtained and an 8-hour half-life is assumed, it can be seen that with a dosage interval of 12 hours (1.5 half-lives) the resulting trough level is 11 ␮g/ml. In this example, the peak level of 30 ␮g/ml decreases by 50% to 15 ␮g/ml in 8 hours (1 half-life) followed by 25% (1/2 half-life) to 11 ␮g/ml in the remaining 4 hours of the dosage interval. Similarly, with a peak level of 40 ␮g/ml, a trough level of 15 ␮g/ml is produced if an 8-hour half-life is assumed with a 12-hour dosage interval. 3

PHARMACODYNAMICS

Many factors contribute to the development of antimicrobial resistance. Antimicrobial dosage regimens that expose microorganisms to subtherapeutic antibiotic concentrations are a leading risk factor. An understanding of antimicrobial pharmacodynamics enhances the ability of the clinician to establish optimal antimicrobial dosage. Appropriate dosage

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of antibiotics can improve therapeutic outcomes as well as reduce the potential for the emergence of bacterial resistance. 3.1

General Concepts

Antimicrobial pharmacodynamics examines the effect of antibiotic concentrations on microorganisms. Antibiotics may inhibit growth (bacteriostatic drugs) or kill bacteria (bactericidal drugs). In general, antimicrobials that interfere with cell wall synthesis are bactericidal. Antimicrobials that interfere with metabolic pathways or protein synthesis may be either bacteriostatic or bactericidal. Antimicrobial concentration at the site of action may also determine the bacteriostatic or bactericidal activity of the drug. Antimicrobials may be bacteriostatic at low drug concentrations but bactericidal at high concentrations. An additional factor that determines whether an antimicrobial is bacteriostatic or bactericidal is the bacterial species. Penicillin is bactericidal for most streptococci, but it is bacteriotatic against enterococci. Chloramphenicol is generally bacteriostatic, but it may exert bactericidal activity against Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. Table 1 categorizes commonly used antimicrobials as those generally considered bacteriostatic and those usually considered bactericidal. Antimicrobials are frequently given in combination to treat infections. Reasons for using combination therapy include treatment of severe or life threatening infections, empirical therapy when the pathogen is unknown, avoidance of resistance, and desire for synergistic activity. Synergy is observed when the activity of two antimicrobials given in combination is greater than the sum of the activities of each agent given individually. Examples of synergistic therapies include combination of ␤-lactams with aminoglycosides for treatment of infections caused by Pseudomonas or Enterococcus spp. With combination therapy, antagonism can be observed when one antimicrobial reduces the antibacterial activity of the other antimicrobial. For example, ␤-lactams primarily exert bactericidal activity against microorganisms that are in the growth phase. When ␤-lactams are administered with bacteriostatic agents such as tetracyclines, the bactericidal activity of the ␤lactam is antagonized because the tetracycline inhibits microbial growth.

Table 1 Commonly Used Bactericidal and Bacteriostatic Antimicrobial Agents Bactericidal

Bacteriostatic

Penicillinsa Cephalosporinsa Aminoglycosidesb Vancomycina Fluoroquinolonesb Rifampinb Metronidazoleb

Macrolidesb Tetracyclinesb Sulfonamidesb Trimethoprimb Chloramphenicolb Clindamycinb

a b

Interferes with cell wall synthesis. Interferes with metabolic pathways or protein synthesis.

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Relationships Between Antimicrobial Concentrations and Bactericidal Activity

Antimicrobial bactericidal activity can be further characterized by its relationship to antimicrobial concentration. The amount of antibiotic needed to inhibit the visible growth of an organism in the laboratory is the minimal inhibitory concentration, commonly measured in micrograms per milliliter. The amount of antibiotic in excess of the MIC (peak level) may influence the effectiveness of the antibiotic killing of the bacterium. Another measure of the amount of antibiotic affecting bacterial growth is the area under the curve (AUC). This is a measure of the total antibiotic exposure of the bacterium. It incorporates not only the peak level but also total time the bacterium is exposed to the drug. The amount of time that the antibiotic concentration remains over the MIC may also influence antibacterial activity. Bacterial cell death as a result of antibiotic exposure can be classified as either concentration-dependent or concentration-independent. For concentration-dependent bactericidal activity, increasing drug concentrations produce a greater rate of bacterial eradication. For concentration-independent bactericidal drugs, increasing drug concentrations do not produce a greater rate of bacterial eradication. Increasing the amount of time the antibiotic remains above the MIC improves bacterial killing. These drugs are also referred to as time-dependent antibiotics. The rate of bacterial killing for time-dependent/concentration-independent drugs plateaus at concentrations four to five times greater than the MIC. Further increases in drug concentrations result in negligible increases in bacterial killing. 3.2.1

Concentration-Dependent Bactericidal Agents

Antibiotics that demonstrate concentration-dependent bactericidal activity include aminoglycosides and fluoroquinolones. For these drugs, an increase in antibiotic concentration leads to a more rapid rate of bacterial death. The peak drug concentration–MIC ratio (the maximal serum concentration divided by the MIC) is a pharmacodynamic parameter that is linked to clinical outcome (see Figure 2A). For aminoglycosides and fluoroquinolones, peak concentration/MIC ratios of 8–12 have been associated with improved clinical outcomes as well as a reduction in the emergence of bacterial resistance. In addition to the peak concentration/MIC ratio, the AUC to MIC is linked to clinical outcome, especially for fluoroquinolones (Figure 2C). AUC/MIC ratios ⱖ125 have been associated with increased rates of microbiological and clinical cures in patients treated with intravenous ciprofloxacin. 3.2.2

Concentration-Independent Bactericidal Agents

For ␤-lactam antibiotics, including penicillins, cephalosporins, monobactams, carbapenems, vancomycin, macrolides, and clindamycin, the rate of bacterial killing is a function of the time that antibiotic concentrations exceed the MIC. For these antimicrobials, the rate and extent of killing remain essentially constant once drug concentrations are approximately four times the MIC (see Figure 2B). The time above the MIC or T > MIC has been the pharmacodynamic parameter that has been shown to correlate with therapeutic efficacy. The optimal duration that an antibiotic concentration should remain above the MIC for an infecting microorganism remains unknown. Research with ␤-lactam antibiotics suggests that efficacy is observed when concentrations exceed the MIC for at least 40% to 50% of the dosage interval.

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Figure 2 Pharmacodynamic relationships of peak to MIC, time above MIC, and AUC to MIC. Graphs A through C represent drug concentrations versus time after the dose of an antibiotic. The diagonal line in each graph represents the drug concentration as a function of time. A: Concentrationdependent drug activity. Higher concentrations of antibiotic increase antibiotic activity, as indicated by higher peak-to-MIC ratio. Antibiotic (1) is more active than antibiotic (2). B: Concentrationindependent (time-dependent) antibiotic activity. The greater amount of time above the MIC determines drug activity. Antibiotic (1) is active longer than antibiotic (2). C: The area under the curve (AUC) is a measure of total antibiotic exposure to a bacterium. The magnitude of the AUC is dependent on both the peak antibiotic concentration and the time the drug remains above the MIC. This figure has two superimposed triangles representing antibiotic (1) and (2). The area within the triangles represents the AUC of the antibiotic. Antibiotic (1) has a larger AUC and therefore is more active than antibiotic (2).

3.3

Post-Antibiotic Effect

Observations from in vitro and animal experiments reveal that microorganisms do not undergo immediate regrowth once antibiotic concentrations fall below the MIC. This postantibiotic effect (PAE) is persistent suppression of bacterial growth after exposure to an antimicrobial although drug concentrations have fallen below the MIC. The duration of the PAE is dependent on the antimicrobial and microorganism. In general, only antibiotics that inhibit deoxyribonucleic acid (DNA) (fluoroquinolones) or protein (aminoglycosides) synthesis demonstrate a PAE against gram-negative microorganisms. The exception to this rule are the cell wall active antibiotics imipenem and meropenem. Under experimental conditions a PAE lasting 2–6 hours is observed with aminoglycosides and fluoroquinolones when used against gram-negative bacteria (see Figure 3). Under the same testing conditions, a PAE is not observed with ␤-lactam antibiotics against gram-negative microorganisms but a 2-hour PAE is generally observed against gram-positive microorganisms. The mechanism of action of the PAE remains unknown. Proposed explanations have suggested that the presence of nonlethal damage induced by the antimicrobial or persistence of nonlethal antibiotic concentrations at the antimicrobial site of action may interfere

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Figure 3 Concentration-dependent antibiotics: Represented are two methods for gentamycin dosage. Curve A represents once daily dosing using 7 mg/kg. This causes a high peak level followed by a prolonged period when the serum level is below the MIC. Curve B represents traditional multidose administration with lower peaks. For concentration-dependent antibiotics the administration represented by curve A is preferable since higher drug levels are more bactericidal, are potentially less toxic, and take advantage of the postantibiotic effect (PAE).

with subsequent regrowth. Factors that can influence the observed PAE include the bacterial inoculum, the growth rate of the microorganism and the presence of host defenses. In theory, the PAE should be taken into account in the design of antibiotic dosage regimens. An antimicrobial with a long PAE should have a longer dosage interval than an antimicrobial with little or no PAE. Unfortunately, the exact length of the PAE in vivo may be quite unpredictable. In addition, the technology that can rapidly and accurately characterize the PAE is not currently available in the clinical setting. Because of these limitations, the PAE remains primarily a research tool at the present time. 3.4

Clinical Application of Antimicrobial Pharmacodynamics

The goal of an antimicrobial dosage regimen is to administer an antimicrobial in a manner that achieves maximal bacterial killing with minimal toxicity to the host. With concentration-dependent killing agents, optimizing the peak/MIC ratio and 24-hour AUC/MIC ratios enhances bacterial killing and minimizes the potential for the development of bacterial resistance. This strategy has been applied to aminoglycosides through the practice of administering large single doses at extended intervals (i.e., once daily dosage). This dosage approach has been shown to be as effective as multiple daily dosage (see Figure 3). It has also been associated with a similar or lower incidence of nephrotoxicity. Concern regarding the potential for central nervous system toxicity has generally precluded the administration of large single daily doses of fluoroquinolones in clinical practice. However, attempts to increase the 24-hour AUC/MIC ratio have been made by increasing the total daily dose through increasing the frequency of administration. This effect has been observed for intravenous ciprofloxacin, for which a 400-mg q8h regimen is generally preferred to 400 mg q12h for the treatment of less susceptible pathogens such as Pseudomonas aeruginosa.

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For antimicrobial agents that demonstrate concentration-independent killing, optimizing the time spent above the MIC (T > MIC) appears to be the primary determinant of efficacy (see Figure 4). For ␤-lactam antibiotics with short half-lives, frequent administration or continuous infusion can be used to maximize this pharmacodynamic principle. Continuous infusion of cephalosporins and penicillins has been utilized in clinical practice. Despite the theoretical advantages of this mode of administration, questions remain. The optimal serum concentration during continuous infusion has not been defined. In addition, there are few prospective clinical studies that have compared clinical outcomes for continuous infusion versus intermittent administration. Cephalosporins with longer half-lives such as ceftriaxone or glycopeptide antibiotics such as vancomycin can be administered once or twice daily and maintain concentrations above the MIC for a majority of the dosage interval. 4

ANTIMICROBIALS IN RENAL IMPAIRMENT

Many antimicrobials are eliminated renally. The rate of elimination of renally eliminated antibiotics is primarily dependent on the glomerular filtration rate (GFR). The creatinine clearance (Clcr) is a close approximation of GFR. A formula that is frequently used to estimate Clcr is that of Cockcroft and Gault: Clcr =

(140 ⫺ age) ⫻ body weight serum creatinine ⫻ 72

ANTIBIOTIC DOSAGE IN RENAL AND HEPATIC FAILURE AND DRUG INTERACTIONS Renal failure Dosing interval is based on estimated corrected creatinine clearance: 140 ⫺ age serum creatinine (multiply by 0.85 for women) Dose adjustments for antibiotics (see Table 2) Once daily aminoglycoside dosage and monitoring (see Table 3) Traditional dosage of aminoglycosides (see Table 4) Vancomycin dosage and monitoring (see Table 5) Hepatic failure Standardized recommendations for dosage in hepatic failure not available Suggestions for dosage of certain antibiotic during hepatic failure (see Table 6) Drug interactions Drug interactions common Always check for drug interactions between the antibiotic and other drugs the patient is taking before antibiotic use (see Table 7) Bioavailability Many antibiotics have excellent oral absorption and attain serum levels adequate to treat most infections Antibiotics with good oral bioavailability should be used orally whenever possible to prevent complications and costs of parenteral therapy (see Table 8)

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Figure 4 Concentration-independent (time-dependent) antibiotics. Curves A and B represent two vancomycin dosage regimens. The vancomycin dosage regimen of curve A produces a peak level of 40 ␮g/ml and a trough level of 15 ␮g/ml. The vancomycin dosage regimen of curve B produces a peak of 30 ␮g/ml and a trough of 10 ␮g/ml. The rate of bacterial killing with vancomycin is maximal at concentrations of 5 ⫻ MIC. Concentrations above this threshold do not enhance the rate of killing. As a result, maximal rate of bacterial killing is achieved with curve B (trough level of 10 ␮g/ml is 5 ⫻ MIC). The higher peak and trough levels associated with curve A do not enhance the rate of bacterial killing. The dosage regimen of curve A may be undesirable as the patient would be exposed to higher vancomycin concentrations without additional bactericidal activity.

where Clcr is expressed in milliliters per minute, age in years, weight in kilograms, and serum creatinine concentration (SCr) in milligrams per deciliter. This equation has been formulated for males. When it is applied to females, the result should be multiplied by 0.85. The Cockcroft and Gault formula provides a Clcr estimate that is not normalized for body size (uncorrected). As a result, larger patients have higher Clcr estimates than smaller patients at equivalent age and SCr values. However, this should not be interpreted to mean that larger patients eliminate antimicrobials at a faster rate. This is because the elimination rate is measured by the T1/2. The T1/2 of an antimicrobial is dependent on its clearance, as estimated by creatinine clearance and volume of distribution (see Sec. 2.4). The Vd is proportional to body size. A larger patient has a larger Vd; a smaller patient has a smaller Vd. Therefore, a larger clearance in a larger patient is offset by a proportional increase in the Vd. Thus, even though the larger patient has a higher Clcr, the rate of antimicrobial elimination is identical to that of a smaller patient with an equivalent age and SCr.

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A more useful index of renal function is the Clcr normalized or corrected for body size. Most tables that provide dosage recommendations in renal impairment assume a Clcr of 100–120 ml/min. This is the value in a healthy 72-kg male. As a result, Clcr is frequently normalized to a reference weight of 72 kg. The Cockcroft and Gault formula can be normalized to a reference weight of 72 kg. This produces the following weight corrected formula for calculating Clcr: Corrected Clcr =

(140 ⫺ age) Serum creatinine concentration

For a female, the result is multiplied by 0.85. The corrected Clcr can be used to compare the rates of renal elimination of antimicrobials in patients who are of different body size. Patients with an identical corrected CLcr have equivalent rates of elimination (equal halflives). For patients with a reported SCr < 1 mg/dl, consideration should be given to rounding the SCr to 1 mg/dl. This issue may be clinically important in patients who are above 60 years of age or have reduced muscle mass resulting from cachexia, malnutrition, or spinal cord injuries. In these patient populations, the use of SCr values < 1 mg/dl may overestimate renal function. It is recommended that a corrected Clcr be used to guide dosage adjustment of antimicrobials in patients with renal impairment. Suggestions for dosage adjustment of commonly used antimicrobials in renal impairment are provided in Table 2. These recommendations generally involve increasing the dosage interval. Alternatively the dose may be reduced while maintaining the dosage interval; also see Chapter 3, Table 7. Recommendations for the dosage and monitoring of aminoglycosides are provided in Table 3 for high-dose or once-daily dosage and in Table 4 for traditional dosage. Excluded from once daily dosage are pediatric patients; pregnant women; patients with estimated ClCr < 40 ml/min; patients with ascites, endocarditis, severe burn injuries, or cystic fibrosis; and patients with aminoglycoside dosage intervals > 48 hours. Dosage recommendations for vancomycin are summarized in Table 5.

5

ANTIMICROBIALS IN HEPATIC IMPAIRMENT

In contrast to that in renal disease, in hepatic disease simple versatile dosage recommendations for the use of antimicrobial agents do not exist. The heterogeneity of hepatic disease coupled with the lack of a single marker that represents overall hepatic function makes quantification of hepatic elimination difficult. The physiological effects of hepatic disease likely alter the clearance and volume of distribution properties of antimicrobials. Unfortunately, extensive research into these issues has not been performed. As a result, most dosage guidelines for antimicrobials in hepatic impairment are broad and general. Recommendations usually consist of decreasing doses or extending dosage intervals with concomitant serum drug concentration monitoring if available. Table 6 lists antimicrobials for which dosage adjustment should be considered for hepatic disease patients.

6

ANTIMICROBIAL DRUG INTERACTIONS

Drug interactions with antimicrobial agents can be classified into pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic interactions include those that alter the

5–10 mg/kg q8h 200–800 mg 5⫻/day 0.5–1 mg/kg q24h 250–500 mg q8h 250–500 mg q8h 1–2 g q4–6h 500 mg on day 1 then 250 mg on days 2–5 500 mg q24h 1–2 g q8h 1–2 g q8h 1–2 g q12h 200–400 mg q12h 1–2 g q8h 1 g q24ha 750 mg q8h 250–500 mg q6h 200–400 mg q8–12h 500–750 mg q12h 600–900 mg q8h 150–450 mg q6h

Acyclovir IV Acyclovir PO Amphotericin B Amoxicillin Amoxicillin/clavulanate Ampicillin Azithromycin PO

Azithromycin IV Aztreonam Cefazolin Cefotetan Cefpodoxime proxetil Ceftazidime Ceftriaxone Cefuroxime IV Cephalexin Ciprofloxacin IV Ciprofloxacin PO Clindamycin Clindamycin PO

Dosing range

Antimicrobial agent

q8h q8h q8h

q12h

100% 100% 100% q12h 100% 100% 100% q12h 100% 100% 100% 100% 500 mg q12h 100% 100%

100% 100% 100% 100% 100% 100% 100%

30–50

Table 2 Suggested Antimicrobial Dosage Adjustments in Renal Impairment

q12h q12h q8–12h

q24h q8h

100% 100% q12h 50% q12h 100% q24h 100% q24h 100% q24h 100% 100% q12h 100% q8–12h 100% q18h 500 mg q18h 100% 100%

100% 100% 100% 100% 100% 100% 100%

10–30

<10

100% 100% q24h 50% q24h 100% q48h 100% q24h 50% q24h 100% 100% q24h 50% q12h 100% q24h 500 mg q24h 100% 100%

50% q24h 100% q12h 100% 100% q24h 100% q24h 100% q12–16h 100%

Doses for renal failure: Clcr (ml/min)

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500 mg q24h 500 mg q8h 1–2 g q4–6h 1–2 million U q4–6hd 3–4 g q6h 3.375–4.5 g q6h 200–300 mg q24h 100–200 mg q24h

Levofloxacin IV/POc

Metronidazole IV/POc Nafcillin Penicillin G Piperacillin Piperacillin/tazobactam Trovafloxacin IV Trovafloxacin PO

1 Single-strength q12h 100% 100% 100% 50% q24h 25% q24h 50% q12h

100% 100% 100% 100% 50% q24h 50% q24h 50% q6–8h

100% 100% 100% q6h 100% q8h 2.25 g q6h 100% 100%

b

100% 100% 100% q6–8h 100% q8–12h 2.25 g q8h 100% 100%

500 mg ⫻ 1 Then 250 mg q24h; for Crcl = 10–19, use 250 mg q48h

50% q12h

100%

For central nervous system infections, the dose of ceftriaxone is 2 g q12h. Not recommended for creatinine clearance of less than 15 ml/min. c Intravenous and oral dosage regimens are identical. d For central nervous system infections, the dose of penicillin G is 4 million units q4h.

a

10–20 ml q12h (10 ml = 1 double-strength tablet) 1 Double-strength q12h 100 mg q12–24h 500–750 mg q6h 250–500 mg q6h 200–400 mg q24h 5 mg/kg q12h 500 mg q6–8h

Co-trimoxazole IV (80 mg tmp/5 ml) Co-trimoxazole PO Doxycycline IV/POc Erythromycin IV Erythromycin PO Fluconazole IV/POc Ganciclovir (induction) Imipenem/cilastatin

100% q8–12h 100% 100% q8–12h 100% q12h 2.25 g q8h 100% 100%

500 mg ⫻ 1 Then 250 mg q48h

1 Single-strength q24hb 100% 100% q8h 100% q8h 50% q48h 25% q24h Not recommended

50% q24hb

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Table 3 Large Dose/Extended Interval Aminoglycoside Dosage Method: Once Daily Dosage Dosing 1. Calculate creatinine clearance 2. Calculate dose and dosage interval Creatinine clearance

Gentamicin and tobramycin dose and interval

>60 ml/minute 40–60 ml/min ⱕ39 ml/min

7 mg/kg every 24 hr 7 mg/kg every 36 hr Not recommended

For amikacin, the dose is 15 mg/kg with a dosage interval determined by the creatinine clearance as noted. 3. Determine dosing weight The 7-mg/kg dose should be based on actual body weight (ABW). If the patient is obese (defined as >20% over ideal body weight [IBW]), the dose is based on an obese dosage weight. • IBW (male) = 50 kg ⫹ 2.3 kg/in over 5 ft • IBW (female) = 45.5 kg ⫹ 2.3 kg/in over 5 ft Obese dosage weight = IBW ⫹ 0.4(ABW ⫺ IBW) Monitoringa 1. Initial random level: A single random aminoglycoside level should be obtained between 6 and 14 hours after the start of the infusion. The level should be interpreted according to the following nomogramb:

Time between start of infusion and drug level blood draw (hr) 2. Subsequent random levels: Random levels should be repeated every 5 days. a

A serum creatinine concentration should be obtained at least every other day while the patient is on aminoglycoside therapy. Periodic assessment of hearing and balance should be performed to assess for ototoxicity. b Compare the random level result on the Y axis to the appropriate time on the X axis. The intersection point indicates the maintenance dosage interval that should be chosen for the patient. If the random level falls near the line of a longer dosage interval, the longer dosage interval should be chosen to prevent drug accumulation. For amikacin, the resulting random level can be halved and then applied to the normogram. If the random level is off (i.e., above) the normogram between the 6- and 14-hour time points, the scheduled therapy should be discontinued. A subsequent dose should not be administered until the serum concentration decreases to <1 ␮g/ml. Reprinted with permission. Nicolou DP et al. Experience with a Once Daily Aminoglycoside Program Administered to 2,184 Adult Patients. Antimicrobial Agents and Chemotherapy 39(3):650–655, 1995. American Society for Microbiology.

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Table 4 Traditional Aminoglycoside Dosage Method Loading dosea Gentamicin

Tobramycin

Amikacin

2 mg/kg

2 mg/kg

7.5 mg/kg

Maintenance doseb 1. Calculate creatinine clearance. 2. Determine dosing weight (see Table 3). 3. Dosing normogram: For gentamicin and tobramycin, a dose of 1.5 mg/kg should be given at a dosage interval that is indicated by the normogram. For amikacin, the dose should be 5 mg/kg. Creatinine clearance (ml/min)

Dosage interval (hr)

>75 50–74 40–49 25–39 15–24 <15

8 12 18 24 36 48–72

Monitoring Peak and trough levels should be obtained around the third dose. Desired peak levels for gentamicin and tobramycin are 5–10 ␮g/ml and <2 ␮g/ml for trough levels. For amikacin peak levels of 25–30 ␮g/ml and 4–8 ␮g/ml for trough levels are generally desired. a b

The loading dose should be based on the patient’s actual body weight. The maintenance dose should be based on actual body weight. If the patient is obese, the dose is based on the obese dosage weight.

absorption, distribution, metabolism, or excretion of another drug. For example, the administration of fluoroquinolones with aluminum- or magnesium-containing antacids results in decreased absorption of the fluoroquinolone. Interactions involving distribution and metabolism can be illustrated by co-trimoxazole (Bactrim or Septra) and warfarin. Cotrimoxazole may displace warfarin from its albumin binding sites, resulting in a higher fraction of pharmacologically active warfarin in the plasma. In addition, co-trimoxazole inhibits the hepatic metabolism of warfarin. Interactions involving excretion are seen with probenecid and penicillin G. Probenecid blocks the active secretion of penicillin G by the kidney. This results in higher (approximately twofold) as well as more prolonged plasma levels of penicillin. Antibiotics that have the greatest potential for drug interactions include co-trimoxazole, tetracyclines, fluoroquinolones, fluconazole, erythromycin, clarithromycin, metronidazole, rifampin, and rifabutin. A list of common antimicrobial drug interactions is presented in Table 7. Pharmacodynamic interactions occur when drugs with additive, synergistic, or antagonistic pharmacological properties are combined. For example, combining nephrotoxic agents such as aminoglycosides with cyclosporine or vancomycin may increase the risk of nephrotoxicity.

Table 5 Vancomycin Dosage and Monitoring Guidelines Dosagea Dosage The recommended dose of vancomycin is 15 mg/kg.b The dose should be rounded to the nearest 250-mg increment The dosage interval is dependent on the estimated creatinine clearance (Clcr): Clcr (ml/min)

Dose

>90 70–89 46–69 30–45 20–29 <20

15 mg/kg q12h q18h q24h q36h q48h q3–7 days, depending on levels

Monitoring Vancomycin peak and trough levels have not been correlated with either efficacy or toxicity. Therefore, peak and trough levels are generally not indicated. However, consideration may be given to obtaining a vancomycin trough level if the following conditions are present: 1. 2. 3. 4.

Patients Patients Patients Patients

receiving vancomycin plus an aminoglycoside with rapidly changing renal function receiving higher than usual doses of vancomycin (e.g., for meningitis) with endocarditis

Vancomycin trough levels can be obtained before the fourth dose in patients with normal renal function. In general, a trough level of 5–20 ␮g/ml is acceptable. a

Hemodialysis: The dose and frequency of vancomycin administration depend on the hemofilter that is used (high-flux versus conventional). Consultation of a nephrology specialist is recommended. Peritoneal dialysis: Vancomycin may be administered intraperitoneally (IP). Consultation of a nephrology specialist is recommended. b Actual body weight.

Table 6 Antimicrobials for Which Dosage Adjustment Has Been Suggested in the Presence of Hepatic Disease Drug Ceftriaxone

Chloramphenicol Clindamycin Metronidazole Nafcillin Rifampin

Trovafloxacin

Comment In patients with both hepatic dysfunction and significant renal disease, the ceftriaxone dose should not exceed 2 g daily without close monitoring of serum concentrations. In patients with hepatic failure, an initial 1-g load followed by 500 mg q6h has been suggested. Serum concentrations should be followed. Dose reduction has been suggested in the presence of severe hepatic failure. Specific dosage recommendations are not presently available. In patients with significant liver disease, it has been suggested that doses be reduced by 50%. In patients with both hepatic and renal dysfunction, doses should be reduced to one-half the normal dose. Serum levels should be monitored. It has been suggested that the use of rifampin be avoided or administered at a lower dosage in patients with hepatic dysfunction. Specific dosage recommendations are not presently available. For Child-Pugh A and B cirrhosis patients, the indication of intravenous doses of 300 mg should be reduced to 200 mg; indication of intravenous and oral doses of 200 mg should be reduced to 100 mg. Data are not available for Child-Pugh C cirrhosis.

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ABSORPTION AND BIOAVAILABILITY

Antimicrobials that are administered orally must traverse the gastrointestinal tract to reach the systemic circulation. The amount of drug that reaches the systemic circulation is expressed as a percentage of the total amount that could have been absorbed. This percentage is defined as the drug’s bioavailability. Factors that affect gastrointestinal absorption and thus bioavailability include gastric pH, gastrointestinal tolerance of the antibiotics, coadministration of food, gastrointestinal transit time, and ileal function. The antimicrobials listed in Table 8 have oral and intravenous formulations. The oral formulations have good bioavailability, resulting in adequate serum drug levels. The oral dosage forms should be utilized whenever the patient is taking oral medication and has a functional gastrointestinal tract. The oral route of administration prevents the negative effects of prolonged intravenous drug administration, including intravenous catheters, toxicities, and costs. In addition, the literature is replete with evidence than an early switch or the initial use of oral antibiotics can result in positive patient and economic outcomes.

8

ANTIBIOTIC TISSUE PENETRATION

The process of passive diffusion primarily controls antibiotic penetration into tissues. Exceptions include the renal tubules and the biliary tree, which are sites of active transport, which result in higher drug levels than present in the serum. Anatomical sites that have permeability barriers to passive diffusion include the cerebrospinal fluid, abscess cavities, and eye. Factors that influence antibiotic tissue concentrations include the degree of tissue perfusion, serum drug concentrations, binding to serum proteins and tissue sites, membrane permeability, transport systems, and presence of inflammation at the tissue site. Tissue can be divided into intracellular and extracellular compartments. Distribution of antimicrobials within the two compartments is dependent on lipid solubility of the drug. Nonlipophilic drugs such as ␤-lactams and aminoglycosides do not penetrate cell membranes. As a result they are confined to the extracellular compartment. In contrast, lipophilic drugs such as macrolides and tetracyclines as well as some water-soluble drugs such as the fluoroquinolones readily penetrate cell membranes and distribute into the intracellular compartment. As a result, these antimicrobials are effective in the treatment of intracellular infections such as those produced by Legionella spp., whereas ␤-lactam and aminoglycoside antibiotics are not effective. Tissue-to-serum ratios relate the concentration of antibiotic found in tissue to the concentration found in serum. These ratios assume that tissue is homogeneous and that bacteria are evenly distributed throughout tissue. Both of these assumptions are invalid. As a result, tissue-to-serum ratios have been misleading in predicting antibacterial efficacy against extracellular gram-negative and gram-positive bacteria. In contrast, serum concentrations of ␤-lactams, aminoglycosides, and fluoroquinolones have been correlated with efficacy in the treatment of tissue infections. The extracellular fluid in tissue is in equilibrium with the serum. As a result, concentrations in serum may predict antibacterial responses better than tissue concentrations as long as bacteria are extracellular. This generalization would not apply to sites that have permeability barriers to passive diffusion.

• • • • •

Fluconazole

Fluoroquinolones Ciprofloxacin Norfloxacin Levofloxacin Trovafloxacin Ciprofloxacin Enoxacin Macrolides Erythromycin Clarithromycin

Antacids Warfarin

Doxycycline

• Theophylline • Caffeine • Benzodiazepines Midazolam Triazolam • Carbamazepine • Cyclosporine • Theophylline • Warfarin

• Sucralfate

Cyclosporine Oral sulfonylureas Phenytoin Warfarin Al2⫹, Ca2⫹, Mg2⫹ containing antacids, multivitamins with Zn2⫹

• Phenytoin • Warfarin • Oral sulfonylureas (chlorpropamide glipizide glyburide)

Interacting drug

Co-trimoxazole

Antibiotic

Table 7 Important Drug Interactions with Antimicrobials

Significant decrease in absorption of antibiotic Increase in plasma levels of theophylline and caffeine Increased plasma levels of interacting drug due to inhibition of CYP3a enzymes of cytochrome P450 oxidase system

Significant decrease in absorption of antibiotic

Increased plasma levels of interacting drug due to inhibition of cytochrome P450 oxidase system

Increased plasma levels of interacting drug due to decreased clearance Increased hypoglycemic effect due to decreased protein binding of interacting drug Decreased absorption of doxycycline Potentiation of anticoagulant effect

Effect

Decrease dose of interacting drug by 50% and monitor Avoid interaction or decrease dose of interacting drug by 25% to 50% Monitor closely

Avoid or give interacting drug at least 6 hr before or 2 hr after fluoroquinolone Avoid entirely

Separate by at least 2 hr Avoid or monitor INR (International Normalized Ratio) closely Avoid interaction or decrease dose of interacting drug by 25% to 50% Monitor closely

Avoid interaction or monitor closely for toxicity Avoid interaction or monitor for hypoglycemia

Management

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Source: Adapted from Grace et al., 2000.

Warfarin • ␤-blockers • Corticosteroids • Cyclosporine • Digoxin • Estrogen • Fluconazole • Opioid analgesics • Quinidine • Sulfonylureas • Verapamil

Alcohol

Metronidazole

Rifampin Rifabutin

• Cisapride • Nonsedating antihistamines Astemizole Loratidine Terfenadine Digoxin

Macrolides Erythromycin Clarithromycin

Monitor for digoxin toxicity

Increased digoxin levels due to decreased gut metabolism in 10% of population Inhibition of alcohol dehydrogenase causing disulfiram-like effect Potentiation of anticoagulant effect Decreased plasma levels of interacting drugs due to induction of multiple enzymes of cytochrome p450 oxidase system

Avoid or monitor INR closely Avoid or monitor closely for decreased clinical efficacy of interacting drug

Avoid alcohol-containing products

Absolute contraindication due to lifethreatening arrhythmias

Increased plasma levels of interacting drug due to inhibition of CYP3a enzymes of cytochrome P450 oxidase system

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Table 8 Antimicrobials with Oral and Intravenous Formulationsa Ciprofloxacin Clindamycin Co-trimoxazole Doxycycline Fluconazole Levofloxacin Metronidazole a

The oral dosage forms are well absorbed. As a result, these antimicrobials should be administered orally whenever a patient has a functional gastrointestinal tract and can take oral medications.

BIBLIOGRAPHY Craig WA. Pharmacokinetic/pharmacodynamic parameters: Rational for antibacterial dosing of mice and men. Clin Infect Dis 26:1–12, 1998. D’Angio R, Platt DR, Gannon R. Creatinine clearance: Corrected versus uncorrected. Drug Intell Clin Pharm 22:32–33, 1988. Estes L. Review of pharmacokinetics and pharmacodynamics of antimicrobial agents. Mayo Clin Proc 73:1114–1122, 1998. Grace C, Ahern J, Lynch T, eds. Guide to antimicrobials for adults. Burlington, VT: Fletcher Allen Health Care, 2000. Levison ME. Pharmacodynamics of antibacterial drugs. Infect Dis Clin North Am 14:281–291, 2000. McCormack JP, Cooper J, Carleton B. Simple approach to dosage adjustment in patients with renal impairment. Am J Health Syst Pharm 54:2505–2509, 1997. Mulligan MJ, Cobbs CG. Bacteristatic versus bactericidal activity. Infect Dis Clin North Am 3:389– 395, 1989. Nicolau DP, Quintiliani R, Nightingale CH. Antibiotic kinetics and dynamics for the clinician. Med Clin North Am 79:477–495, 1995. Nix DE, Goodwin D, Peloquin CA, Rotella DL, Schentag JJ. Antibiotic tissue penetration and its relevance: Impact of tissue penetration on infection response. Antimicrob Agents Chemother 35:1953–1959, 1991. Schentag JJ. Clinical significance of antibiotic tissue penetration. Clin Pharmacokinet 16(1):25–30, 1989.

5 The Clinician and the Microbiology Laboratory Daniel J. Diekema University of Iowa, Iowa City, Iowa, U.S.A.

1

INTRODUCTION

The goal of the clinical microbiology laboratory is to detect pathogenic microorganisms in clinical samples as accurately and as rapidly as possible. Inpatients are carefully monitored, and response to test results (e.g., narrowing of antimicrobial therapy, institution of treatment for a newly detected pathogen) can be immediate. Outpatients present unique challenges to clinical microbiology. The era of cost containment for microbiology laboratories has seen consolidation of many laboratory services. As smaller hospitals send more of their tests to commercial and/or academic referral laboratories, decisions must be made about which services to provide on site. In particular, for a test to be relevant to the initial management of most common outpatient infections, results must be available almost immediately. Practitioners managing outpatient infectious disease problems may have fewer services available in their own office laboratories, or even in the laboratories of their closest affiliated hospitals. The Clinical Laboratory Improvement Act (CLIA) has also had an impact on the availability of certain rapid tests (e.g., Gram stains) in the outpatient setting. There are many excellent and detailed chapters addressing the clinician’s use of microbiology laboratory services (see the Bibliography). This chapter focuses primarily on the use of tests to detect the presence of microorganisms in the outpatient setting— with emphasis on those tests that can be performed immediately, on site. Specimen collection and transport, pathogen identification by microscopy, rapid diagnostic testing, culture, and antimicrobial susceptibility testing are reviewed. 2

SAMPLE COLLECTION AND TRANSPORT

The yield and accuracy of a microbiology test are critically dependent on the quality of the sample. When sampling for culture from nonsterile sites, one must ensure that the specimen is from the site of infection, and therefore is likely to represent pathogenic rather than colonizing flora. The Gram stain plays an important role in evaluating specimen quality. If a sputum specimen Gram stain result reveals predominantly squamous epithelial cells and few inflammatory cells (e.g., neutrophils), the specimen represents oropharygeal

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CLINICAL MICROBIOLOGY LABORATORY Communicate with the laboratory before sending samples, especially for nonroutine requests and search for unusual organisms. Use appropriate sample collection methods and transport media. Transport specimens to the lab ASAP. Send adequate volumes of material for culture and Gram stain. Use Gram stain results to guide empirical therapy if possible. Drawing of two sets of blood cultures from different venipuncture sites can help in interpretation of possible contaminant isolates. Use selected rapid diagnostics tests in the office (Table 4). Know available non-culture-based detection methods (direct detection and serological tests, Tables 5 and 6). Keep abreast of rapid advances in viral and molecular diagnostics.

contamination rather than a sample from the lower respiratory tract. No important information can be obtained from culturing such a specimen: it should be discarded. Knowledge of the microbiological characteristics of each body site is helpful in differentiating colonizing flora from pathogens. A list of common colonizing flora at each body site is found in Table 1. For specimens obtained from sterile sites (e.g., blood, cerebrospinal fluid), the most important factor in sample collection is attention to site preparation. Many pathogenic bacteria are also common skin and mucous membrane colonizers. For example, viridans group streptococci are often found as contaminants in blood cultures but are the most common cause of native valve endocarditis in adults. Poor attention to preparation of the venipucture site during blood culture collection can therefore lead to unnecessary and expensive further evaluation and treatment. A single blood culture contaminant in a hospitalized patient may result in up to $4000 in excess health care costs. It is also well documented that performance of blood cultures by trained personnel (e.g., phlebotomists) is associated with a significant reduction in blood culture contaminants. When a specimen is obtained from a site that may contain anaerobes, the yield is much greater if a large amount of material is collected and transported promptly to the laboratory in the syringe in which it was collected. Unfortunately, in many cases material is smeared onto a swab—providing the laboratory with a smaller quantity of material that has been exposed to oxygen. As just one example, the yield of culture for the anaerobic Actinomyces spp. from patients with suspected cervicofacial actinomycosis is much improved by proper collection techniques, prompt transport, and alerting of the laboratory to the reason for obtaining the culture. Prompt transport to the laboratory or proper refrigeration/preservation of a sample is important for all microbiology specimens. For example, a delay in transportation or refrigeration of a urine sample for culture could allow low-level contaminating bacteria to grow up to much higher colony counts (>104 [CFU]/ml) prior to culture. Most importantly, every office laboratory should have up-to-date manuals on specimen collection and transport readily available, and the personnel responsible for specimen collection should receive periodic training.

a

Candida spp. Malassezia spp.

Micrococcus spp. Peptostreptococcus spp. Propionibacterium spp. Staphylococcus spp. Streptococcus spp.

Aerococcus spp. Bacillus spp.

Chilomastix spp. Endolimax spp. Entamoeba coli Entamoeba hartmanni Entamoeba polecki Iodamoeba spp. Trichomonas hominis

Candida spp.

Actinomyces spp. Bacteroides spp. Clostridium spp. Corynebacterium spp. Enterobacteriaceae Enterococcus spp. Fusobacterium spp. Helicobacter spp. Lactobacillus spp. Peptostreptococcus spp. Prevotella spp. Propionibacterium spp. Pseudomonas spp. Staphylococcus spp. Streptococcus spp. Veillonella spp.

Gastrointestinal tract

Many organisms on this list can also be pathogenic in the proper clinical setting.

Parasites

Fungi

Bacteria

Skin

Table 1 Common Colonizing Floraa at Four Body Sites

Prevotella spp. Propionibacterium spp. Staphylococcus spp. Streptococcus spp. Stomatococcus spp. Treponema (non-pallidum) spp. Veillonella spp. Candida spp.

Peptostreptococcus spp. Prevotella spp. Propionibacterium spp. Staphylococcus spp. Streptococcus spp. Treponema (non-pallidum) spp. Ureaplasma spp. Candida spp.

Entamoeba gingivalis Trichomonas tenax

Actinomyces spp. Corynebacterium spp. Eikenella spp. Enterobacteriaceae Haemophilus spp. Kingella spp. Moraxella spp. Mycoplasma spp. Neisseria spp. Peptostreptococcus spp.

Respiratory tract

Actinomyces spp. Bacteroides spp. Clostridium spp. Corynebacterium spp. Enterobacteriaceae Enterococcus spp. Gardnerella spp. Haemophilus spp. Lactobacillus spp. Mycoplasma spp.

Genitourinary tract

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MICROSCOPY

In today’s high-technology environment, it is important to remember that direct microscopic examination of a clinical specimen frequently provides a diagnosis more rapidly and cheaply than a battery of molecular tests. Direct microscopy provides the additional satisfaction of seeing the pathogen with your own eyes. 3.1

Gram Stain

Careful review of the Gram stain of a clinical specimen serves two important purposes. First, the Gram stain result allows for an assessment of specimen quality—the presence of many squamous epithelial cells demonstrates contamination of a sample with mucosal cells and accompanying resident flora, suggesting that the sample is not suitable for further processing. Conversely, an abundance of neutrophils documents the inflammatory response and an increased likelihood that the cultured specimen will yield a bacterial pathogen if one is present. Secondly, the Gram stain allows for detection of the pathogenic bacteria. Staining characteristics and morphology sometimes allow for presumptive identification of the organism. Be aware that the morphological and staining characteristics of bacteria can be altered by exposure to antimicrobial agents (particularly cell-wall-active agents). Using culture as the gold standard, the sensitivity of Gram stained smears depends on the concentration of bacteria in the obtained sample, ranging from 25% for specimens with <103 CFU/ml to 95% for specimens with ⱖ105 CFU/ml. Gram stain results can be reported semiquantitatively. For example, a laboratory might examine Gram stains under oil immersion (100⫻) and grade the number of bacteria per microscopy field as follows: (1) rare: <1 organism per field, (2) few: 1–5 organisms per field, (3) moderate: 6–10 organisms per field, and (4) many: >10 organisms per field. Although in sterile site samples (e.g., cerebrospinal fluid) any bacteria are significant, semiquantitative reporting may improve the clinician’s ability to interpret a sample obtained from a nonsterile site (e.g., sputum), where some bacteria can be either colonizing flora or pathogens. Unfortunately, the Gram stain can only be performed and interpreted in a laboratory that is CLIA-inspected and approved for moderate- to high-complexity testing. Delays in obtaining Gram stain interpretations may result in delays in initiating appropriate antimicrobial therapy—as well as a tendency to use unnecessarily broad-spectrum antibiotics. Ideally, office-based laboratories should be able to transport specimens promptly to a nearby hospital or reference laboratory for rapid performance and interpretation of the Gram stain. 3.2

Wet Mounts

Saline solution and KOH wet mounts are extremely useful in determining the cause of vaginitis. In addition to the gross appearance and pH of the vaginal discharge, microscopic findings of clue cells, motile trichomonads, budding yeast, or pseudohyphae provide an immediate diagnosis (Table 2). 3.3

Other Microscopic Examinations

Many other microscopic exams are important to the outpatient practice of infectious diseases, but these are generally performed in a referral, hospital-based, or public health laboratory (rather than in the office or outpatient clinic laboratory). Acid-fast stains (e.g., Ziehl-Neelsen, Kinyoun, auramine-rhodamine) are necessary for the detection of myco-

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Table 2 Office Evaluation of Vaginitis, Using Microscopic Examination of a Vaginal Wet Mount Vaginal discharge Diagnosis

Etiological agents

Gross characteristics

pH

Bacterial vaginosis

Gardnerella vaginalis and others

ⱖ5.0

Trichomoniasis

Trichomonas vaginalis Candida spp.

Grayish, thin, frothy, positive ‘‘whiff’’ test result Yellowish, frothy Thick, adherent, curdlike

ⱕ4.5

Candidiasis

ⱖ5.0

Wet preparation microscopic findings Epithelial cells covered with coccobacillary forms (clue cells) Motile trichomonads (70% sensitive) Budding yeasts and pseudohyphae (KOH preparation)

bacteria and some actinomycetes. The sensitivity of three consecutive sputum smears in a patient with active Mycobacterium tuberculosis infection exceeds 95%. A ‘‘modified’’ acidfast stain (employing gentler decolorization) is used to detect Nocardia spp. Dark-field examination of material from a genital ulcer (or other skin lesion in the case of secondary disease) is the only examination that can provide the immediate diagnosis of syphilis— and may yield the only positive test result very early in the course of primary syphilis. Ova and parasite (O and P) examination of stool samples can detect a number of pathogens, including Entamoeba histolytica and Giardia lamblia. Giemsa stains of peripheral blood are necessary for the diagnosis of malaria and can also be used to detect other parasites (e.g., Babesia spp., trypanosomes, filarial parasites, and leishmania). In the case of suspected malaria, three sets of thick and thin smears should be examined by an experienced microscopist before the diagnosis is excluded. Careful examination of the peripheral smear can also occasionally detect the morulae of ehrlichiosis, and Gram stain of the peripheral smear or buffy coat can sometimes detect bacteria in cases of high-grade bacteremia. 4

RAPID ON-SITE DIAGNOSTIC TESTS FOR INFECTION

CLIA limits the number of on-site diagnostic tests that can be performed in many outpatient settings. Table 3 lists those infectious disease–related tests that are ‘‘CLIAwaived,’’ and those that can be performed by laboratories that have been certified to

Table 3 Infectious Disease–Related Tests Waived by the Clinical Laboratory Improvement Act and Microscopy Procedures Allowed in Labs with Certification for Provider-Performed Microscopya CLIA-waived infectious disease tests Dipstick urinalysis Rapid group A Streptococcus detection Helicobacter pylori IgG detection Heterophile antibody detection Rapid influenza A and B detection a

Provider-performed microscopy procedures Wet mounts (vaginal, cervical, skin) All potassium hydroxide (KOH) preparations Pinworm examinations Urinalysis (microscopic) Fecal leukocyte examination

CLIA, Clinical Laboratory Improvement Act; IgG, immunoglobulin G.

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perform provider performed microscopy (PPM) procedures. Additional office-based testing requires meeting standards for CLIA certification to perform tests of moderate to high complexity. 4.1

Group A Streptococcus Rapid Antigen Detection

In adults, viruses represent the most common cause of acute pharyngitis. However, the detection of group A ␤-hemolytic streptococcus (GABHS)—the most common bacterial cause of acute pharyngitis—remains important (see Table 4). Antimicrobial therapy of GABHS pharyngitis can decrease symptom duration and prevent both suppurative (e.g., abscess) and nonsuppurative (e.g., rheumatic fever) complications of GABHS infection. Although the gold standard test for GABHS infection is throat culture, the 24- to 48-hour time delay can interfere with prompt therapy or lead to overprescribing of antimicrobials to patients with viral pharyngitis. Many offices have therefore adopted one of a large number of available rapid GABHS antigen detection kits. Although these kits all have excellent specificity (>95%), their sensitivity has been demonstrated to range from 62% to 100% (it should be noted that the sensitivities of both throat culture and rapid tests for GABHS are improved when a generous throat swab specimen is obtained). Since most rapid tests have a sensitivity of 80%–90%, a negative result must still be followed by a culture. And since the prevalence of GABHS infection in adult patients is quite low (compared to that in children), false positive results can also occur, even given the excellent specificity of the test. One study in a low-prevalence population (⬃25% prevalence of GABHS by culture) revealed the positive predictive value of a rapid antigen detection kit to be only 61%. For these reasons, most adult outpatient settings are not likely to benefit greatly from performing a rapid GABHS detection test. In some settings in which the ability to provide follow-up care is in question, the rapid GABHS result may allow for immediate treatment. However, in most cases the patient can easily be informed by phone either to stop antibiotics if the culture result is negative or to start them if the culture finding returns positive.

Table 4 Summary of Selected Rapid Tests for Infectious Agentsa Pathogen

Rapid test detection

Specimen type

Sensitivity, %

Specificity, %

Group A streptococcusb Helicobacter pylorib Influenza A and Bb

Group A antigen Anti–H. pylori IgG Viral antigens

62–100 92–97 73–81d

>95 71–84c >95

Human immunodeficiency virus 1 Legionella pneumophila serogroup 1 Epstein-Barr virus (EBV)b

Anti-HIV-1 IgG

Throat swab Blood Nasopharyngeal wash/swab Serum

>99

>99

Serogroup 1 antigen

Urine

95

95

Heterophile IgM

Blood

85

>95

a

CLIA, Clinical Laboratory Improvement Act; IgG, immunogloblin G; HIV-1, human immunodeficiency virus 1. CLIA-waived test commercially available. c Compared to gastric biopsy as gold standard. d For nasal swab, 73%; for nasopharyngeal wash specimens, 81%. b

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Rapid Influenza A and B Antigen Detection

A rapid (10-minute) point of care immunoassay for the detection of influenza A and B antigens has been released (QuickVue, Quidel, San Diego, CA), and other such tests may follow. Using either nasal swab or nasopharyngeal wash specimens, this test has demonstrated a sensitivity of 73% (for nasal swab) to 81% (for nasal wash or aspirate) and a specificity of >95% for the detection of influenza A and B antigens. The test does not differentiate between influenzas A and B. Although patients with influenza may be treated empirically in the proper clinical setting, the ability to diagnose the condition rapidly may aid treatment decisions in some clinical situations and may be important for epidemiological purposes. Negative results require confirmation by cell culture techniques. The rapid point of care test for influenza detection has recently become a CLIA-waived test. 4.3

Heterophile Antibody Screen for Epstein-Barr Virus (Monospot)

For patients with signs and symptoms of infectious mononucleosis, detection of heterophile antibodies is diagnostic of Epstein-Barr virus (EBV) infection. Several qualitative agglutination or enzyme-linked immunoassays are available for rapid detection of heterophile antibodies. The sensitivity of these tests is approximately 85%, but the specificity is excellent. Most cases of falsely negative heterophile antibody test results occur in the pediatric population (in whom the clinical course may be less severe) or early in the clinical illness (in which case the heterophile antibody may become detectable later in the clinical course). A persistently negative heterophile antibody finding in the proper clinical setting should prompt a more diligent search for other infectious causes of a mononucleosis syndrome (e.g., cytomegalovirus [CMV], toxoplasma, human immunodeficiency [HIV]). 4.4

Helicobacter pylori Antibody (Immunoglobulin G) Detection Immunoassay

Helicobacter pylori infects approximately two-thirds of the world’s population. In the United States, the overall prevalence of H. pylori is 30% but varies with age. Although most people who are infected with H. pylori are asymptomatic, the organism has been associated with peptic ulcer disease (PUD), gastritis, gastric cancer, and mucosal-associated-lymphoid-type lymphoma. Since PUD is a commonly diagnosed condition, and since antimicrobial treatment of H. pylori infection in the setting of PUD is recognized to prevent recurrences of disease, the clinician frequently needs to know whether a patient is infected with H. pylori. Several rapid (⬃10-minute) immunoassays are now available for the detection of immunoglobulin G (IgG) antibodies to H. pylori and are comparable in sensitivity and specificity to the traditional serological tests. These tests are useful as relatively inexpensive, noninvasive diagnostic tools to assist in deciding whether to treat a PUD patient with antimicrobials in addition to the usual antacid therapy. Because these tests detect antibody to H. pylori they are not useful for following response to therapy—some patients remain seropositive for an extended period after therapy. 5

OTHER RAPID DIAGNOSTIC TESTS PERFORMED IN THE LABORATORY

There are several other rapid tests available for the diagnosis of infectious diseases, and the list will certainly grow each year. As clinics and hospitals increasingly outsource

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microbiology services, there will be more demand for ‘‘point of care’’ tests that can quickly, easily, and accurately detect common infectious agents in clinical specimens. Two of these tests merit specific mention. 5.1

Rapid Human Immunodeficiency Virus Testing

A rapid (⬃30-minute) enzyme immunoassay for the detection of antibody to HIV-1 has been available for several years (HIV-1 SUDS, Murex), and other rapid tests will soon be available. This test has a sensitivity and specificity comparable to those of the traditional HIV-1 enzyme-linked immunosorbent assay (ELISA) (>99%). As does any HIV antibody detection test, the rapid HIV test requires prior confirmation by Western blot before the result is reported as positive—in a low-prevalence population, the positive predictive value of the rapid test alone is poor. However, because of the extremely high sensitivity and high negative predictive value, the rapid HIV test has been helpful in at least two important clinical settings. After exposure of a health care worker (HCW) to potentially HIV infected blood, a negative rapid HIV test on the source patient can provide important information to be used in deciding whether the exposed HCW should receive antiretroviral prophylaxis. Similarly, rapid HIV test results for a woman in labor with unknown HIV status can aid the obstetrician and pediatrician in deciding whether to administer antiretroviral therapy during labor and/or in the perinatal period to prevent HIV transmission from mother to child. Rapid HIV serological testing has the same limitations that all HIV serological testing has—namely, detectable HIV antibody may not appear until 3–6 months after HIV infection. If the patient practices risky behavior within that window, a false-negative test result can be seen. Conversely, false-positive results are common in low-prevalence populations—so confirmation of positive rapid HIV test results with Western blot analysis is required. 5.2

Legionella Urinary Antigen

Because Legionella spp. require special growth requirements, they are not detected in routine sputum culture samples; special media are required. For this reason, legionellosis is underdiagnosed—some have estimated that <5% of Legionella spp. infections are laboratory confirmed. The relatively recent introduction of Legionella pneumophila serogroup 1 urinary antigen detection has greatly improved the ability of laboratories to detect this pathogen. The urinary antigen test can be performed in less than 30 minutes and is ⬃95% sensitive and specific for the detection of Legionella pneumophila serogroup 1. Importantly, the urinary antigen test is much less sensitive for other serogroups of L. pneumophila and does not reliably detect other species of Legionella. Although up to 70%–80% of legionellosis cases are caused by L. pneumophila serogroup 1, a negative urinary antigen test result in a patient with suspected legionellosis should prompt a sputum/ respiratory tract culture on special media for Legionella spp. (e.g., buffered charcoal yeast extract agar). 6

OTHER NON-CULTURE-BASED TESTS FOR PATHOGEN DETECTION

Outside a few office-based tests and microscopy procedures discussed previously, most microbial detection occurs in the clinical microbiology laboratory. The most common method of diagnosis is still the traditional culture (agar or broth medium for bacteria and fungi, cell culture for viruses). However, an increasing array of non-culture-based methods

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are available; these methods include direct detection of nucleic acid (polymerase chain reaction [PCR], deoxyribonucleic acid [DNA] probes) or antigen (immunofluorescence [IF], enzyme immunoassay [EIA], latex agglutination [LA]) in a sample, and detection of an antibody (serological) response to infection (complement fixation [CF], IF, EIA, Western blot [WB], indirect hemagglutination [IHA]). A detailed description of these procedures is beyond the scope of this chapter and can be found in Isenberg (1998). Table 5 is a list of some currently available direct detection tests, and Table 6 reviews many currently available serological tests for nonviral infectious agents. 7

CULTURE DETECTION OF COMMON BACTERIAL PATHOGENS

Most bacterial pathogens are still identified by traditional culture techniques. Issues specific to specimens from various sites are outlined further in this section. A variety of primary culture media are used in clinical laboratories, but certain common principles apply. Agar medium can be either selective or nonselective. Nonselective medium does not contain inhibitors to growth and can be used to isolate most bacteria commonly encountered in the clinical laboratory. Sheep blood agar is the most commonly used nonselective medium. Selective media contain inhibitors to the growth of certain organisms, thereby increasing the ease with which specimen cultures are interpreted and preventing mixed cultures from obscuring the identification of the pathogen(s) of interest. MacConkey or eosin methylene blue (EMB) agar is a commonly used selective medium for the isolation of gram-negative bacteria. Finally, supplemented media may be necessary to support the growth of certain fastidious organisms (e.g., chocolate agar is supplemented with various heme products to support growth of Haemophilus influenzae). Anaerobic specimens require additional media for isolation. Individual laboratories differ with respect to the primary isolation medium used for each specimen type. Importantly, each laboratory should communicate with physicians regarding which organisms are not recovered routinely from specific specimens unless specifically requested. This can be accomplished by the publication of such a list in a newsletter or memo to referring physicians. 7.1

Blood Specimens

Because of the clinical importance and potentially devastating consequences of bacteremia, blood cultures are considered the most important specimens received by the microbiology laboratory. Most laboratories have therefore invested in the most up-to-date blood culture technology—an automated, continuously monitoring blood culture system. These systems are based on the noninvasive detection of CO2 in blood culture vials, which are automatically monitored every 10 minutes. When the sensor detects a positive culture, the blood culture bottle is removed from the instrument and a Gram stain performed. The clinician should then be immediately notified of the positive culture result (and of the Gram stain morphological characteristics). The sample is then cultured on agar plates for isolation, identification, and eventual susceptibility testing of the organism. Compared to manual systems, the automated technology provides shorter detection times, less hands-on processing time, and reduced rates of contaminant blood cultures. The yield of blood cultures for detection of bacteremia depends on two major variables: (1) the amount of blood cultured—yield increases by 3.2% for each milliliter of blood cultured; therefore, a minimal volume of 10–15 mL per blood culture is recommended for adults; and (2) the number of blood cultures obtained—in bacteremic patients without endocarditis, 80%–90% are detected by the first blood culture, 90%–99% by the

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Table 5 Direct Antigen or Nucleic Acid Detection Tests for Some Common Pathogens Organism/disease

Method(s)a

Usual specimen type

Adenovirus spp. Bordetella pertussis Chlamydia trachomatis

IF, EIA IF, PCR DNA probe PCR EIA LA, EIA EIA DNA probe PCR EIA PCR EIA PCR PCR IF PCR RIA, EIA PCR PCR DNA probe IF, EIA PCR EIA PCR DNA probe PCR IF, EIA IF, EIA EIA EIA IF

Respiratory, stool Nasopharygeal Cervical, urethral, conjunctival Above plus urine Stool Serum, CSF Stool Blood (both assays can be quantitative) Stool CSF Stool Serum (can be quantitative) Serum (can be quantitative) Lesion sample CSF Serum, urine CSF, serum Plasma (can be quantitative) Cervical swab or biopsy Nasopharyngeal, other respiratory CSF Urine Sputum/bronchoalveolar lavage Cervical, urethral, conjunctival Above plus urine Nasopharyngeal, other respiratory Nasopharyngeal, other respiratory Stool Throat swab Lesion scraping

Clostridium difficile (toxin assay) Cryptococcus neoformans Cryptosporidium parvum Cytomegalovirus Entamoeba histolytica Enteroviruses Giardia lamblia Hepatitis B virus Hepatitis C virus Herpes simplex virus (1/2), skin/soft tissue Herpes simplex virus (1/2), CNS infection Histoplasma capsulatum Human herpes virus 6 (HHV-6) Human immunodeficiency virus Human papilloma virus Influenza A or A/B JC virus Legionella pneumophila (serogroup 1 only) Mycobacterium tuberculosis Neisseria gonorrhoeae Parainfluenza virus Respiratory syncytial virus Rotavirus Streptococcus pyogenes (group A) Varicella zoster virus a

IF, direct or indirect fluorescent antibody; EIA, enzyme immunoassay; LA, latex agglutination; PCR, polymerase chain reaction (may include other nucleic acid amplification methods); CNS, central nervous system; DNA, deoxyribonucleic acid; CSF, cerebrospinal fluid.

second blood culture, and 99.6% by at least one of the first three cultures. The timing of collection has never been demonstrated to impact the yield of blood cultures. If a patient requires immediate antimicrobial therapy, a reasonable approach is to obtain two sets of blood cultures (from separate venipunctures) prior to the institution of antibiotics. If a patient is being evaluated for fever of unknown origin or possible endocarditis, these two initial sets may be followed by a third set obtained on the first day, followed by an additional one or two sets the following day. Little additional benefit is likely to accrue from obtaining blood cultures after the first three sets—provided that at least 10–15 mL of blood is obtained with each culture. Prior receipt of antibiotics decreases blood culture yield, and most automated systems now provide media with resins to remove antimicrobials.

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Table 6 Serological Diagnosis of Selected Bacterial, Fungal, and Parasitic Diseasesa Organism/disease Amebiasis Bacillus anthracus (anthrax) Blastomyces dermatitidis Borrellia burgdorferi (Lyme) Brucella spp. Bartonella hensellae (cat scratch) Chlamydia pneumoniae Chlamydia psittici Coccidioidis immitis Coxiella burnetti (Q fever) Cryptococcus neoformans Cysticercosis Echinococcosis Ehrlichia spp. Francisella tularensis Histoplasma capsulatum Legionella spp. Leptospirosis Mycoplasma pneumoniae Rickettsia Streptococcus pyogenes Strongyloidiasis Toxocariasis Treponema pallidum Trichinosis Yersinia pestis (plague) a

Method(s)

Comments on positivity

IHA, EIA EIA CF, EIA EIA, WB Agglutination IFA CF, IFA CF EIA EIA, CF, IFA Latex agglutination WB IHA, IFA, WB IFA Agglutination CF IFA EIA CF, EIA IFA, EIA ASO titer EIA EIA FTA-ABS, MHA-TP EIA, BF Hemagglutination

ⱖ1:128 4-Fold rise, ⱖ1:64 >1:8 (CF); ⱖ32 (EIA) Confirm ⫹ EIA with WB 4-Fold rise, ⱖ1:80 4-Fold rise 4-Fold rise, IgG ⱖ 512 4-Fold rise 4-Fold rise 4-Fold rise Any titer positive Specific band(s) diagnostic Confirm ⫹ IHA/IFA with WB 4-Fold rise 4-Fold rise or ⱖ1:160 4-Fold rise, IgG ⱖ32 ⱖ1:128 Positive ⱖ1:128 Positive 4-Fold rise 4-Fold rise 4-Fold rise ⱖ1:8 ⱖ1:32 To confirm positive RPR/VDRL ⱖ1:5 4-Fold rise

CF, complement fixation; IFA, immunofluorescence assay; IHA, indirect hemagglutination; EIA, enzyme immunoassay; WB, Western blot (Immunoblot); ASO titer, anti–streptolysin O titer; FTA-ABS, fluorescent treponemal antibody adsorption; MHA-TP, microhemagglutination test for Treponema pallidum; BF, bentonite flocculation; RPR, VDRL, Venereal Disease Research Laboratory.

As previously discussed, contamination of blood culture specimens can increase costs and cause diagnostic confusion. The best preventive measure against contamination is optimal site preparation. In addition, separate venipunctures should be performed to help interpret cultures containing common skin contaminants (coagulase-negative staphylococci, diphtheroids, etc.). Obtaining blood cultures through central venous lines should be discouraged, since increased isolation of contaminants and line colonizers results. If blood cultures are obtained through central venous catheters (CVCs), a simultaneous culture from a peripheral venipuncture site should be obtained to assist in interpreting the blood culture result. For example, the isolation of coagulase-negative staphylococcus from a single bottle obtained from a CVC is less likely to be clinically significant if results of peripheral cultures obtained simultaneously are negative. The most common manual blood culture system still in use is the Isolator (Wampole Laboratories, Cranbury, NJ). This is a lysis-centrifugation system in which the cellular components in the blood are lysed, the tube is centrifuged, and the sediment is cultured onto a variety of media for isolation of microorganisms. The Isolator is still used in many

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institutions to enhance detection of some (usually fungal) organisms. Although broth-based automated systems perform comparably in the detection of virtually all bacteria and Candida spp., the lysis centrifugation system may enhance detection of certain intracellular pathogens such as Histoplasma capsulatum, Mycobacterium spp., Bartonella spp., and Legionella spp. In addition, a lysis-centrifugation method provides the flexibility to culture a blood sample immediately to special media for detection of pathogens with particular growth requirements. Some organisms are difficult to isolate in blood cultures and require special consideration by the laboratory. Brucella spp. are slow growing, fastidious intracellular organisms. Their recovery may be enhanced either through the use of lysis-centrifugation blood cultures (plated to Brucella spp. blood agar) or with prolonged incubation of blood culture bottles (up to 3 weeks) with blind subculture each week to a Brucella spp. blood agar plate. Abiotrophia spp. (formerly known as nutritionally variant streptococci) require vitamin B6 for growth. The broth based automated systems support growth of these organisms, which may not grow on a standard sheep blood agar plate after subculture. A positive signal from a blood culture and lack of growth on subculture should raise suspicion of Abiotrophia spp.—subculture to a plate streaked with Staphylococcus aureus or containing a pyridoxal (B6) disk demonstrates growth of tiny satellite colonies. Other bacteria that may require special handling to optimize recovery include Mycobacterium spp., Bartonella spp., and certain organisms from the HACEK group of fastidious gram-negative organisms responsible for some cases of ‘‘culture-negative’’ endocarditis (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). If these organisms are suspected, the laboratory should be notified to improve the likelihood of successful recovery. 7.2

Respiratory Tract Specimens

Most outpatient respiratory tract infections are treated empirically, without obtaining a specimen for culture. In general this is appropriate. Respiratory tract cultures in outpatient practice should primarily consist of throat cultures obtained for the diagnosis of group A streptococcus (for which the properly obtained throat swab culture is the gold standard). Many have questioned the value of cultures of expectorated sputum—patients with bacteremic pneumonia often do not demonstrate the offending organism in sputum culture, and sputum is frequently contaminated with oropharygeal flora. If a sputum sample is obtained, a Gram stain assists in determining whether it is appropriate for culture; in addition, the Gram stain may provide all the information necessary for initiation of antimicrobial therapy. Many bacterial respiratory tract pathogens are not easily cultured in the laboratory, requiring special media or non-culture-based detection methods. A partial list of these organisms includes Legionella spp., Mycobacterium spp., Mycoplasma pneumoniae, Chlamydia spp., Nocardia spp., and Bordetella pertussis. Text and tables in other sections of this chapter address detection of many of these organisms. 7.3

Cerebrospinal Fluid Specimens

Obtaining cerebrospinal fluid (CSF) for bacterial culture is an emergency procedure, since untreated bacterial meningitis can be rapidly fatal. Empirical treatment for suspected bacterial meningitis should never be withheld because of a delay in obtaining CSF for culture. If a lumbar puncture (LP) is delayed by difficulty in performing the procedure or the need to obtain a computed tomography (CT) scan prior to the LP, antibiotics should be admin-

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istered as blood cultures are obtained. The most common causes of bacterial meningitis (e.g., Streptococcus pneumoniae, Neisseria meningitidis) are often detectable in blood cultures, and CSF parameters are not immediately altered by antibiotic therapy. When CSF is collected for bacterial culture, it should be sent immediately to the laboratory to enhance organism detection. Commercial bacterial antigen detection procedures (for H. influenza, N. meningitidis, S. agalactiae, and S. pneumoniae) do not add significantly to Gram stain of a centrifuged CSF specimen in the diagnosis of bacterial meningitis—sensitivities of Gram stain for the detection of specific organisms in CSF are outlined in Table 7. 7.4

Urinary Tract Specimens

Specimens from voided urine are commonly contaminated with periurethral and genital tract flora. To decrease the likelihood of contamination, careful preparation of the periurethral area and collection of a midstream specimen are recommended. Even in this setting, up to a third of voided urine specimens harbor contaminants. The reason quantitative urine culture techniques are important is that they can distinguish between contamination and true infection—contaminants are generally present in quantities of <104 CFU/ ml, whereas true urinary tract infections are usually associated with bacterial concentrations of >104 CFU/ml. Most laboratories use a calibrated loop to obtain a specified standard volume of urine for culture (e.g., 0.001 ml), allowing for colony counts to provide quantitative results (e.g., 1 colony equals 1000 CFU/ml). Contaminants can sometimes be present in larger numbers (e.g., >104 CFU/ml), causing false-positive results—often as a result of a specimen’s sitting at room temperature for too long or contaminating bacteria’s growing to high levels in a urinary catheter collection bag or tube. Rapid transport of specimens to the lab (or refrigeration if a delay occurs) and careful attention to collection technique can minimize this problem. Conversely, some patients (particularly young women) can have urinary tract infection associated with <104 CFU. The laboratory should be able to alert you to a lower colony count (102 –104) of a recognized urinary tract pathogen in these situations. The bacterial species causing uncomplicated cystitis are predictable, and urine culture and susceptibility results are often not returned until after empirical antimicrobial therapy is completed. For this reason, patients with urinary tract infection may be treated on the basis of symptoms alone or symptoms plus the results of urinalysis for nitrate reductase and leukocyte esterase.

Table 7 Sensitivity of Spun Gram Stain for Detection of Bacterial Meningitis Due to Selected Pathogens Organisms Overall Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis Listeria monocytogenes

Sensitivity, % 60–90 90 50–80 75 <50

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Urinalysis

The nitrate reductase test takes advantage of the fact that most urinary pathogens (Enterobacteriaceae) produce enzymes that reduce nitrate to nitrite. False-negative results can be seen for some gram-positive uropathogens (e.g., Enterococcus spp.) that do not reduce nitrates. Leukocyte esterase is an enzyme produced by inflammatory cells and serves as a marker for pyuria. The sensitivity and specificity of this combination screen are good (sensitivity, 78%–93%; specificity, >95%) for the detection of urinary tract infection with high colony counts (>104 CFU/ml). As noted, however, patients may have urinary tract infection associated with lower colony counts (102 –104 CFU/ml). Nitrate reductase and leukocyte esterase screening tests have lower sensitivity in this case, so a negative test result in the proper clinical setting should be confirmed by a urine culture. 7.5

Genital Tract Specimens

Most genital tract specimens are submitted to the clinical microbiology laboratory for detection of two predominant pathogens, Neisseria gonorrhoeae and Chlamydia trachomatis. N. gonorrhoeae is a fastidious organism that does not grow well in the presence of other flora. For this reason, various chocolate-agar-based selective media (containing antibiotics to inhibit commensals) have been developed for isolation of N. gonorrhoeae. These media are available in transport systems (e.g., JEMBEC, Ames) that contain an individual agar plate with selective media and a CO2 generating tablet. These systems allow for immediate plating of the specimen, which improves yield (since N. gonorrhoeae is intolerant of drying and low-CO2 environments). Direct tests (nonculture) for N. gonorrhoeae are available (Table 5). Some that are based on nucleic acid amplification can be used to detect Chlamydia trachomatis simultaneously. These tests do not significantly enhance the sensitivity of a well-collected culture specimen, but they allow for detection of these pathogens in urine as well as cervical or urethral specimens. Because an organism’s DNA may persist for days to weeks after successful therapy, the nucleic acid detection tests cannot be used to test for cure. In addition, such tests are not admissible evidence in medicolegal cases (e.g., sexual abuse, sexual assault). Of the genital ulcer syndromes (herpes simplex, syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale), only one is due to a bacterial pathogen easily isolated in the laboratory—Haemophilus ducreyi, the cause of chancroid. If chancroid is considered (in contrast to syphilis, these ulcers are painful and do not have indurated margins), a swab specimen from the base of an ulcer should be collected and the laboratory notified that H. ducreyi is suspected. The diagnosis of syphilis is based on dark-field microscopy and serological evaluation, whereas herpes simplex is easily detected with direct techniques and/or viral culture. The evaluation of vaginitis is based on clinical and microscopic characteristics (Table 2). Cultures of vaginal discharge are not recommended. 7.6

Skin and Soft Tissue Specimens

Because skin and wound surfaces are colonized with bacteria that can be either pathogenic or commensal, cultures of skin, soft tissue, and wound surfaces rarely provide useful information. If an infected collection or abscess is present, careful disinfection of the wound surface prior to incision and drainage may provide good material for culture. The largest amount of material possible should be sent to the laboratory for culture—preferably in the syringe with which it was collected or in a collection tube. Rapid transport of such

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a specimen to the laboratory allows optimal detection of anaerobes or mixed aerobic– anaerobic infections. 7.7

Stool Specimens

Although most cases of acute diarrhea are self-limited, protracted or severe symptoms merit investigation, including stool cultures to identify common bacterial causes. Because stool contains so many bacteria (>1010 CFU/g), isolation of one of the few recognized enteropathogens in culture is challenging. Most laboratories routinely attempt to identify common pathogens such as Salmonella, Shigella, and Campylobacter spp. in all diarrheal stools submitted for enteropathogen detection. However, some laboratories do not routinely attempt to detect many other potential pathogens, including Aeromonas spp., Plesiomonas spp., Vibrio parahaemolyticus, Vibrio cholerae, Yersinia enterocolitica, or Escherichia coli 0157:H7. When you suspect these pathogens, you should call your laboratory to determine whether they use procedures to detect these organisms and specifically request them if they do not. A careful exposure history and attention to the epidemiological details can help to focus laboratory efforts. Toxin producing strains of Clostridium difficile commonly cause antibiotic-associated diarrhea. Since C. difficile can also be part of fecal flora without producing toxin, most laboratories do not attempt to culture the organism but offer a toxin assay. Many EIA tests are commercially available for the detection of C. difficile toxin A or B, with reported sensitivities ranging from 63% to 99% and specificities from 75% to 100%. Because of varying sensitivities, three negative toxin assay results should be obtained prior to excluding the diagnosis if the suspicion is high. Rare C. difficile strains may produce toxin B without producing toxin A, so EIA assays for toxin A only may produce some falsenegative results. In addition to having bacterial culture, patients with appropriate travel or exposure history should have stools sent for ova and parasite exam, Giardia spp. antigen, and Cryptosporidium spp. antigen detection. 8

CULTURE DETECTION OF COMMON FUNGAL PATHOGENS

Serious fungal infections have increased in frequency with an increase in numbers of immunocompromised patients (e.g., acquired immunodeficiency syndrome [AIDS], transplantation). For the clinician in the outpatient setting, few occasions call for culture identification of fungal pathogens. Mucocutaneous fungal infections are generally diagnosed clinically and treated empirically (e.g., yeast vaginitis, oropharyngeal candidiasis). An extremely wide variety of fungi can cause skin infection (dermatophytes); culture and species level identification of these organisms serve little purpose in most clinical settings. In some clinical situations it is important to know the identity of a fungal pathogen in outpatient practice. For example, refractory oropharyngeal candidiasis in an AIDS patient may require culture for susceptibility testing of the Candida spp. responsible. Table 8 gives recommendations for studies that should be available in the laboratory to assist in the management of fungal infections. 9

CULTURE DETECTION OF COMMON VIRAL PATHOGENS

Laboratory detection of viruses includes (1) culture techniques for viral isolation, (2) rapid assays that detect viral antigens (e.g., EIA, LA), (3) nucleic acid amplification techniques (e.g. PCR), and (4) serological tests that detect antibody response to viral infection.

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Table 8 Recommendations for Studies of Fungal Isolates from Clinical Specimens (Outpatient) Setting

Recommendation

Routine

Species level identification of all Candida spp. isolates from sterile sites Genus level identification of molds Routine antifungal susceptibility testing not recommended; some institutions may wish to batch test annually to establish local antibiogram

AIDSa and oropharygeal candidiasis

Routine antifungal susceptibility testing not required Susceptibility testing potentially useful in patients unresponsive to treatment Relevant drugs: fluconazole, itraconazole

a

AIDS, acquired immunodeficiency syndrome.

Viral culture involves growing viruses in cell lines and observing for cytopathic effect (CPE). Each virus grows best in particular cell lines. When CPE is detected, definitive identification of the virus can proceed by using antigen detection techniques (e.g., direct or indirect fluorescent antibody assays) or molecular methods. Shell vial assays are modifications of viral culture in which the inoculum is centrifuged onto a cell monolayer grown on a circular cover slip. The cover slips can be removed early in the incubation period (18–48 hours), at which time direct fluorescent antibody assay (DFA) or indirect fluorescent antibody assay (IFA) can be performed to detect viral antigens prior to the development of CPE. Shell vial techniques and rapid detection assays have greatly reduced the time needed for diagnosis of many viral infections. Serological evaluation remains a common method for diagnosis of viral infections. Serological data for viral pathogens must be interpreted in light of the usual time course of infection, the particular antibody detected, and the nature of the viral antigen to which the immune response is measured. For many common viral infections (e.g., Herpes simplex virus) serological analysis is of limited utility—except to document previous infection. Viral infections diagnosed by serological analysis include Epstein-Barr virus, parvovirus B19, rubella virus, hepatitis viruses (A, B, C, D, E, G), HIV, human T-cell lymphotropic viruses (HTLV-1 and HTLV-2), arboviruses (encephalitis viruses, dengue, Colorado tick fever virus), and hantaviruses. Rapid, direct detection of viral antigens or nucleic acids has revolutionized viral diagnostics. A partial listing of commonly used direct viral detection methods can be found in Table 5, but new tests are introduced regularly. Given the complexity and rapid evolution of viral diagnostics, it is best to call the laboratory prior to collecting and sending a specimen for virus detection. In addition, if you collect specimens for viral diagnostics, up-to-date viral transport media should be readily available in your office refrigerator to prevent undue delays in specimen collection. 10 10.1

ANTIMICROBIAL SUSCEPTIBILITY TESTING Bacteria

Increasing rates of resistance of common bacterial pathogens to antibiotics are a worldwide crisis. Several systems for antibiotic susceptibility testing (AST) are available to the clin-

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ical microbiology laboratory. Traditional reference methods include macro- or microtube dilution, which provides an exact measure of minimal inhibitory concentration (MIC), and disk diffusion, which provides a zone of inhibition that is converted to a categorical value of susceptible, intermediate, or resistant. In the United States, the breakpoint MICs and zone diameters that define these categories are set by the National Committee on Clinical Laboratory Standards (NCCLS). Conventional tube dilution or disk diffusion AST has been replaced in many laboratories by automated commercial systems, which are convenient, less-labor intensive, and more rapid for many organisms. The Etest (AB Biodisk, Solna, Sweden), a gradient diffusion system, is based on disk diffusion but allows for determination of MICs by using an agar-based method. Although AST results can be useful to help guide treatment, they are often not predictive of the success or failure of antimicrobial therapy. The susceptibility of an organism to an antibiotic should always be interpreted in light of the clinical setting, site of infection, and response to empirical therapy. For example, it is well recognized that penicillin resistance in S. pneumoniae is clinically relevant for closed space infections (e.g., meningitis and otitis media) but does not appear to correlate with clinical response in cases of pneumonia. This is because much higher penicillin concentrations reach lung tissue than may cross into middle ear fluid or CSF. Likewise, there is little correlation between susceptibility category and successful treatment of urinary tract infection for antibiotics that are concentrated to high levels in the urine. 10.2

Fungi

Antifungal susceptibility testing advanced considerably in the 1990s. A standardized testing method for yeast isolates to fluconazole and itraconazole is now available in many laboratories. The correlation between antifungal susceptibility testing and clinical outcome has been established mainly in the therapy of oropharyngeal candidiasis in AIDS patients. Table 8 gives current recommendations for susceptibility testing of fungal isolates in clinical laboratories. 10.3

Viruses

Antiviral susceptibility testing in the outpatient setting is limited primarily to genotypic and/or phenotypic testing of HIV for patients on antiretroviral therapy. Rarely, a patient with refractory herpes simplex virus (HSV) infection may harbor an acyclovir-resistant strain, and it is not uncommon for cytomegalovirus-causing retinitis to develop resistance to antiviral therapy. These resistances are usually suspected clinically and treated empirically, but they can be detected in referral or research laboratories.

11

CONCLUSION

Diagnostic testing for infectious agents is advancing rapidly, as new methods for rapid or molecular detection of pathogens become available each year. In addition, as new emerging pathogens are described, new diagnostic tests soon follow. The future holds many exciting prospects, including rapid direct detection of bacterial pathogens in clinical specimens— and perhaps the rapid direct detection of resistance genes in the same samples. The astute clinician will keep abreast of the literature, in order to adopt those technologies most likely to have a direct, beneficial impact on patient management in the office setting.

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BIBLIOGRAPHY Cockerill FR. Conventional and genetic laboratory tests used to guide antimicrobial therapy. Mayo Clin Proc 73:1007–1021, 1998. Gill VJ, Fedorko DP, Witebsky FG. The clinician and the microbiology laboratory. In: Mandell GL, Bennett JE, Dolin R, ed. Principles and Practice of Infectious Diseases. 3rd ed. Philadelphia: Churchill Livingstone, 2000, pp 184–221. Hines J, Nachamkin I. Effective use of the clinical microbiology laboratory for diagnosing diarrheal diseases. Clin Infect Dis 23(S1):S97–S101, 1996. Isenberg HD. Essential Procedures for Clinical Microbiology. Washington, DC: American Society for Microbiology Press, 1998. Lewis RE, Klepser ME, Pfaller MA. Update on clinical antifungal susceptibility testing. Pharmacotherapy 18:509–515, 1998. Miller JM. A guide to specimen management in clinical microbiology. 2nd ed. Washington DC: American Society for Microbiology Press, 1999. Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical Microbiology. 7th ed. Washington, DC: American Society for Microbiology Press, 1999. Pezzlo M. Detection of urinary tract infections by rapid methods. Clin Microbiol Rev 1:268–280, 1988. Reimer LG, Carroll KC. Role of the microbiology laboratory in the diagnosis of lower respiratory tract infections. Clin Infect Dis 26:742–748, 1998. Reimer LG, Wilson ML, Weinstein ML. Update on the detection of bacteremia and fungemia. Clin Microbiol Rev 10:444–465, 1997.

6 Outpatient Parenteral Antibiotic Therapy Donald M. Poretz Inova Fairfax Hospital, Falls Church, Virginia, U.S.A.

1

INTRODUCTION

Traditionally, the treatment of certain infections such as osteomyelitis, infective endocarditis, and severe wound infections has required hospitalization for up to several weeks to administer parenteral antibiotics. Over the past several years, however, many of these infections have been shown to be treated effectively and safely on an outpatient basis with parenteral antibiotics. Extensive experience has documented clinical efficacy and cost saving for outpatient parenteral antibiotic therapy (OPAT), and in many instances this has become the standard of care for a variety of infectious processes. Most of the initial studies focused on bone and joint infections. Currently, though, a wide variety of other infectious diseases have been shown to be amenable to outpatient treatment, including soft tissue and wound infections, osteomyelitis, septic arthritis and prosthetic joint infections, pneumonia, sinusitis, otitis media and mastoiditis, endocarditis and vascular graft infections, visceral abscesses, complicated urinary tract infections, pelvic inflammatory disease, meningitis, neutropenic fevers, bacteremias, fungal infections, severe herpetic infections, and cytomegalovirus infections. The advent of new potent antimicrobics with prolonged half-lives that can be infused over 30 to 60 minutes without sacrificing antimicrobial activity together with miniaturized infusion devices that allow for ease of administration have made OPAT a reasonable alternative to hospitalization. Additionally, economic pressures from third-party payers and managed care providers have promoted less expensive alternatives to hospitalization. New drugs with excellent bioavailability have expanded the types of infections being treated orally. Agents such as the flouroquinalones (ciprofloxacin, levofloxacin, gatifloxacin), macrolides (azithromycin), clindamycin, metronidazole, trimethoprim-sulfamethoxazole, and doxycycline are very well absorbed orally and should be used parenterally only if the patient is unable to take them orally. An approach to the patient being considered for OPAT is outlined in Figure 1. Infectious disease consultation should be considered prior to the initiation of OPAT to assist with patient selection, antimicrobial use, and type of venous access and to help with drug and complication monitoring. 115

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OUTPATIENT PARENTERAL ANTIBIOTIC THERAPY Complex (Table 1) ID consultation suggested Adverse effects (Table 7) Need for close monitoring (Table 6) Amenable to a wide array of infections (Table 3) Varied venous access devices (Table 2 and Figure 2) Cost savings compared to hospitalization Antibiotics expensive (Table 5) More convenient for patient Team approach needed Physician Nurse Pharmacist Supply vendor Patient Attending physician ultimately responsible Approach to the patient when OPAT considered (Figure 1)

2

PATIENT SELECTION

The primary consideration in selection of candidates for OPAT is the clinical status of the patient. Experience has shown that certain criteria are necessary to evaluate a candidate for outpatient therapy (Table 1). The patient’s vital signs should be stable with body temperature either being normal or heading in that direction. If a wound is present, the drainage needs to be contained in a bandage that is easily manipulated by the patient, the patient’s family member, or a health care provider. In cases of infective endocarditis, there should be no recent evidence of embolic phenomena, conduction abnormalities, or congestive heart failure. Patients with respiratory infections should be able to handle their own secretions. Any concurrent disease such as diabetes mellitus obviously requires appropriate attention. The patient and his or her family must be educated about all aspects of OPAT and what their responsibilities will be, and consideration given to family responsibilities such as care of small children or elderly patients that could hinder compliance. Adequate venous access needs to be established. Consideration of the patient’s social circumstances and general psychological state is important. Patients need to understand that their medications have to be administered at regular specific intervals either by them, a family member, or a home care provider. Contraindications for OPAT include drug abuse, alcoholism, psychotic behavior, or a home environment that would prohibit proper treatment because of lack of electricity, running water, refrigeration, or adequate cleanliness. Financial considerations including reimbursement by third-party payers must be investigated before OPAT is instituted. An understanding of the cost of drugs, equipment, and other aspects of home and outpatient care is important. The attending physician is ultimately responsible for any potential adversities associated with OPAT.

Outpatient Parenteral Antibiotic Therapy

Figure 1 Approach to outpatient parenteral antibiotic therapy (OPAT).

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Table 1 Candidates and Contraindications to Outpatient Parenteral Antibiotic Therapy Candidates Inability to take oral medications Organism sensitive to parenteral antimicrobials only Infection amenable to OPAT (Table 3) Adequate insurance Ability to insert and maintain chronic venous access Stable and safe home environment Good patient compliance Contraindications Active drug and alcohol abuse Poor compliance Psychiatric and social instability

3 3.1

EQUIPMENT REQUIRED Catheters

Several intravenous access devices are commercially available to treat individuals on an outpatient basis (Table 2). For short courses of therapy lasting for a few days, a butterfly needle, also called a winged infusion needle, can be used. These devices are short, insert easily, and can usually accept 30- to 60-minute infusions without infiltrating. They infiltrate easily, though, and are difficult to stabilize. They are infrequently used for individuals who require prolonged courses of therapy. A heparin lock, also called an over-the-needle catheter or angiocatheter, is commonly used for short-term therapy lasting from a few days to a couple of weeks. These lines can be difficult to insert when patients have poor venous access and like the butterfly needle cannot be used by individuals who need prolonged courses of therapy. Several catheters that can be used for prolonged periods are illustrated in Figure 2. Midline catheters fill the void between short peripheral devices and longer central catheters. These catheters are typically 6 to 10 inches in length. They are inserted into the antecubital fossa but do not enter the thoracic cavity and are therefore not true central catheters. They are made of elastomeric hydrogel that softens and expands when in contact with the venous system. Heparin must be used to prevent clotting, and sterile dressing changes are recommended. Midline catheters can be kept in place for several weeks. There have been reports of anaphylactic-type reactions associated with some of these catheters. Peripherally inserted central venous catheters (PICCs) are commonly used for longterm therapy in individuals with poor venous access. They are inserted in the antecubital fossa and threaded into the superior vena cava. These lines are particularly useful when irritating solutions are being infused. Sterile dressing changes are required and maintenance with heparin is necessary. A chest radiograph must be taken after insertion to make sure that the tip of the catheter lies in the superior vena cava. Indwelling surgically introduced central venous catheters (CVCs) such as Groshong and Hickman catheters are good for long-term therapy (many months or even years). Hickman catheters require daily maintenance with heparin, whereas Groshong catheters require weekly maintenance with saline solution. They both require frequent dressing changes. Potential complications of insertion include pneumothorax, hemohydrothorax,

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Table 2 Intravenous Access Devicesa Device

Duration of use

Advantages

Butterfly

Day(s)

Heplock

Days

Midline

Weeks

PICC

Weeks to months

Long duration of use Safety of insertion

CVC Groshong Hickman

Weeks to months

Long duration of use Can draw blood from

Central port Port-A-Cath Mediport

Months to years

Long duration of use Can draw blood from Less maintenance than CVC Lower infection rates

a

Ease of insertion small infection risk Ease of insertion limited infection risk Ease of insertion limited infection risk

Disadvantages Short duration of use Short duration of use Not a true central catheter; requires heparin flush Need for professional insertion and maintenance Requires heparin flush Infection, thrombophlebitis Clotting Invasive procedure Need for professional insertion and maintenance Requires heparin or saline solution flush Invasive procedure Need for professional insertion and maintenance Access by Huber needle Requires heparin or saline solution flush

PICC, peripherally inserted central catheter; CVC, central venous catheter.

hemorrhage, air embolism, venous thrombosis, catheter thrombosis, catheter tip migration, and catheter sepsis. Blood can be drawn from these lines, eliminating the need for potential repeat venipunctures. Implanted catheters (Port-A-Cath and MediPort) are disklike devices with which the entire access system is placed under the skin. They are good for long-term therapy and infusion of irritating solutions. Less maintenance is required, but they require surgical placement and access for intravenous therapy with a special Huber needle. Some patients prefer these devices because they are cosmetically more acceptable. They have the same insertion complications as CVCs. 3.2

Infusion Devices

Antibiotics can be administered via several types of mechanical infusion devices. The simplest and least expensive method is the gravity drip bag. This is often used in conjunction with a lyophilized antibiotic that is mixed with sterile precautions into the bag before infusion. Fixed rate infusion pumps include elastomeric reservoirs or electronic syringe pumps. Elastomeric reservoirs have distended balloons that force the medication through a capillary tube, with a fixed resistance, allowing for a preset rate of drug infusion

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Figure 2 Torso showing positions of midline catheter in the right arm, peripherally inserted central catheter (PICC) in the left arm, tunneled central venous catheter (CVC) in the left chest, and implanted infusaport in the right chest. All catheters, except the midline, enter the chest cavity. The catheter tip generally resides in the superior vena cava.

wherever the device is placed in relation to the body. Programmable pumps allow drugs to be administered from a cassette or external reservoir at a determined rate and interval. These programmable pumps can infuse antibiotics intermittently and are useful for administration of antibiotics with short half-life and frequent dosing intervals such as benzyl penicillin (every 4 hours). The antibiotic cassettes can be replaced once daily. These devices, which offer accuracy and convenience, also add to the cost of infusions.

4

LOCATION

Patients who are receiving OPAT can be infused with medication at infusion centers, in the physician’s office, or at home. An ‘‘infusion center’’ often incorporates physicians’ offices, laboratory and treatment facilities, and nursing, pharmacy, and financial services under one roof. It essentially functions as a daytime hospital but with much easier access for patients. The main advantage of these centers is that physicians are on site to exercise maximal control over the infusions. Patients can be examined, laboratory studies can be obtained as necessary, the entire staff is on hand to handle any complications or emergencies as they arise, and communication among physicians, nurses, pharmacists, and

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administrators is instantaneous. The infusion center is an ideal location to care for higherrisk patients who cannot be treated effectively and safely at home. Office-based infusion is similar to the infusion center concept but without all of the ancillary personnel. Antibiotic administration in the office setting requires careful scheduling to ensure that office space needed for regular practice activities is not occupied by patients who require infusions. A third OPAT model is infusion of patients with antibiotics at home. This procedure is often contracted to a commercial home infusion company that supplies trained personnel, antibiotics, and all other necessary intravenous equipment, although some physicians are able to administer these programs through their own office. Home infusions are usually given by nurses who specialize in intravenous therapy or by the patients themselves. Nurses examine the patient at regular intervals, change the intravenous devices when indicated, maintain sterile technique, manage catheter dressings and flushing, and communicate with the attending physician. Each home infusion company has its own quality assurance guidelines, but it is important to emphasize that the attending physician is still ultimately responsible for the care of the patient regardless of who is administering the medication. 5

TREATABLE INFECTIONS

Experience from many centers has shown that a wide variety of infections requiring parenteral antibiotics can be treated on an outpatient basis (Table 3). Many of these patients may require therapy for up to 6 weeks, and some may need rehospitalization for de´bridement of wounds and other surgical procedures but can be quickly discharged to resume their care at home. These patients may also have diabetes mellitus, renal insufficiency, and other medical problems that also need to be closely monitored. Because these patients require prolonged therapy, long-line vascular access (PICC, CVC, or port) devices are commonly used. Osteomyelitis and skin and soft tissue infections are probably the most common entities treated outside the hospital. Patients with chronic urinary tract infections including those with neurogenic bladders, recurrent prostatic disease, congenital abnormalities of the urinary tract, and other chronic conditions often have infections caused by microorganisms that are susceptible to drugs that can only be given parenterally. These patients can often be treated as outpatients without ever being admitted to the hospital. Various pulmonary infections including acute exacerbations of chronic bronchitis, cystic fibrosis, and bron-

Table 3 Infections Amenable to Outpatient Parenteral Antibiotic Therapy Bone, joint, and soft tissue Genitourinary Ears, nose, and throat Pulmonary Intraabdominal Endovascular Prosthetic device Infections associated with immunodeficiency states Febrile neutropenia (nonseptic)

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chiectasis are amenable to outpatient therapy. Ear, nose, and throat infections including acute and chronic sinusitis recalcitrant to oral antibiotic therapy are additional conditions that can be safely treated on an outpatient basis. Endothelial surface infections such as infective endocarditis and infected vascular grafts often require prolonged intravenous therapy. Assuming patients are free of emboli and conduction abnormalities and are not in congestive heart failure, OPAT is an acceptable alternative to hospitalization as long as patients are monitored closely. More recently, opportunistic infections associated with the acquired immunodeficiency syndrome (AIDS) that require intravenous medications including acyclovir, ganciclovir, cidofovir, foscarnet, and amphotericin B have been effectively treated outside the hospital. Additionally, it has been shown that febrile neutropenic patients who are not septic can be begun on outpatient intravenous therapy after blood cultures are obtained without exposure to a potentially more pathogenic hospital environment. Regardless of the type of infection being treated, patients usually elect to be treated either at home, in a doctor’s office, or in an infusion center rather than a hospital. Figures 3–7 illustrate varied infections treated by OPAT.

6

ANTIBIOTICS USED IN THE OUTPATIENT SETTING

Almost any antibiotic can be administered in the outpatient arena. Those that have longer half-lives and are not irritating to veins have been particularly well accepted by patients and prescribing physicians (see Table 4). Ceftriaxone, for example, needs to be given only once daily, is non venoirritative, and has few side effects. Aminoglycosides are easily administered on an outpatient basis, both intravenously and intramuscularly, and are commonly given once daily. Monitoring of trough levels of aminoglycosides and vancomycin correlates well with potential nephrotoxicity (see Chapter 4, Tables 3 and 4). A knowledge of serum half-life, potential side effects, and drug interactions is necessary before a final decision is made as to which antimicrobic will be used. The cost of these antibiotics is often quite high (see Table 5).

Figure 3 Heel ulcer with contiguous osteomyelitis of the calcaneus (polymicrobic).

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Figure 4 Saphenectomy site infection secondary to Staphylococcus aureus and Streptococcus pyogenes.

7

MONITORING OF PATIENTS

Patients receiving OPAT need to be carefully monitored, wherever they are receiving their medications. Protocols and teaching guides that include explanations of parenteral antibiotic therapy, aseptic technique, and emergency procedures should be written and followed carefully by nurses, pharmacists, and physicians administering the medications. Patients need to be physically evaluated at regular intervals, and appropriate laboratory studies should be maintained on a flow sheet for rapid review (see Table 6). Complete blood counts and renal and hepatic function should be tested once or twice weekly.

Figure 5 Cytomegalovirus retinitis.

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Figure 6 Facial cellulitis and abscess secondary to Staphylococcus aureus infection.

The most common side effects seen with parenteral antibiotics include gastrointestinal complaints such as nausea, loose stools, and abdominal discomfort. Occasionally significant diarrhea, which may be related to Clostridium difficile toxin production, occurs. This may necessitate changing to a different antibiotic or adding oral metronidazole. Other common reactions related to antibiotics include a variety of rashes and renal and hepatic toxicities. A peculiar disulfiram-like reaction to cephalosporins with a methylthiotetrazole side chain (cefamandole, cefoperazone) can be seen when alcohol is taken concurrently with one of these drugs. Therefore, all patients should be told that they cannot consume alcohol while they are taking these medications. Vancomycin can be associated with ‘‘redman syndrome,’’ a flushing erythema of the upper torso that may occur during infusion.

Figure 7 Infected skull prosthesis secondary to coagulase-negative Staphylococcus spp. infection.

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Table 4 Half-Life of Selected Antibiotics Antibiotic Cefazolin Ceftriaxone Ceftazidime Ampicillin Nafcillin Meropenem Imipenem

Half-life, h 1.5 7.0 2.0 1.0 0.5 1.0 1.0

Table 5 Dosing and Cost of Commonly Used Parenteral Antibiotics Dose

Cost per dose in dollarsa

1–4 ⫻ 106 U 1–2 g 3g 1–2 g 3.1 g 4.5 g 1–2 g 1.5 g 1–2 g 1–2 g 1–2 g 500 mg 1g 1–2 g 700 mg (7 mg/kg/day for 100-kg person) 700 mg (7 mg/kg/day for 100-kg person 600 mg 500 mg 1g 50 mg (0.5 mg/kg for 100-kg person) 500 mg (5 mg/kg for 100-kg person) 300–500 mg (3–5 mg/kg for 100-kg person) 200–400 mg 500 mg 500 mg 400 mg 500 mg

0.89–3.56 1.55–3.10 15.50 3.15–6.30 15.40 21.93 2.60–5.20 13.80 14.70–29.40 45.60–91.2 17.06–34.12 31.00 52.56 16.98–33.96 12.64

Drug (trade name) Penicillin G Ampicillin Ampicillin-sulbactam (Unasyn) Nafcillin Ticarcillin-clavulanate (Timentin) Piperacillin-tazobactam (Zosyn) Cefazolin Cefuroxime (Zinacef) Ceftazidime (Fortaz) Ceftriaxone (Rocephin) Cefepime (Maxipime) Imipenem (Primaxin) Meropenem (Merem) Aztreonam (Azactam) Gentamicin Tobramycin Clindamycin Azithromycin (Zithromax) Vancomycin Amphotericin B (Fungizone) Amphotericin B lipid complex (Abelcet) Amphotericin B Liposone (Ambisome) Fluconazole (Diflucan) Acyclovir Ganciclovir (Cytovene) Ciprofloxacin (Cipro) Levofloxacin (Levaquin) a

Average wholesale price (2000 Drug Topics Red Book).

63.00 26.25 24.40 27.50 11.64 1000.00 1130.40–1884.00 87.60–175.20 40.00 35.67 30.00 39.60

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Table 6 Laboratory Parameters That Should Be Monitored during Outpatient Parenteral Antibiotic Therapy Times per week Antiinfective agent

␤-Lactams Aztreonam Cephalosporins Imipenem Meropenem Piperacillin Ticarcillin Aminoglycosides

Complete Creatinine Potassium Magnesium blood count level level level 1

1

1 1

1 2

Clindamycin Vancomycin Trimethoprimsulfamethoxazole Pentamidine

1 1 1

1 2 1

1

2

2

2

2

Amphotericin B Fluconazole Ganciclovir Acyclovir Foscarnet

1 1 2 1 1

2 1 1 1 2

2

2

1

1 1

Cidofovir

1

1

Other Nafcillin, oxacillin, ceftriaxone; monitor LFTs weekly

2 Peak and trougha levels, consider audiograms Trough levelsb

Daily glucose level; chemistry profile 2⫻/wk

Chemistry profile, calcium 1⫻/wk Urinalysis and chemistry profile 1⫻/wk

a

See Chapter 4, Tables 3 and 4. See Chapter 4, Table 5. Source: Williams et al. 1997.

b

This can often be controlled when the infusion is slowed to 1–2 hours or the patient is pretreated with an antihistamine. The first dose of any antibiotic should always be given in the presence of either medical or nursing personnel to make sure that an acute accelerated allergic reaction does not occur. The most common laboratory abnormality noted during infusions of ␤-lactam antibiotics, but also seen in patients who are receiving clindamycin and vancomycin, is leukopenia, which is usually dose-related and reverses within a few days after the drug is discontinued. Elevation of liver enzyme levels may be nonspecific or related to the antibiotic being used. Attention to drug levels is of particular importance when aminoglycosides (peak and trough) or vancomycin (trough only) is being administered. Infections are uncommon when heparin locks are used. Midline catheters, PICC lines, and CVCs can cause localized inflammation and infection at the insertion site, thrombophlebitis along the course of the catheter, venous thrombosis, and bacteremias. These longer catheters occasionally clot, requiring thrombolytic therapy or removal, or may break or leak, requiring replacement (see Table 7).

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Table 7 Adverse Effects of Outpatient Parenteral Antibiotic Therapy Catheter related Phlebitis and thrombosis Access site infections Bacteremia Drug toxicity–related Leukopenia Elevated liver enzyme levels Renal toxicity Clotting abnormalities Antabuse effect Diarrhea and C. difficile colitis Infusion-related Vasovagal reactions Red man syndrome Drug interactionsa a

See Chapter 4, Table 4.

8

FINANCIAL AND LEGAL CONSIDERATIONS

Several studies have documented a 50%–75% reduction in cost when comparing OPAT to in-hospital care. Many third-party payers have recognized these dramatic financial savings and have routinely included this type of coverage in their policies. As of this writing, Medicare has not covered OPAT, although several legislative bills have been awaiting congressional approval to make this a covered service. As hospitals and physicians become more involved in home health care programs, medicolegal liability will also become an important issue. There have been a few instances of litigation by patients who have experienced adverse events while being treated as outpatients, the most common of which is ototoxicity from aminoglycosides, but other adverse reactions will undoubtedly occur. When a patient is discharged from the hospital to receive parenteral antibiotics as an outpatient, the physician who signs the orders is ultimately responsible for any potential complication. Doctors who wish to participate in overseeing outpatient intravenous programs need to understand all aspects of this type of care and carefully monitor their patients. BIBLIOGRAPHY Francioli P, Etienne J, Hoigne R, Thys J-P, Gerber A. Treatment of streptococcal endocarditis with a single daily dose of ceftriaxone sodium for four weeks. JAMA 26:264–267, 1992. Gilbert DN, Dworkin RJ, Raber SR, Leggett JE. Outpatient parenteral antimicrobial-drug therapy. N Engl J Med 337(12):829–838, 1997. Outpatient parenteral antibiotic therapy. Infec Dis Clin North Am 12(4):1998. Outpatient parenteral antimicrobial therapy: Current status. Proceedings of an OPAT Advisory Board Meeting, May 16–18, 1996, Chicago. A special report from Scientific American Medicine, July 1997. Poretz DM. High tech comes home (editorial). Am J Med 91(5):453–454, 1991. Poretz DM. Home intravenous antibiotic therapy. Clin Geriatr Med 7:749–763, 1991. Poretz DM. Commentary: A decade’s experience. IDCP 4(3):217–218, 1995.

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Tice AD. Outpatient parenteral antibiotic therapy: Management of serious infections. Hosp Pract 28(suppl 1 and 2):6–10, 36–39, 1993. White MC, Ragland KE. Surveillance of intravenous catheter-related infections among home care clients. Am J Infect Control 22:231–235, 1994. Williams DN, Rehm SJ, Tice AD, Bradley JS, Kind AC, Craig WA. Practice guidelines for community-based parenteral anti-infective therapy. CID 25:787–801, 1997.

7 Fever and Rash Mary Beth Ramundo University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

The differential diagnosis of fever and rash in an adult is quite extensive and includes a variety of infectious and noninfectious causes. Some of these are infectious disease emergencies such as toxic shock syndrome and meningococcemia. Others such as measles are a public health risk. Making a timely and specific diagnosis in an adult with a fever and rash is extremely important. There are a limited number of ways the skin can react to an infection. Generally the diagnosis cannot be made through the characteristics of the rash alone; a characteristic rash can be suggestive of a specific etiology but is usually not diagnostic. A specific type of rash may not be unique to a particular pathogen. The skin manifestations associated with a specific infectious agent may be variable, and different types of skin lesions may be seen at different times in the course of one infection. Host factors such as neutropenia may also affect the way the skin reacts to infection. Skin lesions associated with infection can result from several different mechanisms. Organisms may replicate within the skin itself. They can produce toxins that can damage the skin or elicit an inflammatory response. Vascular involvement can result in skin lesions. Multiple mechanisms of skin damage may be involved simultaneously. A microorganism can have systemic effects not only on the skin (exanthem) but also on the mucous membranes (enanthem). This chapter concentrates on systemic infections that cause fever and rash. Chapter 8 reviews the more common noninfectious causes of fever and rash, and Chapters 19 and 20 review localized bacterial and nonbacterial infections of the skin, respectively.

2

APPROACH TO THE PATIENT

A thorough history is extremely important in limiting the differential diagnosis for the adult with fever and rash (see Table 1). Exposures to potential pathogens should be sought, including those related to occupation, contact with ill individuals or animals, ingestion of specific foods, sexual practices, and insect bites. Knowledge of known allergies may be useful. A thorough medication history including vaccines and the use of over-the-counter medications should be obtained. Past medical history is especially important in regard to 129

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APPROACH TO THE PATIENT WITH FEVER AND RASH Obtain a thorough history (Table 1) Characterize the rash (Table 2) Assess for life-threatening illnesses (Table 3) Compare risks and exposures with the type of rash to help determine the differential diagnosis (Table 4)

a patient’s immune status. History of a heart murmur or splenectomy may be especially important. Social history should include questions regarding injection drug use (IDU) and travel. The time of year may be a vital consideration in the differential diagnosis. The history should also include specifics about the rash such as when and where the lesions were first noticed, the nature of the lesions, the timing of the development of the skin findings with any associated symptoms, the pattern of spread or any change in the morphological features of the lesions, and painful or pruritic effects of the lesions. When examining the patient who has a fever and rash, it is important to examine the entire skin surface in good light, preferably natural light. As some skin lesions may

Table 1 Important Historical Information in Evaluation of the Adult with Fever and Rash Allergies Medications Past and present Immunosuppressives Vaccines Over-the-counter medications Corticosteroids Past medical history Valvular heart disease Renal failure Diabetes mellitus Liver disease

Rash Where and when it appeared Pattern of spread Type of lesion (Table 2) Timing of rash Associated symptoms Pain or pruritus Change in morphological features of lesions

Immune status Malignancy Transplantation Splenectomy Human immunodeficiency virus Social history Occupation Travel (domestic and foreign) Animal contact Injection drug use Contact with ill persons Insect exposure Sexual practices Alcohol use

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be contagious, it is advisable to wear gloves for the exam. The lesions should be palpated. In addition to accurate characterization of the skin lesions, attention to their distribution and arrangement is necessary. For example, are the lesions grouped or linear in their arrangement? Mucous membranes in both the oral and genital regions, in addition to the scalp, hair, nails, and intertriginous areas, should all be examined. Lymphadenopathy, hepatosplenomegaly, joint effusions, and heart murmurs should be looked for. The differential diagnosis of fever and rash in an adult can be approached by assessment of the predominant type of skin lesion. Thus, it is important that the skin findings be accurately characterized. Table 2 summarizes the types of common skin lesions. Several dermatological definitions and examples follow. A macule is a flat discoloration less than 1 centimeter in diameter and is exemplified by a freckle. A patch is a large macule; a cafe´ au lait spot is considered a patch. Papules are elevated and palpable but measure less than 1 centimeter in diameter; molluscum contagiosum is best described as an umbilicated papule. A plaque is a flat-topped raised lesion measuring more than 1.5 centimeters in diameter; the lesions of psoriasis can be described as plaques. Nodules are rounded raised lesions greater than 1 centimeter in diameter. Tumors are usually greater than 2 to 3 centimeters in diameter. Vesicles are well-circumscribed, fluid-filled lesions up to 1 centimeter in diameter. Vesicles that are greater than 1 centimeter in diameter are classified as bullae. Pustules are elevated lesions filled with pus. A wheal or hive is a well-demarcated, elevated lesion that is usually pink in color and present for less than 24 hours. Petechiae and purpura represent bleeding into the skin, may or may not be palpable, and do not blanch with pressure. Ecchymoses are large areas of bleeding into the skin. Certain infections can present a diffuse erythema that blanches with minimal pressure. Crusts, scales, ulcers, and excoriations are secondary lesions that can complicate any of the primary skin lesions. An assessment of the degree of illness of the patient is important. Unstable vital signs or an acutely ill appearance suggests a life-threatening illness, the need for hospitalization, and urgent empirical therapy (see Table 3). Rashes can be divided into six categories: macules/papules, diffuse erythema, vesicles/bullae, nodules, petechiae/purpura, and urticaria. Combining information from the history and the type of rash can help determine the causative agent (see Table 4).

Table 2 Types of Skin Lesions Macule = flat discoloration <1 cm in diameter Patch = flat discoloration >1 cm in diameter Papule = solid elevated lesion <1 cm in diameter Plaque = flat-topped elevated lesion >1.5 cm in diameter Nodule = rounded elevated lesion >1 cm in diameter Vesicle = fluid-filled elevated lesion up to 1 cm in diameter Bulla = vesicle >1 cm in diameter Pustule = elevated lesions filled with pus Wheal = well-demarcated raised lesion lasting <24 hours Petechiae = pinpoint hemorrhage Ecchymosis = large areas of bleeding into the skin Diffuse erythema = large area of redness that blanches with pressure

Maculopapular rashb Headache Leukopenia, thrombocytopenia Petechiae and purpura or maculopapular rash Sepsis and shock Erythema marginatum

Ehrlichiosis

Viral hemorrhagic syndrome

GNR sepsis

Typhoid

Rheumatic fever

Petechiae and purpura

‘‘Rose spots’’ rash Diarrhea or constipation Hepatosplenomegaly Ichthyma gangrenosum

Petchiae and purpura

RMSF

Capnocytophaga spp.

Petechiae and purpura or maculopapular rash Sepsis and shock

Presentation

Meningococcemia

Infection

International travel

Neutropenia

International travel

Contact with ill persons in confined areas such as schools or military barracks Tick bite Travel to southeastern and south central U.S. Tick bite Travel to northeastern, southeastern, or south central U.S. Dog contact, especially dog bite Cat bite or scratch S. pyogenes pharyngitis

Risk/exposure

Table 3 Life-Threatening Illnesses That Cause Fever and Rasha

Serological evaluation

Blood culture

Blood, stool, bone marrow culture

Jones criteria (see Chapter 8)

Blood culture

Serological evaluation Morulae on blood smear

Serological Skin biopsy

Skin lesion aspirate for Gram stain and culture Blood culture

Diagnosis

Ceftazidime or ciprofloxacin for Pseudomonas spp. Supportive

Supportive Salicylates Ciprofloxacin

Ceftriaxone

Tetracycline

Tetracycline

PCN G Ceftriaxone

Treatment

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b

a

Diffuse erythroderma Lymphadenopathy Hepatosplenomegaly Diffuse erythroderma Lymphadenopathy Conjunctivitis and pharyngitis

Bullae

Scarlet fever–like rash Flaccid bullae that rupture readily Diffuse erythroderma Shock Multiorgan involvement

Young children More common in Japanese

Clinical syndrome

Dilantin use Skin biopsy

Skin biopsy

Criteria (Table 7)

Staphylococcal or streptococcal infections

Drugs, especially phenytoin, barbiturates, sulfonamides, penicillins, and allopurinol Dilantin

Blood culture Skin biopsy

Neonates and young children

PCN, penicillin; RMSF, Rocky Mountain spotted fever; IVIG, intravenous immune globulin; GNR, gram-negative rod. Of patients with human monocytic ehrlichiosis 30% have a rash; of patients with human granulocytic ehrlichiosis <10% have a rash.

Dilantin hypersensitivity syndrome Kawasaki disease

Noninfections Toxic epidermal necrolysis (TEN)

Staphylococcal scalded skin syndrome (SSSS) Toxic shock syndrome (TSS)

Supportive IVIG

Supportive ?Steroids

Supportive

Supportive Nafcillin or PCN G

Supportive Nafcillin

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Table 4 Risks and Exposures, Types of Infections and Rashesa Exposure or risk Contact with sick persons

Season

Travel

Food Tick bite

Splenectomy Animal contact

Injection drug use

Skin infection

Tampon use Pregnancy Sexual

Water

Infections Measles (rubeola) German measles (rubella) Meningococcemia Enterovirus Varicella Hepatitis B virus CMV RMSF (spring, summer) Ehrlichia (spring, summer)b Lyme (spring, summer) Enterovirus (summer, fall) International Viral hemorrhagic fever Dengue Typhoid fever Schistosomiasis, strongyloidiasis, filaria Southeastern, south central U.S. RMSF Ehrlichiab Northeastern, north central U.S. Ehrlichiab Lyme Vibrio vulnificus (raw seafood) RMSF Lyme Ehrlichiab S. pneumoniae and H. influenzae Capnocytophaga spp. Dog (Capnocytophaga spp.) Birds (Chlamydia spp.)b Ratsc (rat-bite fever) Endocarditisc S. aureus HIV S. pyogenes TSS S. aureus TSS SSSS S. aureus TSS Rubella HIV Syphilis N. gonorrhoeae Contact with animal urine Leptospirac Salt water V. vulnificus

Rash MP MP PP MP, less often U V MP or U MP PP MP MP (ECM) MP, less often V PP PP MP U

PP MP MP MP (ECM) B PP MP (ECM) MP PP PP PP MP MP PP MP E E E and B E MP MP MP and mucosal PL P MP B

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Table 4 Continued Exposure or risk

Infections

Immunocompromised host

Fungi Mycobacterium Nocardia spp. Bartonella spp.

Rash N N N N

a

PP, petechial/purpura; MP, maculopapular; E, erythroderma; PL, plaques; V, vesicle; B, bullous; P, pustula; N, nodule; U, urticarial; RMSF, Rocky Mountain spotted fever; HIV, human immunodeficiency virus; CMV, cytomegalovirus; ECM, erythema chronicum migrans; TSS, toxic shock syndrome; SSSS, staphylococcal scalded skin syndrome. b Of patients with human monocytic ehrlichiosis 30% have a rash; of patients with human granulocytic ehrlichiosis <10% have a rash. c Rashes are an uncommon part of the clinical syndrome.

3

PETECHIAE/PURPURA

Since several life-threatening infectious diseases may cause fever and petechiae/purpura, a knowledge of the differential diagnosis is critical for designing empirical antimicrobial therapy (see Table 5). 3.1

Bacteremia

Bacteremia of any cause can be complicated by disseminated intravascular coagulation (DIC), vascular occlusion by organisms, immune vasculitis, embolic events, or vascular effects of toxins. All of these mechanisms can contribute to the development of petechiae/

PETECHIAE/PURPURA AND DIFFUSE ERYTHEMAa Petechiae and purpura (Table 5 and Figure 1) Bacterial sepsis: GNR, meningococcus, S. aureus Asplenia: S. pneumoniae, H. influenzae, Capnocytophaga sp. RMSF (Chapters 2, 30) Viral hemorrhagic fever with international travel TTP, vaculitis Diffuse erythema (Table 6) Scarlet fever (Table 9) TSS: S. aureus and S. pyogenes Criteria for diagnosis (Table 7) Staphylococcal scalded skin syndrome (Table 3) Arcanobacterium sp. with pharyngitis Noninfectious Kawasaki disease Dilantin hypersensitivity a

GNR, gram-negative rod; RMSP, Rocky Mountain spotted fever; TTP, thrombocytic thrombotic purpura; TSS, toxic shock syndrome.

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Table 5 Infections Associated with Petechiae or Purpura Neisseria meningitidis Rickettsia rickettsii (Rocky Mountain spotted fever) Streptococcus pneumoniae with asplenia Capnocytophaga canimorsus with asplenia Staphylococcus aureus endocarditis Enterovirus (coxsackievirus and echovirus) Epstein-Barr virus (infectious mononucleosis) Hemorrhagic fever group of viruses Atypical measles

purpura. The most common offending organisms are Neisseria meningitidis, aerobic gramnegative rods (GNRs), Staphylococcus aureus, and, less often, Listeria monocytogenes. Purpura can also be present without overt DIC. 3.1.1

Meningococcemia

The patient who has meningococcemia may have acute fever and a petechial rash. The patient usually has a rapidly progressive course with systemic toxicity. Central nervous system (CNS) involvement may or may not be present. Organisms may be visible on Gram stain of an aspirate of the petechiae or skin biopsy specimen. Blood culture findings are usually positive. Empirical antimicrobial therapy should be started as soon as possible (see Chapter 2). Hospitalized patients should be placed on respiratory isolation until they have received 24 hours of effective antimicrobial therapy. Prophylactic antibiotics are administered to close contacts (see Chapter 2) of confirmed cases to prevent secondary cases. Lumbar puncture should be performed if the clinical picture is consistent with meningitis. The organism is sensitive to penicillin or ampicillin, but ceftriaxone is often used in view of its superior penetration into the CNS. 3.1.2

Asplenia

Patients with asplenia can exhibit fever and petechial rash with sepsis. Encapsulated organisms including Streptococcus pneumoniae and Haemophilus influenzae are the most common causes. A history of a dog bite (less often cat bite or scratch) should raise the concern of infection with Capnocytophaga canimorsus (dysgonic fermenter 2 [DF-2]). It must be kept in mind, though, that 20% of patients who have this infection have had nonbite exposure to dogs. Empirical therapy should be started as soon as possible. A thirdgeneration cephalosporin such as ceftriaxone can be used to treat all of the above pathogens. If the frequency of penicillin resistance in S. pneumoniae is high in your community, vancomycin may be added. 3.1.3

Endocarditis

Patients with acute endocarditis, usually secondary to S. aureus, can also experience systemic toxicity, fever, and a petechial or purpuric rash. A history of preexisting valvular heart disease may or may not be present. A history of active IDU or a new or changing murmur revealed by physical examination may also raise suspicion of this entity. Empirical therapy should be started after blood cultures have been obtained. Nafcillin is the drug of choice, but vancomycin may be substituted if the patient has a severe penicillin allergy or

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if the prevalence of methicillin-resistant S. aureus (MRSA) in the community is significant (see Figure 1). 3.2

Rocky Mountain Spotted Fever

A similar clinical picture can be seen when patients have Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii (see Chapters 2 and 30). Patients exhibit fever,

Figure 1 Patients with fever and a petechial rash need rapid evaluation to rule out life-threatening infections. Toxicity or unstable vital signs should prompt hospitalization and assessment for Rocky Mountain spotted fever, meningococcemia, and bacteremias associated with asplenia. Blood cultures should be drawn and empirical antibiotics begun.

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rash, and headache. The rash may be maculopapular initially and become more petechial as the illness progresses. The rash starts on the extremities and spreads centrally. RMSF appears in the spring and early summer. It is acquired most commonly in the Carolinas or in the south central states such as Oklahoma. Patients may recall a tick bite. If the time of the year and exposure history are consistent with RMSF, empirical therapy with tetracycline should be started. There are no rapid diagnostic tests for RMSF that are routinely available. Skin biopsy or serological testing can support the diagnosis. 3.3

Nonbacterial Infection

There are a variety of nontreatable infections that may produce fever and petechial rash. Many common viruses such as enteroviruses and Epstein-Barr virus (EBV) can cause a petechial rash as part of a systemic febrile illness. The exposure history, associated symptom complex, and physical examination findings may help to differentiate among these entities. Viral hemorrhagic fever should be a concern when patients have traveled internationally and exhibit a hemorrhagic rash. Dengue is the most widespread of these viruses. Lassa fever virus, Ebola virus, Marburg virus, and Machupo virus have been associated with life-threatening infection and can be spread nosocomially. Patients suspected of having one of these viruses should be placed in isolation. The Centers for Disease Control and Prevention (CDC) and the state health department should be contacted immediately. Several noninfectious entities can produce fever and a petechial rash. Thrombotic thrombocytopenia purpura (TTP) and the systemic vasculitic syndromes are important considerations in the differential diagnosis of the patient who has fever and a petechial/ purpuric rash. 4

DIFFUSE ERYTHEMA

The major infectious syndromes that cause fever and diffuse erythema are associated with specific toxins produced by the organisms. Table 6 lists those infections and noninfectious diseases that may cause diffuse erythroderma. 4.1

Scarlet Fever

Scarlet fever results from infection with a strain of streptococcus that elaborates streptococcal pyrogenic exotoxin. It is usually associated with pharyngitis, but it can follow streptococcal infections at other sites. The erythroderma is more pronounced in the skin

Table 6 Fever and Diffuse Erythema Infectious Scarlet fever Staphylococcal toxic shock syndrome Streptococcal toxic shock syndrome Arcanobacterium haemolyticum Staphylococcal scalded skin syndrome Noninfectious Mucocutaneous lymph node syndrome (Kawasaki disease) Toxic epidermal necrolysis (TEN)a Drug hypersensitivity syndrome a

Can also have bullous and vesicular lesions.

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folds (Pastia’s lines). Circumoral pallor is generally present. The classic oral manifestation is the strawberry tongue: yellow or white coating with papillae protruding through (white strawberry), progressing to a beefy swollen red tongue without coating (red strawberry). The rash is followed by extensive desquamation. With extensive use of antimicrobial therapy for streptococcal infections, scarlet fever has become uncommon (see Table 9). 4.2

Toxic Shock Syndrome

4.2.1 Staphylococcus Aureus Staphylococcal toxic shock syndrome (TSS) occurs in patients who harbor strains of S. aureus that elaborate either toxic shock syndrome toxin 1 (TSST-1) or related enterotoxins. Patients have a syndrome of fever, a diffuse erythematous rash, hypotension, and multisystemic involvement. The mucous membranes are often hyperemic, and there is desquamation of the rash after 7–10 days, especially on the palms and soles. Table 7 summarizes the criteria for TSS. Results of blood cultures and skin cultures are usually negative, but the causative organism can be cultured from a colonized site. In addition to aggressive supportive therapy, patients should receive an antistaphylococcal antibiotic such as nafcillin. Whereas in the past there was an association of TSS with the use of superabsorbent tampons by women, the majority of the recent cases have been attributed to nonmenstrual sources. 4.2.2 Streptococcus Pyogenes A similar toxic shock syndrome has been associated with Streptococcus pyogenes (group A ␤-hemolytic streptococcus) and less commonly other streptococci. In streptococcal TSS, patients usually are bacteremic or have an active streptococcal infection; the skin is the most common site. Patients experience shock, fever, diffuse erythroderma, and multiorgan failure. Nausea, vomiting, and diarrhea may occur early in the course of the illness. Pain at the site of infection precedes other signs of infection such as erythema. Bullae may develop at the local site of infection. The diffuse rash may desquamate during the convalescent phase of the illness. Treatment includes aggressive supportive measures and

Table 7 Criteria for Staphylococcus Toxic Shock Syndromea Temperature >38.9⬚C Systolic blood pressure <90 mm Hg Rash with subsequent desquamation, especially on palms and soles Involvement of ⱖ3 organ systems Gastrointestinal: vomiting and diarrhea Muscular: myalgia, CPK >5 times normal Mucous membranes: hyperemia (vagina, conjunctiva, pharynx) Renal insufficiency: pyuria, with BUN and creatinine levels twice normal/ Hepatic: bilirubin, AST, ALT levels twice normal Blood: platelets <100,000/mm3 CNS: disorientation without focal neurological signs Negative serological test results for RMSF, leptospirosis, and measles a

CPK, creatinine phosphokinase; BUN, blood urea nitrogen; AST, aspartate transaminase; ALT, alanine transaminase; RMSF, Rocky Mountain spotted fever; CNS, central nervous system.

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empirical antibiotic therapy effective against streptococcus such as penicillin G or ceftriaxone. 4.3

Staphylococcal Scalded Skin Syndrome (Ritter’s Disease)

Patients with staphylococcal scalded skin syndrome (SSSS) experience fever and a scarlatiniform eruption that is due to production of an exfoliative toxin by S. aureus. It is a disease predominantly of neonates or young children, although adults with renal insufficiency, lymphoma, or immune suppression are also at risk. The rash is followed by the development of flaccid bullae, which result, on rupture, in raw denuded areas. These bullae tend to occur at sites of minor trauma (Nikolsky’s sign), and the denuded areas eventually desquamate. Blood culture findings may be positive. Skin biopsy is important to rule out toxic epidermal necrolysis (TEN), generally caused by a drug reaction. TEN is characterized by fever and subepithelial bullae with subsequent full-thickness skin necrosis. There is a 10%–30% mortality rate. 4.4

Arcanobacterium Species Infection

Arcanobacterium haemolyticum (formerly Corynebacterium haemolyticun, a gram-positive bacillus) can cause pharyngitis along with a diffuse erythroderma in young adults. The pharyngitis can mimic that caused by S. pyogenes. The rash is localized to the trunk and proximal upper extremities and desquamates with time. The organism is sensitive to a variety of antibiotics, including tetracycline, erythromycin, and clindamycin, but it may be tolerant to penicillin. A. haemolyticum may be overlooked on routine throat culture results. 4.5

Noninfectious Causes

Noninfectious causes of a diffuse erythroderma include drug reactions, Kawasaki disease, and dilantin hypersensitivity syndrome. Kawasaki disease or mucocutaneous lymph node syndrome is vasculitis that affects young children. It is most prevalent in Japan. It is characterized by fever, a diffuse erythroderma that includes the palms and soles, lymphadenopathy, pharyngitis, and conjunctivitis. There is usually multiorgan involvement including cardiac, hepatic, and pulmonary manifestations. Dilantin hypersensitivity is a severe drug reaction characterized by fever, diffuse erythroderma including the palms and soles, generalized lymphadenopathy, hepatosplenomegaly, and leukocytosis.

5

MACULES/PAPULES

The most common skin manifestation associated with infection is a maculopapular rash. The differential diagnosis for fever and a maculopapular eruption is extensive and includes many noninfectious entities. The typical drug reaction that is seen 7 to 10 days into therapy is most commonly maculopapular in character. The majority of infections associated with fever and a maculopapular rash are viral and are not treatable (Table 8). With aggressive vaccine programs some of these infections have become uncommon.

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MACULOPAPULAR, VESICULAR, AND NODULAR RASHESa Maculopapular (Table 8) Childhood exanthema in adults (Table 9) Drug reactions (Chapter 8) CMV, HIV, EBV, enteroviruses Syphilis Tick-borne (Chapters 2, 30): RMSF, ehrlichia, Lyme International travel: typhoid and typhus Erythema multiforme (Table 10) Vesicles/bullae (Table 11) Varicella, disseminated HSV Necrotizing fasciitis, Vibrio vulnificus, P. aeruginosa N. gonorrhoeae Nodules (Table 12) Immunocompromised hosts Fungi, mycobacteria Bartonella spp. Erythema nodosum (Table 13) a

CMV, cytomegalovirus; HIV, human immunodeficiency virus; EBV, Epstein-Barr virus; RMSF, Rocky Mountain spotted fever; HSV, herpes simplex virus.

5.1 5.1.1

Febrile Childhood Illness That May Be Seen in Adults Measles

Measles (rubeola) (see Table 9) produces fever, coryza, and a maculopapular rash, which starts in the head and neck region and spreads centrifugally. Mild desquamation may occur. Early in the course of the illness, Koplik’s spots may be visible on the buccal mucosa opposite the lower molars. These small white spots have been described as ‘‘grains of sand’’ embedded in the buccal mucosa. Atypical measles can be seen in individuals who received the killed measles vaccine that was administered between 1963 and 1967. The rash of atypical measles can be vesicular or purpuric and starts on the extremities and

Table 8 Maculopapular Rash Rubella Rubeola Fifth disease Roseola Enterovirus Ehrlichiosis Typhoid fever Psittacosis Dengue a

Rocky Mountain spotted fever Primary HIV infectiona Epstein-Barr virus Cytomegalovirus Secondary syphilis Lyme disease Leptospirosis Rat-bite fever Typhus

Human immunodeficiency virus.

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Table 9 Febrile Childhood Illnesses That May Occur in the Adult Population Disease/pathogen Scarlet fever/S. pyogenes

Rubeola (measles)/rubeola virus

Rubella (German measles)/rubella virus

Erythema infectiosum (Fifth disease)/ parvovirus B19

Roseola infantum (exanthem subitum, sixth disease)/human herpesvirus 6

Description of illness and rash Associated with tonsilitis, less often wounds Rash Begins ⬃day 2 of illness ‘‘Sandpaper’’ Pastia’s lines Palms and soles spared Flushed face with circumoral pallor Spreads from upper chest to trunk/arms Fades within a week; may desquamate ‘‘White strawberry’’ tongue changing to ‘‘red strawberry’’ tongue Incubation of 10–14 days Fever, malaise, anorexia Rash appearance after several days of illness Spreads from face to trunk May involve palms and soles Lasts ⬃5 days May desquamate Atypical measles rash Spreads from extremities to trunk May be maculopapular, vesicles, or purpura Conjunctivitis Cough and coryza Koplick’s spots on buccal mucosa ‘‘Mild measles’’ Rash Spreads from face to trunk Cervical lymphadenopathy Palatal petechiae Mild coryza and conjunctivitis Rash more common in children ‘‘Slapped cheeks’’ Circumoral pallor Spreads from face to trunk Symmetrical arthralgia or arthritis in adults Papular-purpuric stocking glove distribution Aplastic crisis in patients with underlying hemolytic disorders Infants and young children Mononucleosis-like illness in adults High fever Cervical lymphadenopathy Face spared by rash

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spreads centrally. In individuals immunized with the live virus, vaccine protection wanes with time and mild measles can occur. Thus, a second dose of measles vaccine is recommended in individuals vaccinated after 1957. Recognition of measles is important because of the significant morbidity rate in immunocompromised patients and in those at the extremes of age. 5.1.2

German Measles

The maculopapular rash of German measles (rubella) (Table 9) begins on the face and spreads to cover most of the body. Patients have fever, malaise, and posterior cervical lymphadenopathy. Petechiae may be visible on the soft palate. The rash may clear with mild desquamation. Recognition of rubella may be especially important to prevent transmission to women of childbearing age who are not immune. Congenital rubella is associated with a large number of birth defects. Rubella can also cause significant arthritis in adults, especially women. 5.1.3

Fifth Disease

Fifth disease (erythema infectiosum) (Table 9) is caused by parvovirus B19. Children exhibit a classic ‘‘slapped-cheek’’ appearance followed by a more generalized maculopapular rash. The rash follows the onset of fever and may be exacerbated by various stimuli, including sun exposure. Less commonly, it can cause painful petechiae and purpura in a stocking-glove distribution. The extremities can be swollen and very pruritic. Arthritis and arthralgias are common features in adults. The arthritis is usually symmetrical and involves the peripheral joints. Parvovirus B19 infection is associated with decreased red cell production in normal hosts. In patients with underlying red blood cell disorders, this infection can precipitate an aplastic crisis. Chronic anemia can develop after parvovirus B19 infection in immunocompromised patients such as those with human immunodeficiency virus (HIV). Symptomatic or asymptomatic acute infection with parvovirus B19 during pregnancy has been associated with fetal death (see Table 9). 5.1.4

Roseola

Another herpesvirus, human herpesvirus 6 (HHV-6), is the cause of roseola (Table 9) or exanthem subitum. This is generally a mild disease in infants and children but can cause a mononucleosis-like illness in adults. The rash is maculopapular, appears after resolution of fever, and spares the face. Acute hepatitis can be seen with primary HHV-6 infection. 5.2

Cytomegalovirus

Cytomegalovirus (CMV) is another common virus that can infect children and adults. CMV infection is common in children in day care, and seronegative parents can acquire CMV through exposure to body fluids of asymptomatic children. CMV can also be sexually transmitted in adults. Children often have mild or asymptomatic infection, whereas adults can experience a mononucleosis-type illness. Pharyngitis, lymphadenopathy, and splenomegaly are less common with CMV than with mononucleosis secondary to EpsteinBarr virus. A mild hepatitis is frequently seen. The skin rash associated with CMV can be variable in appearance but is usually maculopapular. Primary CMV infection during pregnancy is often complicated by congenital CMV infection with resultant multiple organ dysfunction in the fetus and possible fetal death. Primary CMV infection in the immunocompromised patient can result in pneumonia, hepatitis, colitis, esophagitis, retinitis, encephalitis, and myelitis.

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Human Immunodeficiency Virus

Approximately 50% of patients who have acute HIV infection are symptomatic. The most common features of the acute retroviral syndrome (ARS) are fever, pharyngitis, lymphadenopathy, and rash (see Chapter 25). The rash is maculopapular and involves the face, trunk, and occasionally the extremities, including palms and soles. Mucosal ulcerations may occur in the mouth, esophagus, or genital region. Recognition of the ARS is especially important as preliminary data suggest that treatment of primary HIV infection may have long-term clinical benefits. The typical serological tests for HIV may not be diagnostic with acute infection. Demonstration of viremia by polymerase chain reaction (PCR) in a patient with a consistent clinical syndrome supports the diagnosis of ARS. 5.4

Epstein-Barr Virus

Epstein-Barr virus is the most common cause of infectious mononucleosis. Fever, pharyngitis, and lymphadenopathy are characteristic (see Chapter 39). Rash occurs in about 5% of patients and may be variable in nature (maculopapular, petechial, scarlatiniform, urticarial, or vesicular). Thrombocytopenia and a predominance of atypical lymphocytes are common hematological findings, although these findings can be seen with other acute viral infections such as CMV and HIV. Heterophil antibodies measured by the mononucleosis detection slide test (Monospot) test are present in the majority of cases. Falsepositive Monospot test results are rare. 5.5

Enterovirus

A variety of enteroviral infections can cause fever and rash. Most of the rashes are maculopapular, but a few enteroviruses may produce a petechial or vesicular rash. Patients may have associated pharyngitis or diarrhea. Isolation of virus from throat or rectal swab is not diagnostic as patients can harbor enteroviruses and be asymptomatic. Enteroviral infections are seen predominantly in late summer and early fall, but sporadic cases can be seen throughout the year. 5.6

Syphilis

Syphilis is caused by the spirochete Treponema pallidum. Primary syphilis causes a painless chancre (see Chapters 16 and 17). Secondary syphilis is characterized by fever, rash, and lymphadenopathy. The classic rash is a diffuse maculopapular eruption that involves the palms and soles. Mucous patches may be visible on mucous membranes. Moist gray papules, condylomata lata, are visible in the mouth or on the labia, anus, or scrotum. These lesions are highly infectious. Spirochetes can also be found within skin lesions. Patients with secondary syphilis may have hepatosplenomegaly with mild elevation of transaminase levels. Headache and aseptic meningitis can be seen. The result of the rapid plasma reagin (RPR) test should be positive at high titer with a positive fluorescent treponemal antibody absorption test (FTA-ABs) result. 5.7

Tick-Borne Infection

Tick-borne illnesses such as RMSF, ehrlichiosis, and Lyme disease can cause fever and rash (see Chapters 2 and 30 and Table 3). The petechial rash of RMSF has been discussed (see Sec. 3.2). It is important to recognize that RMSF patients may exhibit a maculopapular rash early in the course of the

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illness. The maculopapular rash of ehrlichiosis occurs in approximately one-third of cases of human monocytic ehrlichiosis but in <10% of cases of human granulocytic ehrlichiosis. It rarely involves the palms and soles. The classic rash of Lyme disease, erythema chronicum migrans (ECM), is a rapidly enlarging erythematous macule often with central clearing that causes a ‘‘bull’s-eye’’ appearance. The lesions are usually greater than 5 centimeters in diameter. In approximately 25% of cases there are multiple lesions. 5.8

International Travel

Dengue can cause a more generalized erythematous macular rash in addition to the petechial rash discussed in Sec. 3.3. Typhoid fever, caused by Salmonella typhi or S. paratyphi, is associated with centrally distributed erythematous macules or papules referred to as rose spots. Louse-borne typhus caused by Rickettsia prowazacki or tick-borne typhus caused Rickettsia typhi can produce fever, headache, and a truncal maculopapular rash. 5.9

Other Bacterial Causes

Leptospirosis, psittacosis, and rat-bite fever are uncommon causes of fever and rash syndromes seen in patients with specific exposure histories. Rheumatic fever, a sequela of S. pyogenes pharyngitis, can also cause a fever and rash. Leptospirosis is acquired from water contaminated with animal urine. Patients experience fever, headache, myalgias, nausea, and vomiting. Conjunctivitis and a maculopapular rash are seen on physical examination. Laboratory studies reveal elevated blood urea nitrogen (BUN) and bilirubin levels and thrombocytopenia. Isolation of the organism is difficult. Therefore, diagnosis is usually confirmed by serological findings. Therapy with doxycycline is indicated for mild to moderate disease; intravenous penicillin is suggested for severe illness. Chlamydia psittaci infection is usually associated with bird contact. The presentation can be variable; fever, headache, and cough are common. The classic skin manifestation, Horder’s spots, are pink maculopapular lesions that occur on the trunk. A wide variety of other rashes have been described with psittacosis. Serological results can be diagnostic and tetracycline is the drug of choice. Rat-bite fever caused by Streptobacillus moniliformis can be acquired from a rat bite or by ingestion of contaminated food. Patients have fever, severe polyarthritis, and rash. The rash can be maculopapular, vesicular, pustular, or petechial and is concentrated on the hands, feet, palms, and soles. Blood culture findings are usually positive, and the organism is susceptible to penicillin. In rheumatic fever rash may be a part of the multisystemic illness. The classic rash is erythema marginatum. Less commonly patients may have a maculopapular rash and subcutaneous nodules. Diagnosis is based on the Jones criteria (see Chapter 8). 5.10

Erythema Multiforme

Lesions of erythema multiforme (EM) have central erythema surrounded by normal-appearing skin that in turn is surrounded by another ring of erythema. The central area often vesiculates. These lesions are usually symmetrical in their distribution and involve the palms and soles. Mucosal involvement is often present. When there is extensive mucosal involvement with conjunctivitis and stomatitis, the term Stevens-Johnson syndrome or EMmajor is applied. Drugs (especially sulfonamides) are the most common cause of EM. It

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has been associated with a variety of infectious agents, including mycoplasma, Herpes simplex virus (HSV), and other viruses (see Table 10).

6

VESICLES/BULLAE

Most bullous diseases are immunological in nature. Certain infections, particularly viruses, can cause vesicles and bullae (see Table 11). Varicella virus, herpes simplex virus, coxsackievirus, and echovirus are the most common causes. Primary herpes simplex virus type 1 or 2 can be associated with fever in addition to the vesicular eruption. Relapses of these infections are not usually accompanied by fever. See Chapters 11 (oral infections), 16 and 17 (genital infections), and 20 (cutaneous infections) for further details about herpes simplex infections.

Table 10 Differential Diagnosis of Erythema Multiforme Noninfectious Drugs Radiation therapy Viral infections Herpes simplex virus Epstein-Barr virus (infectious mononucleosis) Influenza A Mumps Hepatitis B Adenovirus Coxsackievirus Echovirus type 6 Varicella Ecthyma contagiosum (orf a) Bacterial infections Mycoplasma pneumoniae Chlamydia pneumoniae Neisseria gonorrhoeae Bartonella henselae S. aureus, S. pyogenes P. aeruginosa Francisella tularensis Salmonella, Shigella, and Yersinia spp. Vibrio hemolyticus Treponema pallidum Mycobacterium tuberculosis Fungal infections Histoplasma capsulatum Coccidioides immitis Parasitic infections Trichomonas vaginalis a

Generally a disease of sheep and goats due to a parapoxvirus. Humans infected by direct contact with the animals, causing a cutaneous nodule at the site of contact. Source: Weber 2000.

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Table 11 Vesicobullous/Pustular Lesions Varicella Disseminated varicella zoster Disseminated herpes simplex virus Vibrio vulnificus Pseudomonas aeruginosa Disseminated Neisseria gonorrohoeae

6.1

Varicella Infection

Varicella, caused by the herpesvirus varicella zoster virus (VZV), is a common cause of fever and generalized vesicular rash. The epidemiological features of this disease may change in the near future with increasing use of the varicella vaccine. Infection occurs as a result of exposure to infectious respiratory secretions or material from a varicella or zoster skin lesion. An individual is infectious prior to development of the rash. Therefore, patients may be unaware of potential exposures. The peak incidence is in the spring. Patients experience fever and malaise followed by a rash described as vesicles on an erythematous base. The lesions crust and gradually heal. Lesions in different stages of evolution are seen on physical examination. Complications include bacterial superinfection, pneumonia, and encephalitis. The latter are more likely to develop in adults. Reye’s syndrome may be a complication in both children and adults. If hospitalized, patients with suspected or proven varicella should be placed in strict isolation. In this day and age of potential bioterrorism smallpox must be considered in the differential diagnosis of chickenpox. The smallpox lesions are more deeply embedded in the skin, are all in the same stage of evolution, and are more concentrated on the face and extremities than the torso (see Chapter 44). Virus can be cultured from skin lesions, but obtaining results may take days and culture may not be readily available outside tertiary care institutions. A rapid diagnosis can be made by staining cells obtained from scraping the base of a lesion with a monoclonal antibody to specific VZV proteins. The antibody is usually tagged with a fluorescent marker. This direct fluorescent antibody (DFA) testing may not be routinely available but can provide a specific diagnosis within hours. Local recurrence of VZV, dermatomal zoster, can disseminate especially in immunocompromised hosts. Disseminated HSV infection can also cause fever and a diffuse vesicular rash. It occurs more frequently in immunocompromised patients or those with severe eczema. Visceral involvement, especially hepatitis, can occur. The mortality rate of disseminated HSV is higher than that of disseminated zoster. The skin lesions are indistinguishable, but the DFA test can rapidly differentiate HSV and VZV. Acyclovir is effective for both HSV and VZV, but the dosage is different for the two viruses. 6.2 6.2.1

Bacterial Infection Necrotizing Fasciitis

Necrotizing fasciitis is a fulminant bacterial infection of the subcutaneous tissue that may involve skin, fat, fascia, and muscle. Dermal necrosis can produce bulla formation in addition to edema, erythema, and gangrene of the skin. Infections can be due to S. py-

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ogenes or S. aureus or be polymicrobic. The hallmarks of infection are systemic toxicity, cutaneous crepitus, necrosis or anesthesia of the skin, and progression to septic shock (see Chapter 2). 6.2.2 Vibrio Vulnificus Disseminated infection with Vibrio vulnificus can result in bullous skin lesions. Persons usually acquire the organism through contact of nonintact skin with salt water or through ingestion of raw seafood. Patients with chronic liver disease, especially cirrhosis, are at increased risk of development of sepsis with this organism. The cellulitis with shock is similar in presentation to that due to S. pyogenes. Patients can have bullae at the site of the cellulitis or scattered bullae with dissemination of the infection. The lesions heal with eschar. Cultures from skin lesions and blood usually yield positive findings. Tetracycline with or without cefotaxime is the recommended treatment. 6.2.3 Pseudomonas Aeruginosa P. aeruginosa bacteremia, especially in the neutropenic host, can be manifested by scattered skin lesions. The classic skin lesion is ecthyma gangrenosum, which is described as an erythematous, indurated lesion with bullous formation followed by ulceration. Blood culture results are commonly positive. P. aeruginosa may also produce a generalized vesiculopustular eruption associated with hot tub exposure. 6.2.4 Neisseria Gonorrhoeae Disseminated N. gonorrhoeae causes fever, arthritis, and a pustular rash that is found predominantly on the extremities. Blood culture findings are often positive, but synovial fluid and skin biopsy samples are usually sterile. N. gonorrhoeae can be recovered from a mucosal site in approximately 80% of patients with disseminated gonococcal infection. Patients should be treated with ceftriaxone initially but can be switched to oral cefpodoxime or ciprofloxacin once they demonstrate clinical improvement. 7

NODULES

Most illnesses associated with fever and nodular skin lesions are seen in immunocompromised patients (see Table 12). Most commonly affected are patients with hematological malignancies, patients status post solid organ or bone marrow transplantation, and patients with acquired immunodeficiency syndrome (AIDS). The most common causes are fungi and atypical mycobacteria. In patients who have leukemia, Candida sp. is the most common isolate. The skin nodules are well circumscribed, firm, and erythematous, often with a pale center. Similar skin lesions can be seen with a variety of other fungi including Sporothrix, Aspergillus, Mucor, Cryptococcus, Coccidioides, Histoplasma, and Fusarium

Table 12 Nodules Candida spp. Mucor spp. Fusarium spp. Aspergillus spp. Sporothrix spp. Coccidioides spp.

Mycobacterium haemophilum Mycobacterium chelonae Mycobacterium fortuitum Cryptococcus spp. Histoplasma spp.

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spp. History of travel to the Ohio River Valley or to the southwestern United States may be a useful clue for Histoplasma, Blastomycosis, and Coccidioides spp., respectively. Skin biopsy for smear and culture is the best means of making a specific diagnosis. Atypical mycobacteria can cause disseminated nodular lesions in immunocompromised hosts. These lesions may be violaceous in color and can ulcerate and drain. Skin biopsy with culture should be performed for diagnosis. Nocardia spp. can also cause nodular skin lesions in immunocompromised patients. Bartonella henselae or B. quintana infection, especially in patients with AIDS, can cause a systemic illness with nodular skin lesions called bacillary angiomatosis. The skin lesions often have a vascular appearance and may be confused with the lesions of Kaposi’s sarcoma. Blood culture findings may be positive, but skin biopsy results should be diagnostic. Serological evaluation for Bartonella species can also be performed. A history of cat exposure should be a clue for bacillary angiomatosis. Erythema nodosum is characterized by tender erythematous nodules, usually confined to the lower anterior extremities. These skin lesions are seen in association with a wide variety of noninfectious inflammatory illnesses and are thought to be immunologically mediated. Infectious agents such as Yersinia spp., Chlamydia spp., fungi, and Mycobacterium tuberculosis can trigger erythema nodosum (see Table 13).

8

URTICARIA

Urticaria and fever are rarely associated with active infection. It is estimated that in up to 25% of patients with acute hepatitis B virus infection a serum sickness–like reaction that may include an urticarial rash will develop. Certain enteroviruses are associated with

Table 13 Erythema Nodosum Noninfection Systemic lupus erythematosus Sarcoidosis Ulcerative colitis Crohn’s colitis Behc¸et’s disease Drugs Pregnancy Infections Hepatitis C virus Herpes simplex virus S. pneumoniae C. psittaci N. meningitides Bartonella henselae Haemophilus ducreyi Yersinia spp. Treponema pallidum Mycobacteria spp. Cryptococcus, Blastocystis, Histoplasma, Coccidioides spp. Filaria Source: Adapted from Weber 2000.

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urticarial eruptions. A variety of parasitic infections can be associated with urticarial rash, including acute schistosomiasis, strongyloidiasis, filarial infection such as loa loa, and trichinosis. BIBLIOGRAPHY Flower FP, Krusinski PA. Dermatology in Ambulatory and Emergency Medicine. Chicago: Year Book Medical, 1984, pp 1–11. Gentry LO, Zeluff B, Kielhofner MA. Dermatologic manifestations of infectious disease in cardiac transplant patients. Infect Dis Clin North Am 8:637–654, 1994. Kingston ME, Mackey D. Skin clues in the diagnosis of life threatening infections. Rev Infect Dis 8:1–11, 1986. Levin S, Goodman L. An approach to acute fever and rash in the adult. In: Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Disease. Boston: Blackwell Science, 1995, pp 19–75. Lynch AM, Kapila R. Overwhelming postsplenectomy infection. Infect Dis Clin North Am 10:693– 707, 1996. Martin DH, Mroczkowski TF. Dermatologic manifestations of sexually transmitted diseases other than HIV. Infect Dis Clin North Am 8:533–582, 1994. Meyers SA, Sexton DJ. Dermatological manifestations of arthropod-borne disease. Infect Dis Clin North Am 8:689–712, 1994. Ray MC, Gately LE III. Dermatologic manifestations of HIV infection and AIDS. Infect Dis Clin North Am 8:583–605, 1994. Stevens DL. The toxic shock syndromes. Infect Dis Clin North Am 10:727–746, 1996. Weber DJ. The acutely ill patient with fever and rash. In: Mandel G, ed. Principles and Practice of Infectious Diseases, ed. 5, vol. 1, p. 637. Philadelphia: Churchill Livingstone, 2000.

8 Noninfectious and Cryptic Fevers Brad E. Robinson and Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Fever is a nonspecific physiological response to inflammation. One of the great challenges in clinical medicine is the diagnosis of the patient who presents with fever with no obvious source. Although most commonly attributed to localized infections, fever may be due to infections that present nonfocally (Table 1) or result from a variety of noninfectious processes. This chapter concentrates on noninfectious causes of fever. Fever caused by drugs, malignancies, collagen vascular diseases, sarcoidosis, gout, inflammatory bowel disease, thromboembolic, and thyroid disease is reviewed. A framework for systematically evaluating the febrile patient without an obvious source is presented. An overview of fever of unknown origin (FUO) is summarized. 2

DRUG FEVER

Drugs may cause fever through several different mechanisms. 1.

2.

Immune mediated or hypersensitivity drug reactions are the most common cause of drug fever. These reactions typically occur after 7–10 days of drug use if the patient has never been exposed to the drug before. A more rapid recall reaction can occur with reexposure to the drug. Several immune mechanisms have been proposed to account for these reactions. The drug, acting as a hapten, combines with endogenous proteins to form an antigen. Antibodies then react with this antigen, forming immune complexes that cause the release of endogenous pyrogen. The drug may cause an autoimmune response by directly interacting with the body’s tissues. A cellular immune response that can be triggered by the drug involves sensitized T cells that in turn activate macrophages with release of pyrogen. It is important to note that the existence of antidrug antibodies does not prove the presence of a hypersensitivity reaction, nor does their absence exclude this possibility. Alteration of thermoregulation is seen with sympathomimetic agents (epinephrine, cocaine, amphetamines) that both act on the central nervous system (CNS) to induce heat production and peripherally cause vasoconstriction to reduce heat 151

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NONINFECTIOUS FEVERa Drug fever (Table 2) Malignancies AML Lymphoma Hepatocellular carcinoma or metastasis to the liver Renal cell carcinoma Collagen vascular diseases Vasculitis (Table 3) Temporal arteritis SLE Still’s disease Miscellaneous Rheumatic fever Sarcoidosis Inflammatory bowel disease Thromboembolic disease Thyroid disease Gout a

AML, acute myelogenous leukemia; SLE, systemic lupus erythematosus.

3.

4.

5.

dissipation. Large doses of anticholinergic agents such as atropine, trihexyphenidyl (Artane), or benztropine mesylate (Cogentin) may also cause fever by impairing heat dissipation by blockade of sweating. These latter effects are more common when these anticholinergic drugs are used in combination with phenothiazines. Agents such as amphotericin B or bleomycin can act directly as pyrogens. Fever from this mechanism usually occurs during or shortly after administration of the drug. Fever resulting from the intended pharmacological effect of the drug is best exemplified by the Jarisch-Herxheimer reaction. This is a febrile reaction caused by the bactericidal effect of penicillin on Treponema pallidum during the treatment of syphilis. Chemotherapy-induced lysis of cancer cells with release of endogenous pyrogens that causes subsequent fever is another example of this phenomenon. Several forms of idiosyncratic drug reactions have been described. Malignant hyperthermia can result from inhaled anesthetic agents such as halothane. Neuroleptic malignant syndrome (extremely high temperatures, muscular rigidity, tachycardia, and blood pressure lability) can occur after use of haloperidol, thiothixene, and phenothiazines. Acute hemolysis can occur in the glucose-6-phosphate dehydrogenase (G-6-PD)-deficient individual exposed to sulfonamides, antimalarials, nitrofurantoin, quinidine, and chloramphenicol with subsequent fever.

The immune mediated or hypersensitivity drug reaction classically causes rash, fever, and eosinophilia. This symptom complex, however, occurs in only a minority of cases.

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Table 1 Infections That May Present Nonfocally Infectiona Infectious endocarditis Staphylococcus aureus bacteremia Rocky Mountain spotted fever and other rickettsial illnesses Listeriosis Viral infections Influenza Hepatitis, including CMV, EBV, parvovirus B19 HIV Malaria Occult intraabdominal abscess Infections in the elderly Pneumonia Cholecystitis Zoonoses a

Chapters 18 9 30 9, 34 14 23 25 40 24 41

8, 37

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus.

One of the largest reported series on drug fever dispelled many of the traditional notions regarding the characteristics of drug fever (Mackowiak, 1987). In this study, a previous history of drug allergy was present in only 10%. The mean time from initiation of the drug to the onset of fever was 21 days with the median of 8 days. For antibiotic-related drug fever, the mean and median durations of drug use before the onset of fever were about 7 days. No distinguishing fever pattern exists to differentiate drug-induced fever from fever of other causes. Temperatures above 103⬚F can be quite common, and shaking chills occur in over half of patients. Relative bradycardia is uncommon. A drug rash is characteristically a maculopapular erythema covering most of the body. It has been reported in only 18% of patients with a drug fever and less than half are pruritic. Leukocytosis is seen in 22% of patients. Eosinophilia is reported in 22% of patients but is generally mild and does not correlate with the severity of the reaction. A number of agents that can cause drug fever are listed in Table 2. Frequently implicated agents include sulfonamides, ␤-lactam antibiotics, quinidine, procainamide, methyldopa, hydralazine, carbamazepine, phenytoin, allopurinol, barbiturates, antihistamines, asparaginase, bleomycin sulfate, and salicylates. Once the implicated drug is discontinued, the fever almost always resolves within 24–36 hours. 3

MALIGNANCIES

In addition to the more common neoplasm-associated symptoms (palpable mass, weight loss, pain) fever may be a presenting symptom and, on occasion, the chief complaint of the patient. General characteristics of neoplasm-related fever include the following: it is more common in elderly patients; patients feel less acutely ill with the fever than with infection-induced fever; rigors, myalgias, and arthralgias are uncommon; weight loss is common; hepatosplenomegaly is more likely with malignancy than with infection. Most routine laboratory tests are too nonspecific to differentiate malignancy from other causes of fever. Even the presence of leukocytosis with a left shift does not exclude malignancy.

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Table 2 Drugs That Can Cause Fever a Antimicrobial ␤-lactams Penicillins Cephalosporins Sulfonamides TMP-SMZ Amphotericin B Tetracyclines Macrolides Streptomycin Vancomycin Isoniazid Para-aminosalicylic acid Nitrofurantoin Mebendazole

Cardiovascular Quinidine Procainamide Hydralazine Methyldopa Nifedipine Triamterene

Antineoplastic Bleomycin Asparaginase Daunorubicin Procarbazine Cytarabine Streptozocin 6-Mercaptopurine Chlorambucil Hydroxyurea

Miscellaneous Allopurinol Antihistamine Iodide Cimetidine Levamisole Metoclopramide Clofibrate

a

Central nervous system Carbamazepine Phenytoin Barbiturates Chlorpromazine Haloperidol Thioridazine Amphetamine

Antiinflammatory Salicylates Ibuprofen Tolmetin

Folate Prostaglandin e2 Ritodrine Interferon Streptokinase Propylthiouracil

Boldfaced drugs are the most common causes of drug fever. TMP-SMZ, trimethoprim and sulfamethoxazole.

The most common malignancies that can cause fever include lymphoma, acute leukemia, hepatocellular carcinoma, renal cell carcinoma, and various solid tumors with metastasis to the liver. 3.1

Lymphoma

Malignant lymphoma, including Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL), is the sixth most common neoplasm in the United States and the most common cancer that causes fever. Fever is found in as many as 25%–30% of patients with HD in some series but typically less than 20% in NHL. Hodgkin’s disease, which makes up about 15% of all lymphomas, is more common in males than in females and has a bimodal age distribution with a major peak in the third decade of life and a second, lesser peak in the seventh decade. Patients with HD typically have a painless enlargement of one or more superficial lymph nodes, generally above the diaphragm. Nodes are usually firm, are freely movable, and may be quite large at the time of presentation. Mediastinal adenopathy is also quite common, especially in younger patients with nodular sclerosing HD. B-symptoms include fever, night sweats, and weight loss. These symptoms are much more likely to occur in patients with advanced disease or in those with mixed cellularity or the uncommon lymphocyte depletion subtype. The clas-

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sic, but in reality infrequent, Pel-Ebstein fever of HD is a pattern of relapsing episodes of evening fevers that last for 3 to 10 days alternating in cyclic fashion with afebrile periods. The most common presentation of NHL is persistent painless peripheral lymphadenopathy. Important differences from HD include less frequent occurrence of B-symptoms, less localized disease with greater tendency toward intraabdominal rather than mediastinal involvement, and greater tendency toward extranodal involvement. Other clues that may raise suspicion of lymphoma include chest wall tenderness (from mediastinal extension), hepatosplenomegaly, abdominal mass, or vertebral tenderness. Laboratory findings may include a normocytic normochromic anemia, elevated erythrocyte sedimentation rate (ESR) and alkaline phosphatase level, and elevated lactate dehydrogenase (LDH) level. Evaluation can be initiated with a chest radiograph and abdominal/pelvic computed tomography (CT) scan. Lymph node biopsy by either open excision or fine-needle aspiration confirms the diagnosis. 3.2

Acute Myelogenous Leukemia

Fever is the presenting symptom in 10% of patients with acute myelogenous leukemia (AML), although a portion of these have associated neutropenic-related infection that is actually causing the fever. Most cases of AML have nonspecific symptoms of fatigue, weakness, anorexia, and weight loss. A small proportion note easy bruising or bleeding. The diagnosis is almost always apparent from the complete blood count, which shows anemia, thrombocytopenia, and either leukocytosis or leukopenia. Leukemic blasts are usually noted on a peripheral blood smear, though <5% of patients do not have these leukemic cells. Bone marrow examination should be considered early in the workup of patients who present this overall picture. 3.3

Hepatocellular Carcinoma and Hepatic Metastasis

Hepatocellular carcinoma (HCC) or hepatoma generally occurs in the setting of underlying cirrhosis, especially that caused by chronic hepatitis B or C virus infection. For this reason the diagnosis can be initially elusive as symptoms are often attributed to the underlying liver disease. HCC most commonly causes a vague, gnawing abdominal pain and a right upper quadrant mass. Jaundice is actually uncommon unless there is marked deterioration of liver function or biliary obstruction. Elevation of alkaline phosphatase level is common. The majority of patients show an elevation of ␣-fetoprotein (AFP) level to greater than 500 ␮g/L. Lower levels of AFP may be seen in patients with hepatic metastases from a primary gastrointestinal (GI) cancer and occasionally in patients with hepatitis. Persistently high levels of AFP in a cirrhotic patient without a known GI tumor raises strong suspicion of HCC. Ultrasound is generally the initial imaging test and can detect most tumors over 3 cm. CT and magnetic resonance imaging (MRI) are also quite sensitive. Diagnosis is confirmed most often by percutaneous liver biopsy from a site localized through imaging. Ascitic fluid cytological evaluation, though less invasive, has very low sensitivity. Hepatic metastasis from solid tumors such as from breast, lung, and gastrointestinal cancers can occasionally cause fever. In addition to symptoms related to the primary cancer, the metastasis can cause right upper quadrant pain, biliary obstruction, and jaundice. 3.4

Renal Cell Carcinoma

Hematuria or flank pain is the most common symptom in patients with renal cell carcinoma, occurring independently in about 40% of patients. Fever occurs in about 20% of

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patients. The classic triad of hematuria, abdominal pain, and a flank or abdominal mass is found in only 10%–20% of cases. Other associated symptoms or signs include weight loss, anemia, varicocele, and elevated ESR. The persistently febrile patient with hematuria in whom urinary tract infection (UTI) is not clearly the source should have abdominal CT scanning and cytological examination of the urine. 4 4.1

COLLAGEN VASCULAR DISEASE Still’s Disease

Still’s disease is a disorder of unknown cause characterized by seronegative polyarthritis, fever, and rash. The illness has a bimodal age distribution. The first peak, termed systemiconset juvenile rheumatoid arthritis, occurs in childhood. The second peak, labeled adultonset Still’s disease, occurs in the third or fourth decade. The rash is evanescent, salmoncolored, macular or maculopapular, and nonpruritic and typically occurs over the neck, trunk, and extensor aspects of extremities. Polyarthritis and less commonly oligoarthritis occur in up to 94% of patients, usually affecting proximal interphalangeal and metacarpalphalangeal joints, wrists, shoulders, knees, ankles, and cervical spine. Lymphadenopathy may be found in slightly more than half of patients, splenomegaly in fewer. The complete blood count (CBC) typically shows a normochromic, normocytic anemia and often a striking leukocytosis with a left shift. ESR is often elevated to over 100. Findings of routine serological parameters such as rheumatoid factor (RF) and antinuclear antibody (ANA) are characteristically negative. 4.2

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisystem disease in which pathogenic autoantibodies and immune complexes result in tissue injury primarily in skin, mucous membranes, joints, serosal membranes, hematological system, kidneys, and central nervous system. The overwhelming majority of patients are women of childbearing age. It is more common in African Americans than in whites. Systemic symptoms of fever, fatigue, malaise, anorexia, nausea, and weight loss are extremely common at some point during the course of illness. Most patients with fever caused by SLE show clinical evidence of active SLE affecting multiple organ systems and often have associated leukopenia and high ANA titers. The American College of Rheumatology criteria for the diagnosis of SLE require at least 4 of the following 11 clinical and/or laboratory markers: • • • • • • • • • •

•

Malar rash: fixed, flat, or raised erythema Discoid rash: erythematous, raised, scaly patches Photosensitivity: skin rash with sun exposure Oral ulcers: painless oral or nasal ulcerations Arthritis: nonerosive arthritis in two or more peripheral joints Serositis: pleuritis or pericarditis Renal disorder: proteinuria >500 mg/day (3⫹ on dipstick), cellular casts Neurological disorder: seizures, psychosis Hematological disorder: hemolyitc anemia, leukopenia (<4000/mm3), lymphopenia (<1500/mm3), or thrombocytopenia (<100,000/mm3) Immunological disorder: positive LE cell preparation or anti-ds deoxyribonucleic acid (DNA) autoantibodies or anti-Sm antibodies or biologically false-positive Venereal Disease Research Laboratories (VDRL) finding Positive ANA result

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Patients may initially have only one or two of these manifestations, though the majority have fever, fatigue, weight loss, anemia, and an elevated ESR. Over time, more manifestations become apparent. ANA, with a sensitivity of 95%, remains the best laboratory screening test. Whenever there is suspicion of SLE, urinalysis should be performed to look for proteinuria, hematuria, and cellular or granular casts as evidence of renal dysfunction. 4.3

Vasculitis

The term vasculitis encompasses a heterogeneous group of illnesses marked by inflammation and injury to blood vessels. It can exist as a primary disorder or as a secondary manifestation of infections (hepatitis B and C virus, Epstein-Barr virus, infective endocarditis), rheumatological diseases (SLE, rheumatoid arthritis, Sjo¨gren’s syndrome), and certain malignancies (hairy cell leukemia). The definitive diagnosis of vasculitis rests on blood vessel histopathological characteristics detected through biopsy of an affected organ. However, the specific pattern of organ involvement often suggests the diagnosis clinically. When considering a diagnosis of vasculitis, special attention should be paid in history and physical examination to the skin, eyes, upper respiratory tract, lungs, GI tract, joints, large arteries, and peripheral nerves. Initial laboratory and radiological tests should focus on the presence of abnormality in the kidneys and lungs. Typical skin findings of vasculitis can include palpable purpura, necrotic ulcers, bullae, subcutaneous nodules, and urticaria. They can be painful or pruritic and are most commonly found on the lower extremities in ambulatory patients and the sacral area in bedridden patients. One may also see hyperpigmentation in areas of recurrent or chronic disease. Eye findings can range from simple conjunctivitis or uveitis to retroorbital mass lesions in the case of Wegener’s granulomatosis. Upper respiratory tract symptoms can include sinusitis or rhinitis, other pulmonary symptoms include bronchospasm, cough, and hemoptysis. GI symptoms are primarily abdominal pain, nausea and vomiting, and bleeding. Joint symptoms are manifested as arthralgias, myalgias, and frank arthritis. Peripheral arterial examination may demonstrate decreased or absent pulses, blood pressure discrepancy between the two limbs, and bruits. The patient may complain of pain over the affected vessel. Peripheral neuropathy or mononeuritis multiplex may reflect involvement of peripheral nerves. Laboratory testing often shows nonspecific abnormalities such as thrombocytosis, leukocytosis, anemia, and an elevated ESR. Urinalysis is critical to look for proteinuria, hematuria, and red blood cell casts, which reflect renal involvement. Antineutrophil cytoplasmic antibodies (ANCAs) are autoantibodies directed against specific proteins in the cytoplasm of neutrophils. The term c-ANCA refers to a diffuse, granular cytoplasmic staining pattern under immunofluorescence; p-ANCA is a more localized perinuclear pattern. Though the presence of c-ANCA is highly suggestive of active Wegener’s granulomatosis and p-ANCA can be found in a varying percentage of other vasculitis syndromes, it is generally recommended that this test be used for confirmation of a diagnostic suspicion formulated on clinical grounds rather than as a ‘‘screening’’ test for vasculitis, an approach that is bound to be misleading. Table 3 summarizes the more well-defined primary vasculitic syndromes, recognizing that these illnesses are relatively uncommon. Temporal arteritis, the most common vasculitis in the elderly, is reviewed in more detail in the following section. 4.3.1

Temporal Arteritis

Temporal arteritis (TA), also known as cranial or giant cell arteritis, is a vasculitis affecting medium- to large-caliber arteries. It typically involves one or more branches of

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Table 3 Vasculitis Syndromesa Syndrome

Population at risk

Symptoms

Polyarteritis nodosa

Middle-aged men > women

Churg-Strauss syndrome

Middle-aged men > women

Fever, weight loss, rash, abdominal pain, arthralgia Fever, weight loss, rash, asthma

Kidneys, GI tract, skin, peripheral nerves Lungs, skin, peripheral nerves

Wegener’s granulomatosis

Male or female, adolescent to middle-aged

Upper and lower respiratory tracts, kidney

Takayasu’s arteritis

Young female, more common in Asia

Henoch-Scho¨nlein purpura

Children and young adults

Essential mixed cryoglobulinemia

Middle-aged women

Fever, weight loss, nasal ulcers, cough, sinusitis, hemoptysis, arthralgia Fever, weight loss, arthralgia, loss of peripheral pulses, pain over vessels Palpable purpura, arthralgia, abdominal pain, bloody stool Purpuric lesions, ulcers, arthralgia, Raynaud’s phenomenon

a

Laboratory assessment

Organs involved

Aortic arch and branches

Leukocytosis, anemia, ↑ESR, p-ANCA, HBsAg, U/A Eosinophilia, p-ANCA, abnormal CXR Leukocytosis, anemia, ↑ESR, c-ANCA, U/A, abnormal CXR Arteriography

Skin, kidneys, GI tract

U/A

Kidney, skin

Low C-3, C-4, CH50, U/A, HCV antibody

GI, gastrointestinal; ESR, erythrocite sedimentation rate; ANCA, antineutrophil cytoplasmic antibody; HBsAg, hepatitis B surface antigen; U/A, urinalysis; CXR, chest radiograph; HCV, hepatitis C virus.

the carotid artery, most commonly the temporal arteries. It is almost exclusively a disease of persons more than 55 years of age (median age 75). The classic clinical complex is seen in an elderly patient with headache, scalp tenderness, thickened tender or pulseless temporal artery, jaw claudication, fever, anemia, and markedly elevated ESR. However, it can often present more insidiously and nonspecifically with malaise, fatigue, anorexia, weight loss, sweats, depression, and proximal muscle aches or weakness. The occurrence of TA is closely associated with polymyalgia rheumatica (PMR), which consists of morning stiffness of at least 30 minutes’ duration, proximal muscle pain, and subjective weakness. The most feared complication of TA is ischemic optic neuritis with sudden visual loss, although most patients have symptoms of head pain for months prior to any objective eye findings. The ESR is elevated (usually >50) in over 80% of cases. A normal ESR in an otherwise suspicious clinical case should not discourage more aggressive diagnostics. Definitive diagnosis is made by characteristic pathological findings on a temporal artery biopsy. Caution in biopsy interpretation is needed since the vasculitis may appear in a spotty fashion and the limited biopsy material may be nondiagnostic because of these skip lesions. 5 5.1

MISCELLANEOUS Rheumatic Fever

Acute rheumatic fever (ARF) is a sequela of Streptococcus pyogenes pharyngitis. In about half of the patients the antecedent pharyngitis is asymptomatic. All patients, however, demonstrate serological evidence of recent S. pyogenes infection. The latent period between pharyngitis and onset of ARF averages about 18 days. Children age 5–15 years are

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most often affected, but adults can present an atypical pattern such as synovitis without carditis. The classic Jones criteria for the diagnosis of ARF require either two major or one major and two minor manifestations plus laboratory evidence of a recent Streptococcal infection. The last three major criteria occur in less than 10% of children and are quite rare in adults. The five major clinical manifestations are as follows: 1.

2.

3.

4.

5.

Carditis: The diagnosis of carditis requires the presence of a heart murmur not previously noted, pericarditis, cardiomegaly, or congestive heart failure. The presentation may be subtle with asymptomatic sinus tachycardia or first-degree atrioventricular block. It affects about 60% of the patients. Polyarthritis: The arthritis is generally migratory, very painful, and of short duration; it may affect mainly the knees, ankles, wrists, shoulders, and elbows. The small joints of the hands and feet are involved less frequently. It occurs in 70% of patients. It is characteristically very responsive to salicylates. Chorea: Also referred to as Sydenham’s chorea or St. Vitus’ dance, the extrapyramidal neurological disorder is characterized by rapid purposeless involuntary movements, jerks, tics, grimaces, and slurred speech. It is generally a late manifestation of ARF. Subcutaneous nodules: These nodules are firm, are painless, and are usually seen in association with severe carditis. The overlying skin is not inflamed. They appear mostly on the extensor surfaces of the elbows, knees, or wrists and occipital and spinous process of the lumbar and thoracic spine. Erythema marginatum: This is a fleeting, migratory macular or papular rash with rounded borders. The lesions expand with central clearing. Adjacent lesions may coalesce, forming serpiginous patterns. The rash is most common on the trunk and proximal extremities.

The four minor manifestations are fever, arthralgias, elevated ESR and/or C-reactive protein (CRP) level, and prolonged PR interval on the electrocardiogram. Laboratory evidence of S. pyogenes infection includes throat culture (25%–40% positive finding), rapid antigen test by pharyngeal swab, or antibody response such as antistreptolysin O (ASO), antideoxyribonuclease B, or antihyaluronidase. At least 80% of ARF cases show an elevated ASO titer at the time of presentation. Adding two other antistreptococcal antibody tests increases the sensitivity to greater than 95%. 5.2

Sarcoidosis

Sarcoidosis is a chronic multisystemic disease of unknown cause characterized by noncaseating granuloma formation primarily in the lungs and lymph nodes and to a lesser extent in the skin, eyes, liver, joints, and CNS. It is more prevalent in women and African Americans. It typically occurs in persons 20–40 years of age with bilateral hilar lymphadenopathy, pulmonary infiltrates, and ocular and dermatological manifestations. In 20%– 40% of cases, the onset is abrupt over a period of 1–2 weeks with fever, fatigue, malaise, anorexia, or weight loss associated with cough, dyspnea, or vague chest pain. Other acute manifestations can include erythema nodosum (EN), arthritis, parotid enlargement, anterior uveitis, and facial nerve palsy. Fever, if present, is usually associated with EN, polyarthralgia, and hilar lymphadenopathy. The other main presentation is more insidious in nature with the onset of dyspnea on exertion and dry cough over a period of months. The chest radiograph may show hilar

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lymphadenopathy and/or diffuse ill-defined nodules and infiltrates. Laboratory abnormalities may include lymphopenia, elevated ESR, increased serum levels of angiotension converting enzyme (seen in two-thirds of patients), and rarely hypercalcemia. Pulmonary function testing reveals restrictive lung disease. Biopsy of involved tissues reveals noncaseating granulomas. 5.3 5.3.1

Inflammatory Bowel Disease Crohn’s Disease

Crohn’s disease (CD) is a type of idiopathic inflammatory bowel disease (IBD) involving inflammation of all layers of the bowel wall, associated with noncaseating granuloma formation. The typical patient is a young person in the second to third decade of life who has diarrhea and abdominal pain. The pain is classically in the right lower quadrant and often associated with fever, fatigue, anorexia, and weight loss. The diarrhea is generally without blood. The symptoms can be intermittent. In contrast to ulcerative colitis, it can affect the entire alimentary tract from mouth to anus though CD most often involves the distal ileum, colon, and rectum. In one third of patients perirectal fistulas develop. In some patients constitutional symptoms may dominate the clinical picture, and they may experience unexplained fever. This latter presentation may be particularly likely to occur in the elderly or in the subset of patients with involvement of only the small intestines (about 30% overall). Extraintestinal manifestations may include ankylosing spondylitis, sacroileitis, arthritis, EN, pyoderma gangrenosum, oral aphthous ulcerations, episcleritis, and iritis. Sigmoidoscopy or colonoscopy is the best means to confirm a clinical suspicion. The examination reveals friable intestinal mucosa with exudates and ulcerations. Diagnosis may also be suggested by characteristic segmental narrowing, fistula formation, and loss of normal mucosal pattern seen on barium contrast radiography, though falsely normal appearing examination findings can occur. Laboratory abnormalities may include anemia, leukocytosis, elevated ESR, and elevations of alkaline phosphatase and hepatic transaminase levels. Clues to isolated ileal involvement are B12 deficiency, hypocalcemia, and hypoalbuminemia. 5.3.2 Ulcerative Colitis Ulcerative colitis (UC) is an idiopathic IBD that involves the mucosa and submucosa of the rectum and colon. In contrast to the patchy nature of CD the inflammation of UC is continuous. Of UC patients 95% have rectal involvement. The small bowel and upper GI tract are spared. Patients, usually in their teens to 40s, have diarrhea, rectal bleeding, abdominal pain, fever, and weight loss. The presentation may be mild with limited diarrhea and slight abdominal pain or fulminant in nature with massive bloody diarrhea, severe abdominal pain, and fever. Extraintestinal manifestations are similar to those of CD. Diagnosis is best made by sigmoidoscopic or colonoscopic examination and biopsy of the rectum and colon. 5.4

Thromboembolic Disease

The sudden onset of pleuritic chest pain, shortness of breath, and hemoptysis is the classic presentation of a pulmonary embolism. Fever may be associated with this presentation and on rare occasion be the sole presenting symptom. The pathogenesis of fever in pulmonary embolus is not certain but most likely includes pulmonary infarction and local vascular inflammation. It is important to keep in mind that the finding of the leg examination for

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deep venous thrombosis is normal in over 50% of patients and the chest radiographic result is often normal. Clinical suspicion can be reinforced with D-dimer assays. Diagnosis can be made by spiral CT scan imaging. Thrombosis of the deep vessels of the leg can occasionally cause fever in addition to the more usual symptoms of pain, swelling, and erythema. 5.5

Thyroid Disease

Thyroid disease can cause fever through two different means. In the case of hyperthyroidism, which is an intrinsic overproduction of thyroid hormone by the gland, the excess hormone can produce fever through altered thermoregulatory mechanisms. In the case of subacute thyroiditis, there is an intense inflammation affecting the gland that can lead to fever both through increased cytokine release and through leakage of preformed thyroid hormone from the injured gland. Either disorder may result in the familiar symptoms and signs of thyrotoxicosis, including nervousness, inability to concentrate, tremor, heat intolerance, diaphoresis, palpitations, weight loss, weakness, and increased GI motility. The main entities that can cause hyperthyroidism are Grave’s disease, toxic adenoma, and toxic multinodular goiter. 5.6

Gout

Gout is an acute arthritis due to deposition of sodium urate crystals in the joint. It is generally a disease of men aged 40–60 or less often of women after menopause. The first metatarsophalangeal joint is affected in more than half the instances of first attack and in at least 90% of affected patients at some time in their course. Over time as attacks recur, other joints, usually of the lower extremities, may become involved. In addition to the intense pain in the afflicted joint, there is a marked inflammatory process with swelling, erythema, and warmth over the affected joint. Fever may accompany the acute arthritis. Polyarticular episodes may occur and tend to be more common in women. In severe polyarticular attacks, high fevers and systemic toxicity are not unusual. Gouty arthritis can mimic acute septic arthritis or cellultis. Diagnosis is definitively made by joint aspiration with demonstration of needle-shaped negatively birefringent monosodium urate crystals. Joint fluid should also be sent for culture as infection may coexist with acute gouty arthritis. Pseudogout, or calcium pyrophosphate deposition disease, can mimic classic gout in producing a mono- or oligoarticular arthritis, though involvement of the first metatarsophalangeal joint is much less common. 6

APPROACH TO THE FEBRILE PATIENT

The approach to the febrile patient must be systematic and accomplished in a stepwise manner (see Figure 1). Many fevers are brief (3–7 days), viral in nature, and self-limited. The initial patient encounter should involve a brief history and physical examination to rule out life-threatening illnesses and to triage patients who need a more thorough evaluation. These latter patients include those who have unstable vital signs or immunocompromised state, who are receiving hemodialysis, who are living in a nursing home, or who are pregnant. Any localizing symptoms or signs that suggest a discrete infection (e.g., urinary tract infection, cellulitis, arthritis, or pneumonia) should be pursued with appropriate diagnostic tests and therapy. For most patients, if the initial history and physical examination findings are unrevealing or suggest a viral respiratory tract infection, watchful waiting is appropriate. If fever persists for more than 1 week without obvious source, then

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EVALUATION OF CRYPTIC FEVERS Detailed history (Table 4) Detailed physical examination Review of epidemiological clues (Tables 6 and 7) Review medications (Table 2) Review of laboratory clues (Table 8) Unusual presentations of common illnesses more common than unusual illnesses Avoidance of empirical antibiotics Paced, stepwise approach to diagnosis (Figure 1) Consultation with infectious disease specialist suggested

further evaluation with CBC, urinalysis (U/A), liver biochemical evaluation, two sets of blood cultures, and chest radiography is warranted. If fever persists after 1–2 weeks and initial laboratory assessment results are not revealing, a more exhaustive history (Table 4) and repeat physical examination should be performed. If the patient becomes more acutely ill, the pace of the diagnostic workup should be increased. In general, therapeutic trials (especially of antibiotics) should be avoided since they only obscure the diagnosis. If the fever continues without resolution or diagnosis, it evolves into the more classic fever of unknown origin (FUO) category. 7

FEVER OF UNKNOWN ORIGIN

In 1961, Petersdorf and Beeson proposed the classic definition of a FUO: • • •

Temperature greater than 38.3⬚ C (101⬚ F) on several determinations Fever of more than 3 weeks’ duration No diagnosis reached after 1 week of study in the hospital

The third portion of this classic definition was modified in 1992 to no diagnosis reached after 1 week of ‘‘intelligent, intensive investigation’’ whether done on an inpatient or outpatient basis. This change was made to accommodate the dramatic changes in health care practices. To account further for the changing epidemiological characteristics of disease occurrence since 1961, Durack and Street proposed in 1991 classifying FUO into the following four categories: classic (as defined previously), nosocomial, neutropenic, and human immunodeficiency virus– (HIV)-associated. Table 5 lists some of the entities that may manifest unexplained fever. The causes and relative frequencies of causes of FUO have significantly changed since Petersdorf and Beeson’s original paper in 1961. This is due to a number of factors: changing epidemiological characteristics of febrile diseases with increased numbers of immunocompromised patients as well as the HIV epidemic; improved diagnostic imaging, which has increased detection of occult malignancies and abscesses; improved microbiological diagnostic methods, which have eliminated many systemic infections such as endocarditis from the FUO category; and more sensitive and specific immunological tests, which have detected many of the more common immunological disorders such as SLE at an earlier stage. The result has been a trend, particularly in the elderly, toward a reduced percentage of infections causing FUO and a corresponding increased percentage of non-

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Figure 1 Approach to the febrile patient. The evaluation of the febrile patient is paced according to severity of symptoms, underlying illnesses, and results of history, physical examination, and laboratory assessment. It should proceed in a stepwise fashion from noninvasive inexpensive testing to the more complex evaluation frequently needed in the evaluation of the patient with fever of unknown origin (FUO). The acutely ill or immunocompromised patient, pregnant woman, and patient receiving dialysis or living in a nursing home should receive a more comprehensive initial investigation. Shaded box on the left side, number of febrile days; numbers in parentheses, book chapters concerning the topic; tables, chapter tables. ICH, immunocompromised host; IE, infective endocarditis; CXR, chest radiograph; CT, computed tomography; TB, tuberculosis; tft, thyroid function test; DVT, deep venous thrombosis; PE, pulmonary embolism; TA, temporal arteritis; GI, gastrointestinal; GU, genitourinary; BC, blood culture; u/a, urinalysis; CA, cancer; CBC, complete blood count.

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Table 4 Key Historical Questionsa Medical history Previously diagnosed conditions Immunosuppressive states HIV Corticosteroids Malignancies Organ transplantation Surgeries Dental procedures Trauma Valvular heart disease Presence of prosthetic material or hardware Recent contacts with persons having similar illness Recent and past travel, places of residence, and military service Animal exposures at home, work, or recreational location Work exposures Recreational exposures, including rustic living arrangements, animals, tick bites Unusual dietary habits TB exposure History of high-risk behavior Multiple sexual partners Injection drug use History of transfusions, immunizations Complete list of medications including over-the-counter and ‘‘alternative’’ remedies. Drug or other allergies Ethnic origin and familial history of fevers, TB, collagen vascular diseases, cancer, thrombosis, anemia Rural residence a

HIV, human immunodeficiency virus; TB, tuberculosis.

infectious inflammatory illnesses. Only 8% of cases of FUO in patients above 65 years of age remain undiagnosed, suggesting that prolonged fevers in the elderly tend to be caused by more serious illnesses that eventually declare themselves. In contrast, up to 30% of cases of FUO in young adults remain undiagnosed. Several key points have emerged from the numerous studies of FUO that may help guide the practitioner. In developed nations, FUO is much more often due to an atypical presentation of a common disease than to a typical presentation of an uncommon one, e.g., in a patient with a diverticular abscess without abdominal pain vs. Still’s disease. One cannot overemphasize the greater importance of an exhaustive history and meticulous physical examination than of any battery of screening laboratory tests or blind diagnostic procedures in evaluating FUO. A directed diagnostic workup based on clues gleaned from such a history and physical examination is the most effective approach. For the patient with a prolonged cryptic fever the importance of HIV testing cannot be overemphasized. In the absence of specific clues it may be best simply to observe the patient for the development of more diagnostic signs and symptoms if the patient’s physical status permits.

Table 5 Causes of Classic Fever of Unknown Origin by Etiologic Categorya Infection Localized bacterial Cat-scratch disease Cholecystitis/cholangitis Dental abscess Hepatic abscess Intraabdominal abscess Perinephric/intrarenal abscess Pelvic abscess Osteomyelitis Prosthetic joint infection Sinusitis Tuberculosis Systemic mycoses Blastomycosis Coccidioidomycosis Cryptococcosis Histoplasmosis Sporotrichosis Endovascular Bacterial aortitis Endocarditis Suppurative thrombophlebitis Vascular catheter infection

Systemic bacterial Bartonellosis Brucellosis Gonococcemia Legionnaire’s disease Leptospirosis Listeriosis Lyme disease Meningococcemia Rat-bite fever Relapsing fever Salmonellosis Syphilis Tularemia Typhoid fever Yersinia spp. K-Rickettsial Murine typhus Rocky Mountain spotted fever Q fever K-Mycoplasma K-Chlamydial Psittacosis C. pneumoniae K-Ehrlichiosis

Viral Colorado tick fever Coxsackievirus B CMV Dengue EBV HAV, HBV, HCV HIV Parvovirus B19 Parasitic Amebiasis Babesiosis Chagas’ disease Leishmaniasis Malaria Strongyloidiasis Toxocariasis Trichinosis Toxoplasmosis

Neoplasm Fever relatively common Hodgkin’s disease Non-Hodgkin’s lymphoma Leukemia and myelodysplasia Hepatocellular carcinoma Renal cell carcinoma

Occasional cause of fever Colon carcinoma Hepatic metastases from any primary Breast carcinoma

Noninfectious inflammatory conditions Rheumatological Still’s disease Rheumatic fever SLE Rheumatoid arthritis Gout Polymyalgia rheumatica Drug fever (See Table 2) Thromboembolism DVT PE

a

Vasculitis (Table 3) Temporal arteritis Polyarteritis nodosa Churg-Strauss syndrome Wegener’s granulomatosis Takayasu’s arteritis Henoch-Scho¨nlein purpura Cryoglobulinemia

Granulomatous diseases Sarcoidosis Granulomatous Hepatitis Crohn’s disease (ulcerative colitis)

Factitious fever Endocrine Hyperthyroidism Subacute thyroiditis Adrenal insufficiency Pheochromocytoma

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HAV, hepatitis A virus; HBV, hepatits B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; SLE, systemic lypus erythematosus; DVT, deep vein thrombosis; PE, pulmonary embolism.

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Table 6 Differential Diagnosis of Cryptic Fever by Agea Fever in the younger adult EBV CMV HIV Viral hepatitis Rheumatic fever Still’s disease SLE Sarcoidosis Crohn’s disease Hodgkin’s disease Leukemia Adrenal insufficiency Hyperthyroidism Subacute thyroiditis a

Fever in the elderly adult Endocarditis Intraabdominal abscess Occult hepatobiliary infection Complicated UTI Tuberculosis Temporal arteritis/polymyalgia rheumatica Lymphoma

EBV, Epstein-Barr virus; CMV, cytomegalovirus; HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus; UTI, urniary tract infection.

It is the epidemiological setting of the patient (Tables 6 and 7) and clues from the history (Table 4) and laboratory investigation (Table 8) that suggest the focus of investigation. Empirical therapy is discouraged since it is rarely curative and has the potential to delay diagnosis. Supportive therapy with nonsteroidal antiinflammatory drugs (NSAIDs) while observing for the evolution of clues appears to be a safe approach. Only very rarely does a patient’s status deteriorate on NSAIDs without presenting new diagnostic clues. Consultation with infectious disease specialists is encouraged.

Table 7 Infectious Causes of Fever in the Patient with Animal Contact Infection

Pathogen

Animal exposure

Brucellosis Brucella melitensis B. abortus B. suis Tularemia Francisella tularensis

Cattle Hogs Wild rabbits, small rodents

Leptospirosis

Leptospira interrogans

Rats, dogs, cattle, pigs

Q fever

Coxiella bur- Cattle, sheep, netti goats

Psittacosis

Chlamydia psittici

a

CSF, cerebrospinal fluid.

Goats, sheep

Birds

Transmission

Clinical signs and symptoms

Diagnosis a

Unpasteurized milk or Fever, chills, arthralgias, Serum antibodies cheese, contaminated lymphadenopath, epimeat, aerosolized anididymoorchitis, mal fluids hepatosplenomegaly Direct contact with in- Ulceroglandular, ocular, Serum antibodies fected tissues, inhalaglandular, pneumonia, tytion of aerosol, tick phoidal fever, and prosbite tration Drinking or swimming Flulike syndrome, then Isolation of spiroin contaminated water meningitis, hepatitis, hechete from urine, maturia blood, CSF, serum antibodies Infected aerosol from Flulike, pneumonia, hepa- Serum antibodies parturient animals, intitis, no rash gestion of contaminated milk Infected aerosol from Flulike, splenomegaly, Serum antibodies bird excreta pneumonia

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Table 8 Laboratory Clues to the Cause of Fevera Lymphocytosis Tuberculosis Epstein-Barr virus Cytomegalovirus Toxoplasmosis Non-Hodgkin’s lymphoma

Atypical lymphocytosis Epstein-Barr virus Cytomegalovirus Toxoplasmosis Brucellosis

Eosinophilia Parasitic disease Drug fever Vasculitis Lymphoma Renal cell carcinoma

Monocytosis Tuberculosis Brucellosis Infective endocarditis Cytomegalovirus Inflammatory bowel disease Hodgkin’s disease Myelodysplasia Solid tumors

Leukopenia Miliary tuberculosis Brucellosis Typhoid fever HIV SLE Felty’s syndrome Lymphoma Drug fever

Lymphopenia Tuberculosis HIV SLE Sarcoidosis

Thrombocytopenia Epstein-Barr virus HIV Myeloproliferative disease SLE Vasculitis

Elevated ESR Infective endocarditis Temporal arteritis Rheumatic fever Still’s disease Lymphoma Renal cell carcinoma (If normal, these diagnoses unlikely)

Elevated alkaline phosphatase level Obstructive, infectious, or infiltrative liver disease from any cause Still’s disease Temporal arteritis Hodgkin’s disease Renal cell carcinoma Subacute thyroiditis

Elevated transaminase levels Hepatitis A, B, and C virus Epstein-Barr virus Cytomegalovirus Toxoplasmosis Q fever Psittacosis Leptospirosis Brucellosis Relapsing fever Drug fever Granulomatous hepatitis a

Abnormal urinalysis result Infective endocarditis Renal tuberculosis Leptospirosis Brucellosis SLE Renal cell carcinoma Vasculitis

HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus; ESR, erythrocyte sedimentation rate.

BIBLIOGRAPHY Allen NB, Bressler PB. Diagnosis and treatment of the systemic and cutaneous necrotizing vasculitis syndromes. Med Clin North Am 81(1):243–259, 1997. Chang JC. Neoplastic fever: A proposal for diagnosis. Arch Intern Med 149:1728–1730, 1989. Cunha BA. Fever of unknown origin. Infect Dis Clin North Am 10(1):111–127, 1996.

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De Kleijn EMHA, Vandenbroucke JP, van der Meer JWM. Fever of unknown origin (FUO). I. A prospective multicenter study of 167 patients with FUO using fixed epidemiologic entry criteria. Medicine 76:392–400, 1997. Durack DT, Street AC. Fever of unknown origin reexamined and redefined. Curr Clin Top Infect Dis 11:35–51, 1991. Hunder GG. Giant cell arteritis and polymyalgia rheumatica. Med Clin North Am 81(1):195–219, 1997. Knockaert DC, Vanneste LJ, Vanneste SB, Bobbaers HJ. Fever of unknown origin in the 1980s: An update of the diagnostic spectrum. Arch Intern Med 152:51–55, 1992. Mackowiak PA, Durack DT. Fever of unknown origin. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000, pp 622–633. Mackowiak PA, LeMaistre CF. Drug fever: A critical appraisal of conventional concepts. Ann Intern Med 106:728–733, 1987. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 336:1224–1234, 1997. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine 40:1–30, 1961. Pinals RS. Polyarthritis and fever. N Engl J Med 330:769–774, 1994. Ross SC, Densen P. The patient from a rural area. In: Murray HW, ed. FUO: Fever of Undetermined Origin. Mount Kisco, NY: Futura, 1983, pp 281–318. Special Writing Group of the Committee on Rheumatic Fever. Guidelines for the diagnosis of rheumatic fever: Jones criteria, 1992 Update. JAMA 268:2069–2073, 1992.

9 Blood Cultures Cheryl A. Smith St. Francis Hospital and Medical Center, Hartford, Connecticut, U.S.A.

1

INTRODUCTION

Bacteremia is a common and potentially deadly clinical problem. There are an estimated 200,000 cases per year with an associated mortality rate of 15% in community acquired infections. It is important that the clinician rapidly identify those at risk, obtain the appropriate type and number of blood cultures, and interpret the results accurately. This necessity must be balanced with the poor yield of blood cultures and the difficulty of differentiating contaminants from true pathogens. In addition, blood cultures are expensive, are uncomfortable for the patient, and place the phlebotomist at risk for needlestick injuries. The most common causes of clinically significant bacteremia in nonhospitalized patients are Staphylococcus aureus, Escherichia coli, other Enterobacteriaceae, Streptococcus species including Streptococcus pneumoniae, and coagulase-negative Staphylococcus spp. The most common sources for these bacteremias are respiratory and genitourinary tract infections, intraabdominal foci, and intravascular catheters. The etiology of the bacteremia may not be identified in as many as 25% of patients. Bacteremias with certain pathogens may indicate the need to assess the patient for underlying malignancies. Bacteremias with Streptococcus bovis, Clostridium septicum, and to a lesser extent Clostridium perfringens have all been associated with gastrointestinal malignancies. With the current importance placed on outpatient management, more extensive evaluation of the febrile patient will be conducted in the office or clinic setting. Many bacteremias will be detected and managed with the patient remaining in the community environment. This chapter addresses some practical issues related to blood cultures including the type and number of blood cultures to order, when and how to order them, interpretation of the results, and recommendations concerning initial antibiotic therapy. 2 2.1

TYPES AND METHODOLOGY OF BLOOD CULTURES Routine

Most common pathogens such as Staphylococcus spp., Streptococcus spp., and gramnegative rods (GNRs) can be isolated by routine blood culture techniques. The technique involves obtaining blood from the patient and inoculating it into blood culture bottles that 169

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BLOOD CULTURESa Candidates for blood cultures (Table 1) Routine cultures Drawing of two sets from different venipunctures (Table 2) Maximal filling of each bottle Most aerobic and anaerobic bacteria and yeast Lysis-centrifugation cultures One tube per pathogen sought Mycobacteria; Legionella, Brucella, Aspergillus spp.; dimorphic fungi Interpretation of common isolates (Table 3) GPC in clusters (Table 4) S. aureus almost always a pathogen Coagulase-negative Staphylococcus spp. most commonly contaminants except in the presence of in situ prosthetic material GPC in chains (Table 5) S. pneumoniae, Enterococcus spp., ␤-hemolytic Streptococcus spp. almost always pathogens Viridans (␣-hemolytic) streptococci group may be contaminants; isolation in multiple blood cultures suggestive of endocarditis GNR (Table 7) Always pathogens UTI or GI source GNR anaerobes (Table 7) GI source generally Part of polymicrobic infection GPR (Table 8) Diphtheroids, Propionibacterium and Bacillus spp. usually contaminants Clostridium spp. infections associated with GI source and malignancy GN coccobacilli (Table 9) Usually pathogen except nongonococcal, nonmeningococcal Neisseria spp. Yeast (Table 10) Always a pathogen Line infection, GU or GI source Initial antibiotic therapy (Table 11) a

GPC, gram-positive cocci; GNR, gram-negative rod; UTI, urinary tract infection; GI, gastrointestinal; GPR, gram-positive rod; GU, genitourinary.

are then placed in an incubator. Most laboratories use an automated system with the capability of continuous monitoring to detect growth as quickly as possible. The newer systems measure changes in optical density, rather than radioactive CO2 production, to identify bacterial growth, eliminating a potential source of contamination from repeated entry into the bottles to sample the CO2. When growth is detected, an aliquot of blood is removed for Gram stain, possibly direct inoculation of biochemicals, and subculture onto agar plates for isolation, identification, and susceptibility testing of the organism. The clinician is then informed of the Gram stain results (see sec. 6). Blood drawn for culture should be inoculated into two blood culture bottles, an aerobic and anaerobic, referred to as a set. Two sets of blood cultures from two different

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venipunctures should be obtained; inoculating more than two blood culture bottles from a single venipuncture is discouraged. The volume of blood cultured is a very important determinant of successful detection of bacteremia. Interpretation of the blood cultures is generally done in terms of sets (either or both bottles) that yield positive or negative results, not the number of bottles that yield positive or negative results. As discussed later, a coagulase-negative Staphylococcus spp. growing in one set (either or both bottles) of blood cultures would generally be interpreted as a contaminant. If both sets grew coagulase-negative Staphylococcus spp., suspicion would be raised that it might be a pathogen, especially if the patient had a central venous catheter or other foreign material in situ. Most common bacteria grow to detectable levels within 24–72 hours. Most laboratories routinely discard blood cultures after 5 to 7 days if no growth is detected. Some less common or fastidious organisms may take longer than 5–7 days to grow. This may preclude identification of pathogens in culture-negative endocarditis due to slow-growing GNRs of the HACEK group (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikinella corrodens, Kingella kingae) which may take up to 4 weeks to grow. If the blood cultures are discarded after 7 days, these fastidious bacteria may be missed, obscuring the correct diagnosis. The laboratory should be informed of any unusual organisms suspected so that the most appropriate culture techniques can be used. 2.2

Lysis-Centrifugation

Some microorganisms may not be detected by routine blood cultures. Such pathogens include mycobacteria (Mycobacterium tuberculosis and M. avium), Legionella spp., Bartonella spp., molds such as Aspergillus fumigatus, and the dimorphic fungi, including Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis. A blood culture technique called lysis-centrifugation may improve the chances of isolating these organisms. This technique involves placing the patient’s blood into a tube (Isolator tube, Wampole Laboratories, Cranbury, NJ) that contains agents that lyse blood cells and prevent coagulation. The tube is then centrifuged and the pellet plated on selective media, depending on the suspected pathogen. It is the culture plates that are then incubated, not the lysis-centrifugation tube itself. Lysis-centrifugation is a labor-intensive culture method that requires multiple manipulations by the technologists and results in a higher contamination rate than the routine blood culture technique. Mycobacteria can be isolated from blood culture bottle systems that contain the appropriate media. The laboratory should be alerted to the pathogen being sought so that the appropriate culture technique can be used. 3

WHO SHOULD HAVE BLOOD CULTURES?

Bacteremias may be transient, intermittent, or continuous, depending on the clinical etiology. Transient bacteremias may follow manipulation of infected tissue or instrumentation of colonized or infected mucosa. Intermittent bacteremias can occur in association with abscesses or a variety of focal infections. Continuous bacteremias are seen with endovascular infections such as endocarditis, vascular graft infections, mycotic aneurysms, infected aortic aneurysms, and vascular catheter infections. Patients for whom blood cultures are warranted include those with fever of >3 days or without an obvious source, those with artificial devices (i.e., prosthetic valves, prosthetic joints, Hickman catheters, Port-A-Caths, dialysis catheters), and those who are immunocompromised (see Table 1). A low threshold for obtaining blood cultures should be main-

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Table 1 Patients Who Are Candidates for Blood Cultures Febrile without an obvious source of infection Febrile for more than 3 to 5 days Elderly with altered mental status or malaise Artificial material present, e.g., prosthetic heart valve, prosthetic joint Vascular access devices, e.g., Hickman catheter, Port-A-Cath, dialysis catheter Immunocompromised, i.e., neutropenic, asplenic, HIV, steroid therapy Febrile with petechial or hemorrhagic rash, necrotic ulcers (ecthyma gangrenosum)

tained for the elderly. This population has a higher incidence of bacteremia, may have nonspecific symptoms of malaise or altered sensorium, and may not be febrile. Comorbid conditions, present in many elderly adults, increase the morbidity and mortality of bacteremia. The presence of a bacteremia would not necessarily mandate intravenous antibiotics or hospitalization if the source were a urinary tract infection (UTI), pneumonia, bronchitis, or soft tissue infection. The blood cultures may help identify the offending pathogen and alert the clinician to bacteria such as S. aureus that would necessitate a more prolonged course of antibiotic therapy. 4

SIGNS AND SYMPTOMS

Most bacteremic patients have fevers, chills, rigors, sweats, and tachycardia. Some may become hypotensive and experience syncope or extreme prostration. The elderly, patients with neutropenia or significant renal or hepatic disease, and those with central venous catheters may not have all these classic symptoms. Constitutional symptoms such as malaise, fatigue, diarrhea, and myalgias are also common. Diarrhea often can lead to a mistaken diagnosis of gastroenteritis. Patients may be misdiagnosed as having a viral or ‘‘flulike’’ illness. Other signs and symptoms are generally related to the underlying disease or site of infection. For example, patients who are bacteremic secondary to endocarditis may have conjunctival petechiae, Janeway lesions, or Osler’s nodes. Patients with cellulitis usually have a painful erythematous localized rash. Other skin manifestations may be important clues to the existence of a bacteremia (see Chapter 7). S. aureus bacteremia may be associated with skin pustules, subcutaneous abscesses, or small areas of purpura with white centers. Neisseria gonorrhoeae can cause purpura with pustular centers, macules, papules, purpuric vesicles and bullae, and purpuric infarcts. The lesions are generally sparse, located on the distal extremities, and frequently painful. N. meningitidis can cause petechiae, purpura, or erythematous macules. In fulminant meningococcemia confluence of petechial and purpuric lesions can result in the development of hemorrhagic necrotic patches. Chronic meningococcemia is characterized by recurrent crops of lesions, usually located on the extremities. The lesions can have a variety of appearances, including petechiae, petechiae with vesiculopustular centers, erythematous maculopapular or erythema nodosum–like nodules. Pseudomonas aeruginosa and other GNR bacteremias can cause ecthyma gangrenosum, a rounded lesion with an indurated erythematous rim surrounding an ulcer with a central black eschar. Salmonella typhi can cause the classic ‘‘rose spots’’ rash, consisting of small, slightly raised, pink papules that tend to occur in crops located on the upper part of the abdomen, lower part

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of the chest, and back. This rash generally develops 7 to 10 days into the course of untreated S. typhi infection. Foul odor from soft tissue infections is usually indicative of the presence of anaerobes or occasionally infection with Proteus mirabilis. 5 5.1

ORDERING BLOOD CULTURES Draw Blood Cultures Before Starting Antibiotic Therapy

Drawing cultures before starting antibiotic therapy enhances both the chance of detecting existing bacteremia and the validity of negative blood culture results (see Table 2). In the absence of preceding antibiotic therapy, negative blood culture results argue strongly against the diagnosis of endocarditis. 5.2

Draw at Least Two Sets of Blood Cultures

The sensitivity of a single blood culture in detecting a bacteremia is 80%–90%. The yield of two to three sets collected over a 24-hour period approaches 100%. The chance of detecting a bacteremia does not improve by drawing more than three sets in a 24-hour period. The volume of blood collected is the single most critical factor in determining the successful detection of a bacteremia. Each bottle of the set should be inoculated with the amount of blood recommended by its manufacturer, usually 20–30 milliliters per set. 5.3

Draw Blood Cultures from Two Separate Venipuncture Sites

If both sets of blood cultures are obtained from the same venipuncture, the significance of the detection of organisms such as coagulase-negative Staphylococcus spp., viridans streptococci, diphtheroids, and Bacillus spp. is difficult to determine. The blood culture sets should be drawn at different times to improve the chances of detecting an intermittent bacteremia and help determine whether the patient has a prolonged and/or persistent bacteremia. Generally, it is preferable to draw the blood cultures at least 1 hour apart. If acute endocarditis is suspected, two or three sets of blood cultures can be drawn from separate sites at 15–30-minute intervals to expedite initiation of antibiotic therapy. Patients with intravascular access catheters (Hickman or Broviac catheters, Port-ACath devices, peripherally inserted central catheters, and dialysis catheters) should have at least one set of blood cultures drawn via the access in addition to at least one set drawn

Table 2 Guidelines for Obtaining Blood Cultures Obtain prior to starting antibiotic therapy. Obtain at least two sets.a Obtaining more than three sets in a 24-hr period is unnecessary. Obtain 1 hour or more apart.b Obtain from separate venipuncture sites. Obtain by using good sterile technique. a b

Yield over 95% with two sets and approaches 100% with three sets. If prompt initiation of antibiotics is necessary, then a shorter interval can be used.

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percutaneously. The drawing of blood cultures from the intravascular access device is controversial because of the high rate of contamination. If the cultures from the catheter and those drawn percutaneously both grow the same bacteria, that isolate most likely represents a pathogen and not a contaminant. 5.4

Use Standard Aseptic Techniques

If your office personnel draw blood cultures, make sure they follow published guidelines for skin preparation and appropriate techniques. Contaminants are usually introduced during the collection of the blood culture and not with laboratory processing. Good aseptic technique reduces the incidence of blood culture contamination. 5.5

Additional Tests

Depending on the patient’s clinical presentation, a urinalysis and urine culture, sputum culture, complete blood count (CBC) with manual differential, liver biochemical studies, and possibly radiological studies (i.e., chest x-ray, abdominal computed tomography [CT scan], or abdominal ultrasound) may be warranted. Isolation of the same organism from both blood and urine would imply the presence of a genitourinary infection. If a GNR is isolated from blood but not urine, a gastrointestinal source should be sought. 5.6

Obtain Two More Sets of Blood Cultures

If the laboratory reports that the initial blood culture(s) result is positive, drawing two additional sets of blood cultures may help define the duration and clinical significance of the bacteremia. This is especially true for the isolation of gram-positive cocci. If the same bacteria continue to be isolated, they are most likely pathogens and an endovascular source or abscess may be their origin. 6

INTERPRETATION OF BLOOD CULTURES

The most common bacteria isolated form blood cultures are listed in Table 3. 6.1

Gram-Positive Cocci

Gram-positive cocci (GPC) are usually described as forming clusters (Table 4) or chains (Table 5). If GPC in clusters are reported, the technologist performs a coagulase test to distinguish S. aureus (coagulase-positive) from coagulase-negative staphylococci, such as S. saprophyticus and S. epidermidis. The same day growth is detected, a coagulase test can be performed by using a couple of drops of blood from the positive blood culture result bottle. A result is often available in 4 hours. The coagulase test can also be performed rapidly once there is growth on the agar plate. A commercial slide test can be used, or the organism can be incubated in serum for 4 hours (see the discussion of S. aureus). Isolation of coagulase-negative Staphylococcus spp. from a single blood culture set would be most consistent with contamination. If coagulase-negative Staphylococcus spp. are isolated from multiple sets of blood cultures, they may be clinically significant. Potential sources include intravenous catheters, prosthetic or native valve endocarditis, dialysis catheters, and ventriculoatrial shunt infection. If GPC in pairs or chains are reported, considerations should include Streptococcus pneumoniae, ␤-hemolytic streptococci, viridans streptococci, Enterococcus spp., and S.

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Table 3 Common Blood Culture Isolates Clinically significant Gram-positive cocci Clusters Staphylococcus aureus Coagulase-negative Staphylococcus spp. Pairs or chains Streptococcus pneumoniae Enterococcus spp. Viridans streptococci Gram-negative rods Escherichia coli Enterobacteriaceae Pseudomonas aeruginosa Bacteroides spp. Yeast Candida spp. Cryptococcus neoformans

Contaminant

Almost always Sometimes

Rarely Usually

Almost always Usually Sometimes

Almost never Sometimes Sometimes

Usually Usually Usually Usually

Rarely Rarely Rarely Rarely

Almost always Always

Almost never Never

bovis. Latex agglutination tests are available for the detection of S. pneumoniae and several of the ␤-hemolytic streptococci, such as Group A and Group B. These are rapid tests that can be performed on the blood culture supernatant. If a pneumonia or bronchitis is suspected as the source of the bacteremia, the technologist can perform a latex agglutination test to detect the more common serotypes of S. pneumoniae. This may be the only way

Table 4 Gram-Positive Cocci in Clusters or Groups Coagulase test result

Species

Contaminant

Coagulase-positive

Staphylococcus aureus

Unlikely

Coagulase-negative

Staphylococcus species S. epidermidis S. saprophyticus

Often, if only a single blood culture set is positive Less likely if multiple sets are positive

Clinical significance Endocarditis Line infection Cellulitis Osteomyelitis Septic arthritis Epidural abscess Pyomyositis Pneumonia/bronchitis Prosthetic valve infection Long-term intravascular line infection Ventriculoatrial shunt infection Prosthetic joint infection Sternal osteomyelitis Native valve endocarditis (rare)

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Table 5 Gram-Positive Cocci in Pairs or Chains Organism Viridans streptococci group Streptococcus pneumoniae

Enterococcus spp.

Group A Streptococci

Group B Streptococci

Peptostreptococcus spp. (anaerobic)

Common source Endocarditis Neutropenic patients Pneumonia Bronchitis Meningitis Peritonitis Endocarditis Intravascular device infection Cellulitis Retropharyngeal abscess Necrotizing fasciitis

Cellulitis Septic arthritis Postpartum endometritis Cellulitis Oropharyngeal infection

Other considerations Contaminant if only one set is positive Endocarditis Sinusitis

Contaminant Urinary tract infection Intraabdominal or pelvic infection Pharyngitis Pneumonia Empyema Pyomyositis Endocarditis Streptococcal toxic shock syndrome Endocarditis Contaminant Gynecological infection Intraabdominal infection Osteomyelitis Contaminant

to confirm the presence of S. pneumoniae in blood cultures when the S. pneumoniae autolyses and fails to grow on subculture. S. pneumoniae isolated from even a single blood culture set is almost always clinically significant. Isolation of a viridans streptococcus group in a single blood culture set most likely indicates a contaminant. When a viridans streptococcus group is isolated from multiple sets of blood cultures, the most likely etiology is endocarditis. Enterococci are normal inhabitants of the bowel. Common sources of enterococcal bacteremia are intraabdominal sites, endocarditis, and UTI. When isolated from blood, enterococci are usually considered pathogenic. If the bacteremia originates from a gastrointestinal (GI) source, the enterococci are usually part of a polymicrobic infection. If S. bovis is isolated, an underlying gastrointestinal malignancy should be sought. 6.1.1 Staphylococcus aureus Bacteremia (SAB) Isolation of S. aureus from the blood deserves special attention because of the high morbidity and mortality associated with this pathogen. Mortality rates of 35%–39% are associated with community acquired infections. Short- and long-term morbidity includes endocarditis with valve destruction, solid organ abscesses, vertebral osteomyelitis, and central nervous system involvement with epidural abscess, meningitis and brain abscess. Staphylococcus aureus bacteremia tends to relapse, especially if the patient is not given an adequate course of parenteral antibiotics, abscesses are not drained, or infected prosthetic material is not removed. Patients at higher risk for S. aureus bacteremia include diabetics, injection drug users, chronic renal dialysis patients, and patients with central

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venous catheters (CVCs). S. aureus in the blood can be filtered in the glomerulus and thus cultured from the urine. S. aureus cultured from the urine should be presumed to be due to a bacteremia until proved otherwise. These patients should have blood cultures drawn. Over the past several decades the epidemiology of SAB has changed. Formerly SAB presented predominantly as endocarditis in older patients with valvular heart disease or in intravenous drug users. All of the nonintravenous drug users required 6 weeks of parenteral therapy. With the increased use of CVCs, SAB is seen more commonly in hospitalized patients with these catheters. If the CVC can be removed and the bacteremia clears rapidly, some patients may be treated with a ‘‘short course’’ of 2 weeks of parenteral antibiotics (see Table 6). Before selection of short-course therapy, a number of determinants need to be evaluated and an infectious diseases consultation is advisable. All patients with SAB should be admitted to the hospital and begun on parenteral antibiotics. The great majority of patients require 4–6 weeks of therapy (see Table 11). A diligent search for endocarditis, vertebral osteomyelitis, and deep abscesses should be made. Obtaining two additional sets of blood cultures prior to initiation of antibiotic therapy is often useful. The duration or persistence of a S. aureus bacteremia is an important factor in determining how long a course of therapy should be administered. 6.2

Gram-Negative Rods (Table 7)

In terms of Gram stain morphological characteristics, most GNRs are indistinguishable from one another. Although they are usually different in appearance from Enterobacteriaceae, Haemophilus spp., Bacteroides spp., and Pseudomonas aeruginosa can have similar (small pleomorphic GNRs) Gram stain morphological characteristics. Fusobacterium spp. are anaerobic GNRs with unique Gram stain morphological features: long, thin GNRs with tapered ends. Many laboratories inoculate biochemicals with an aliquot taken directly from the positive blood culture bottle for potential identification in less than 24 hours. Agar plates containing growth, differential, and selective media are also inoculated. Once growth is visible on combined differential and selective media such as MacConkey and eosin-methylene blue (EMB), it is usually possible to distinguish those that ferment lactose from those that do not. Growth of Klebsiella spp., Escherichia coli, and Enterobacter spp. appear as red/pink colonies on MacConkey or EMB agar. If the GNR is a non–lactose

Table 6 Treatment of Staphylococcus aureus Bacteremia

Risks factors Community-acquired Catheter-related Valvular heart disease present Metastatic foci present or endocarditis Bacteremia detected over several days Immunocompromised host a

Long-course therapy (4–6 wk of parenteral antibiotics)

Short-course therapy (10–14 days of parenteral therapy)

X Xa X X X X

Catheter can be removed quickly and bacteremia is transient and remits. Preferable to discuss with an infectious disease physician before selecting short-course therapy.

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Table 7 Gram-Negative Rodsa Organism Escherichia coli

Klebsiella spp. Enterobacter spp. Morganella spp. Proteus spp. Salmonella spp.

Haemophilus spp.

Pseudomonas aeruginosa

Pasturella multocida Acinetobacter spp. Aeromonas spp.

Anaerobes Bacteroides spp. Fusobacterium spp.

a

Common source UTI Pyelonephritis Liver abscess Diverticulitis Appendicitis Cholecystitis Cholangitis Same as above Pneumonia Same as E. coli Same as E. coli Same as E. coli Bacterial enteritis

Bronchitis Pneumonia Meningitis ECF patient: pneumonia, bronchitis, UTI

Soft tissue infection associated with animal bite or scratch Pneumonia Soft tissue infection and fresh water– associated wound Intraabdominal abscess Diabetic foot infection Traumatic soft tissue infection Septic thrombophlebitis of jugular vein (Lemierre’s disease)

Other considerations Prostatitis Pneumonia Soft tissue infection, e.g., diabetic wound infection Intravascular access Splenic abscess Same as E. coli Same as E. coli Same as E. coli Same as E. coli Aortic aneurysm infection Osteomyelitis (sickle cell disease patient) Typhoid fever Endocarditis Sinusitis IDU endocarditis HIV pneumonia Diabetic foot infection

Rare Endocarditis

Endocarditis

Endocarditis Cholecystitis

Brain abscess Retropharyngeal abscess Individuals with no hospitalization or instrumentation history

Osteomyelitis

Soft tissue infection

Pneumonia

Cholecystitis Cholangitis

Diabetic foot infection Pneumonia

UTI, urinary tract infection; ECF, extended care facility; IDU, intravenous drug user; HIV, human immunodeficiency virus infected patient.

fermenter, other species, such as Proteus spp., Morganella spp., and Pseudomonas spp., should be considered. If a non–lactose fermenter is suspected, the antibiotic prescribed should have anti–Pseudomonas spp. activity. In addition, the technologist may have other clues to the identity of the GNR prior to complete identification such as a fruity odor characteristic of P. aeruginosa or the swarming growth pattern of Proteus spp.

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A GNR isolated from a blood culture is rarely a contaminant. The most common GNR isolated is E. coli. The isolation of E. coli, Klebsiella spp., Proteus spp., or Enterobacter spp. suggests a urinary tract infection, prostatitis, or intraabdominal focus such as diverticulitis or cholecystitis. Isolation of Haemophilus spp. suggests a respiratory source such as pneumonia, bronchitis, sinusitis, or occasionally endocarditis. Salmonella spp. suggest a bacterial enteritis or less commonly an infected aortic aneurysm in the elderly, an osteomyelitis in a young adult with sickle cell disease, or typhoid fever in an overseas traveler. 6.3 6.3.1

Anaerobes Gram-Negative

If only the anaerobic bottle of the blood culture set grows a GNR, the isolate may truly be an obligate anaerobe, e.g., Bacteroides spp., Prevotella melaninogenicus (previously Bacteroides melaninogenicus), or Fusobacterium spp. Facultative anaerobic GNRs such as E. coli or other Enterobacteriaceae (e.g., Klebsiella spp.), which grow in aerobic and anaerobic bottles, remain a possibility, though. In recent studies, the incidence of bacteremias due to anaerobes has declined to 5% or less. The Bacteroides fragilis group accounts for the majority of clinically significant anaerobic bacteremias. The portal of entry for Bacteroides species is the gastrointestinal tract more than 50% of the time. Less common sources are the female genital tract, lower respiratory tract, head and neck infections, and skin and soft tissue sites. Fusobacterium spp. bacteremia have been associated with life-threatening head and neck infections and should prompt an immediate evaluation for a deep neck or jugular vein infection. 6.3.2

Gram-Positive

The gram-positive anaerobes Peptostreptococcus spp. and Clostridium spp. (discussed later) each account for 10% or less of anaerobic bacteremias. Peptococcus or Peptostreptococcus spp. may be contaminants or may be secondary to oropharyngeal, female genital tract, abdominal, or skin and soft tissue infections. 6.4

Gram-Positive Rods

Diphtheroids (Corynebacterium spp.) have a characteristic Chinese character–like appearance with the formation of V shapes and palisades (several organisms aligning along the long axis of the rod) on Gram stain (see Table 8). When growing in a single set of blood cultures, these organisms are usually contaminants. Rarely, Corynebacterium diphtheriae (diphtheria), Bacillus cereus (food poisoning, soft tissue infection) or Bacillus anthracis (anthrax) is isolated. An important pathogen, which may be mistaken for a diphtheroid, is Listeria monocytogenes, a small gram-positive rod. L. monocytogenes is usually a pathogen of pregnant women, elderly adults, or immunocompromised patients. It can cause central nervous system infection, including subacute meningitis, meningoencephalitis, and cerebritis; bacteremia during pregnancy; endocarditis; and rarely focal infections. Morphologically, both Bacillus spp. (including Bacillus anthracis) and Clostridium spp. are large boxcar-like gram-positive rods. Clostridium spp. are usually obligate anaerobes and grow only in the anaerobic bottle, whereas Bacillus spp. can grow in either aerobic or anaerobic blood culture bottles. Clostridium spp. have a tendency to be gramvariable: some of the organisms stain gram-positive and others stain gram-negative.

Contaminanta

Contaminanta

Contaminanta

Corynebacterium spp. (Diphtheroids)

Bacillus spp.

Lactobacillus spp.

a

Other considerations

Transient bacteremia Emphysematous cholecystitis Cholecystitis (rare) Cholangitis Intravascular device (e.g., Hickman catheter, Port-A-Cath) infection Prosthetic valve infection Prosthetic joint infection Peritonitis in continuous ambulatory peritoneal dialysis patient Neurosurgical shunt infection Wound infection Transient bacteremia in drug abusers Intravascular device infections Bacillus cereus—cellulitis, osteomyelitis Bacillus anthracis—anthrax

Endocarditis Peritonitis Bacteremia of unknown origin

If multiple blood culture results are positive, the organism may be a pathogen.

Clostridium spp.

Cerebritis Meningitis Meningoencephalitis Infection in pregnancy Intraabdominal abscess Gas gangrene

Common source

Listeria monocytogenes

Organism

Table 8 Gram-Positive Rods

Consider bioterrorism

Unusual pathogen except in drug users or immunocompromised hosts

Risk groups: elderly, pregnant, immunocompromised Cause of serious in utero/neonatal infection C. septicum often associated with GI or other malignancy

Comments

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Clostridium perfringens bacteremia may be due to an intraabdominal infection, gynecological infection (tuboovarian or pelvic abscesses), gas gangrene, soft tissue infections such as perirectal abscess, decubitus ulcer, or diabetic foot infection. Interestingly, a number of studies have noted the occurrence of C. perfringens bacteremia without any obvious clinical consequence or relationship to an underlying illness. Clostridium septicum bacteremia is often associated with underlying colon cancer, leukemia in relapse, or other malignancies. It has also been associated with gas gangrene, septic arthritis, and neutropenic enterocolitis. Anaerobic diphtheroids or Propionibacterium spp. are usually contaminants when isolated from a single blood culture set. On rare occasions, Propionibacterium spp. bacteremia can be due to endocarditis (native or prosthetic valve), central nervous system shunt infections, or septic arthritis, especially in prosthetic joints. Lactobacillus spp., anaerobic gram-positive rods, are part of the normal vaginal flora. They rarely cause a clinically significant bacteremia, but they have been implicated in a variety of deep-seated infections and amnionitis. 6.5

Gram-Negative Diplococci/Coccobacilli

Gram-negative diplococci include Neisseria meningitidis, Neisseria gonorrhoeae, other Neisseria spp., and Moraxella catarrhalis. Presence of N. gonorrhoeae bacteremia implies disseminated infection or less often endocarditis. Neisseria meningitidis bacteremia may be secondary to meningitis, meningococcemia without meningitis, pneumonia, or bronchitis. Other species of Neisseria are generally skin contaminants. M. catarrhalis is generally associated with respiratory infections, i.e., bronchitis, pneumonia, or sinusitis. Gram-negative coccobacilli or diplococci (see Table 9) may also be Pasturella multocida or Acinetobacter spp. A Pasturella multocida bacteremia may be due to wounds caused by dog or cat bites or scratches. An Acinetobacter spp. bacteremia may occur in association with a soft tissue infection or pneumonia. These latter infections are most commonly hospital-acquired. Veillonella spp. are obligate anaerobic gram-negative cocci. These are rarely pathogens but have been reported to cause endocarditis.

Table 9 Gram-Negative Diplococci/Coccobacilli Organism

Common source

Neisseria meningitidis

Meningitis Disseminated

Neisseria gonorrhoeae Other Neisseria spp. Moraxella catarrhalis

Disseminated Contaminant Pneumonia Bronchitis Pneumonia

Acinetobacter spp. Pasturella multocida

Soft tissue infection associated with animal bite/scratch

Other considerations Bronchitis Pneumonia Endocarditis Endocarditis Endocarditis (rare) Otitis media Sinusitis Cellulitis associated with central venous catheters Osteomyelitis Septic arthritis Meningitis Pneumonia

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Polymicrobial

Occasionally more than one type of bacteria is isolated from a blood culture. These isolates may be contaminants, pathogens, or a combination of the two. Interpretation of their significance is based on which organisms grow and how many blood cultures are positive. If a variety of skin flora organisms grow, they probably are contaminants. If a blood culture(s) grows multiple pathogens, then an intraabdominal source is likely. Polymicrobial bacteremias secondary to urinary tract infections may rarely occur in patients with urinary catheters. 6.7

Yeast

Yeast isolated from the blood should never be considered contaminants (see Table 10). They frequently grow in only the aerobic bottle and often require at least 48-hour incubation to become detectable. The most common yeast isolated from blood are Candida albicans or other Candida spp., but Cryptococcus neoformans and Histoplasma capsulatum may also be isolated from blood. Aspergillus spp. and other fungi are rarely isolated in blood cultures. Candidemias are usually associated with intravascular line infections or, less commonly, urinary tract infections. In debilitated or immunosuppressed hosts, the isolation of Candida spp. from the blood may indicate disseminated candidiasis, esophageal candidiasis, or endocarditis. 6.8

Negative Blood Cultures

Blood cultures may be negative if the patient is truly not bacteremic, if the bacteremia is due to a fastidious organism, if the bacteremia is intermittent, or if the patient has recently received antibiotics. As mentioned, the HACEK group of bacteria may take more than 5 to 7 days to grow and may be missed if blood cultures are routinely discarded after 5 to 7 days. If the blood cultures show growth of gram-positive cocci in chains but bacteria

Table 10 Yeasts Organism Candida spp.

Cryptococcus neoformans

Common source Urinary tract infection Line infection Disseminated disease— immunocompromised or debilitated patients Meningitis Pneumonia

Histoplasma capsulatum

Disseminated

Aspergillus spp.

Pneumonia

Comments Almost never a contaminant Should be treated

May occur in immunocompetent patients Consider lysis-centrifugation blood culture Human immunodeficiency virus infected patients Consider lysis-centrifugation blood culture Rarely isolated from blood Consider lysis-centrifugation blood culture

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do not grow when bottle contents are subcultured onto agar plates, the microbiology laboratory should be asked to look for Abiotrophia spp., previously known as vitamin B6deficient streptococci. The search for mycobacteria, Legionella spp., and certain fungi in the blood is aided by lysis-centrifugation techniques or other special techniques and media, so it is important to inform the laboratory that these pathogens are suspected. Antibiotics may inhibit the growth of bacteria for days to weeks after cessation of their use, causing a false-negative blood culture result. A careful review of all medications used by the patient is important to determine whether antibiotics have been taken in the weeks prior to the blood cultures.

7 7.1

ANTIMICROBIAL THERAPY Patient Is Not Receiving Antibiotic Therapy

If the blood culture isolate is a likely contaminant, other cultures have not identified a bacterial infection, and the patient is clinically stable, antibiotic therapy is not necessary while awaiting the final blood culture results. If the blood culture isolate is judged likely to be a pathogen, antibiotic therapy should be started. Antibiotic selection and mode of delivery depend on the pathogen suspected, the infectious disease source, and the patient’s clinical status. If the patient’s condition is clinically unstable, he or she should be hospitalized and intravenous antibiotics should be administered. If the patient’s condition is clinically stable, but a serious diagnosis such as endocarditis is suspected or the cause of the bacteremia is unknown, the patient should be hospitalized and appropriate intravenous antibiotics begun. If an otherwise uncomplicated infection is suspected and the patient is clinically stable, appropriate oral antibiotic therapy may be adequate while awaiting the final culture results. Examples of bacteremic infections that may be treated with oral agents in the outpatient setting include pyelonephritis, bronchitis, pneumonia, cellulitis, and diverticulitis. 7.2

Patient Is Receiving Antibiotic Therapy

If the blood culture isolate is likely to be a contaminant, it does not require a change in antibiotic therapy. If the blood culture isolate is a likely pathogen, the choice and mode of antibiotic therapy should be reassessed. The patient’s clinical status should be reviewed. Some patients will show clinical improvement by the time the bacteremia is reported, so the current antibiotics can be continued. If the patient’s condition is clinically deteriorating or not improving, a change in the empiric antibiotics should be considered. If the initial antibiotic prescribed was a broad-spectrum agent, a conscious effort should be made to narrow the spectrum of the drug to target the offending bacteria. A patient whose bacteremia is secondary to a UTI, cellulitis, bronchitis, or pneumonia and who is clinically improving by the time the blood culture shows growth can usually complete antibiotic therapy as an outpatient with oral antibiotics. The presence of confounding factors (i.e., prosthetic heart valves or artificial joints, neutropenia, or other immunosuppression) should be considered and may warrant more prolonged intravenous antibiotic therapy. Complicated infections (abscesses, cholangitis, cholecystitis, diverticulitis, endocarditis, meningitis, and prosthesis infections) usually require hospital admission and intravenous (IV) antibiotic therapy.

Clostridium spp.

Gram-positive rods— anaerobes Yeast

GPC = Gram positive cocci. a Assuming normal renal function. b Assuming penicillin resistance. c May consider oral therapy, depending on the clinical status of the patient. d Treatment for suspected endocarditis.

Candida albicans Cryptococcus neoformans Non–Candida albicans

Bacteroides spp. Fusobacterium spp.

Pseudomonas spp.

Enterobacteriaceaec

Enterococcus spp.

Coagulase-negative Staphylococcus spp. Streptococcus pneumoniaeb,c ␤-Hemolytic streptococci (Groups A, B, C, G) Streptococcus viridans group

Staphylococcus aureus

Suspected organism

GNR—anaerobes

Gram-negative rod (GNR)— not anaerobes

GPC in pairs/chains

GPC in clusters

Blood culture Gram stain

Table 11 Preliminary Antibiotic Therapy

Clindamycin Augmentin Metronidazole Clindamycin Fluconazole Amphotericin B Amphotericin B

Ciprofloxacin Ceftazidime Metronidazole

Ciprofloxacin

Ceftriaxone Levofloxacin Penicillin Cefazolin Penicillin Penicillin plus gentamicind Cefazolin Vancomycin Ampicillin Ampicillin plus gentamicind Trimethoprim-sulfamethoxazole (TMP)

Oxacillin Cefazolin Vancomycin if methicillinresistant S. aureus (MRSA) suspected Vancomycin

Antibiotic

1–2 g q12–24h IV 500 mg IV or PO qd 1–2 million U q4h IV As above See above See chapter 18 (endocarditis) See above See above 2 gm q4h IV See chapter 18 (endocarditis) 10 mg/kg TMP daily IV in divided doses Double-strength tab PO bid 400 mg q8–12h IV 750 mg PO bid See above 2 g q8h IV 15-mg/kg load then 7.5 mg/kg q6h IV 900 mg q8h IV 875 mg q12h po See above See above 400 mg/day IV 0.5–0.6 mg/kg/day IV See above

As above

2 g q4h IV 2 g q8h IV 1 g q12h IV

Dosea

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185

Choice of Antibiotic Therapy

Recommendations for preliminary antibiotic therapy for the patient with a positive blood culture are outlined in Table 11. These are organism-based recommendations and should be followed cautiously. There are many factors that can change these recommendations. The site of infection (i.e., meningitis, endocarditis, or osteomyelitis), antibiotic penetration, allergy history, renal function, age, and sensitivity patterns of local pathogens (i.e., the incidence of penicillin-resistant S. pneumoniae or of community-acquired methicillin-resistant S. aureus [MRSA] in your area) are among the factors that should be considered. BIBLIOGRAPHY Aronson M, Bor DH. Blood cultures. Ann Intern Med 106:246–253, 1987. Chassagne P, Perol M-B, Doucet J, Trivalle C, Menard J-F, Manchon N-D, Moynot Y, Humbert G, Bourreille J, Bercoff E. Is presentation of bacteremia in the elderly the same as in younger patients? Am J Med 100:65–70, 1996. Dorsher CW, Rosenblatt JE, Wilson WR, Ilstrup DM. Anaerobic bacteremia: Decreasing rate over a 15-year period. Rev Infect Dis 13:633–636, 1991. Gleckman R, Hibert D. Afebrile bacteremia: A phenomenon in geriatric patients. JAMA 248:1478– 1481, 1982. Lombardi DP, Engleberg NC. Anaerobic bacteremia: Incidence, patient characteristics, and clinical significance. Am J Med 92:53–60, 1992. Mandell G, Bennet J, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000. Meyers BR, Sherman E, Mendelson MH, Velasquez G, Srulevitch-Chin E, Hubbard M, Hirschmann SZ. Bloodstream infections in the elderly. Am J Med 86:379–384, 1989. Siegman-Igra Y, Anglim AM, Shapiro DE, Adal KA, Strain BA, Farr BM. Diagnosis of vascular catheter-related bloodstream infection: A meta-analysis. J Clin Microbiol 35:928–936, 1997. Washington JA, Ilstrup DM. Blood cultures: Issues and controversies. Rev Infect Dis 8:792–802, 1986. Weinstein MP, Towns ML, Quartey SM, Mirrett S, Reimer LG, Parmigiani G, Reller LB. The clinical significance of positive blood cultures in the 1990’s: A prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis 24:584–602, 1997.

10 Upper Respiratory Tract Infections W. Kemper Alston and Kristen I. Fahrner University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Upper respiratory infections (URIs) continue to pose a significant challenge to health care providers for a variety of reasons. First, infections such as the common cold, sinusitis, otitis media, and pharyngitis are common and account for a large proportion of office visits. Second, they are caused by a wide variety of microorganisms with a tremendous range of pathogenicity from the lowly rhinovirus to the virulent ␤-hemolytic Streptococcus species. Third, despite this microbial heterogeneity, the clinical presentations are nonspecific with considerable overlap between self-limited viral infections and invasive bacterial infections. Fourth, the anatomical characteristics involved are complex and may have important diagnostic and therapeutic implications that are frequently underestimated. Fifth, for most of these infections we lack rapid, affordable, and accurate diagnostic tools to assist in management. Sixth, URIs are commonly treated with antibiotics regardless of the cause, and this practice has contributed to the emergence of antibiotic resistance in the community. This worrisome trend has further complicated our decisions by introducing doubt into what was once a predictable response to narrow-spectrum agents. In this chapter we review the common URIs—pharyngitis, otitis, sinusitis, and epiglottitis—and briefly outline some of the more unusual but potentially severe head and neck infections. The pertinent anatomical and microbiological characteristics, clinical manifestations, diagnostic issues, and therapy are discussed.

2

PHARYNGITIS

The pharynx extends from the base of the skull to the level of the sixth cervical vertebra. It is divided into three regions: the nasopharynx, the oropharynx, and the hypopharynx (see Figure 1). The oropharynx includes the tonsils and tonsillar pillars, the tongue base, the soft palate, and the uvula. The hypopharynx is located below the oropharynx and contains the epiglottis. The nasopharynx lies superiorly and contains the eustachian tube orifices and the adenoid bed. 187

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PHARYNGITIS Anatomical features of the pharynx (Figure 1) Microbiological characteristics of pharyngitis (Table 1) Most often viral and self-limited Need to recognize and treat group A Streptococcus sp. (GAS) Sore throat, anterior cervical lymphadenopathy, and pharyngeal exudate Many other causes of exudate (Table 1) Diagnosis with culture or rapid antigen detection test Approach to the patient with suspected GAS pharyngitis (Figure 2) Treatment (Table 2) Penicillin the drug of choice

Figure 1 Anatomical characteristics of the pharynx.

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Acute pharyngitis is most commonly associated with a typical upper respiratory viral syndrome such as the common cold due to rhinovirus and coronavirus. As with other community-acquired respiratory infections, most individuals have a benign, self-limited course that does not require a specific microbial diagnosis. A few unusual causes may have important prognostic or public health implications such as acute human immunodeficiency virus (HIV) infection, gonorrhea, Epstein-Barr virus (EBV) infection, and diphtheria. The challenge is to recognize those patients with an illness suggestive of group A ␤-hemolytic streptococcal infection (GAS), and at the same time understand that GAS may be an asymptomatic colonizer of the oropharynx. Table 1 provides a list of microorganisms that have been reliably implicated as causes of pharyngitis.

Table 1 Microbiology of Pharyngitisa Common causes Exudateb Group A Streptococcus spp.,c groups C and G streptococcid

Yes

Common cold virusese

No

Adenovirus

Yes

Herpes simplex virus Influenza virus

Yes No

Other symptoms and signs Fever Tender lymphadenopathy Leukocytosis Rash with scarlet fever or TSS Generally mild discomfort, rhinitis, cough, mostly fall, winter, spring Conjunctivitis, fever, more severe throat soreness than with common cold viruses, summertime Primary infection, vesicles, ulcerations Myalgia, headache, cough, fever

Uncommon causes Mixed anaerobic (Vincent’s Yes angina) Neisseria gonorrhoeae No Arcanobacterium haemolyticum Yes Yersinia enterocolitica

Yes

Mycoplasma pneumoniae Chlamydia pneumoniae Corynebacterium diphtheriae Coxsackie virus A Epstein-Barr virus

No No Yes No Yes

Cytomegalovirus HIV

No No

a

Halitosis, Lemierre’s diseasef Usually asymptomatic or only mild pain Clinically similar to GAS, rash on trunk and extremities Eating of contaminated food, associated with gastroenteritis Mild sore throat, more prominent cough Associated with bronchitis, pneumonia Subacute onset, less pain, unvaccinated persons Small vesicles on soft palate (herpangina) Fever, cervical lymphadenitis, atypical lymphocytosis, hepatitis (see Chapter 39) Mononucleosis-like illness Primary infection (see Chapter 25)

HIV, human immunodeficiency virus; TSS, toxic shock syndrome; GAS, group A Streptococcus sp. Exudate variably present. c Adults 5%–15%, children 15%–30% of cases. d In 5% of cases. e Rhinovirus, coronavirus, parainfluenza virus, 25% of cases. f Fusobacterium sp. infection–associated jugular vein septic thrombosis, characterized by neck pain and swelling and dysphagia. b

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Other causes of sore throat include malignancy, mucositis from chemotherapy or radiation therapy, reflux disease, thyroiditis, abscess (retropharyngeal, peritonsillar), deep space infection, and epiglottitis. 2.1

Clinical Manifestations

As one might anticipate from the list of organisms associated with acute pharyngitis, the illness may range from trivial to life-threatening. Those cases commonly associated with the common cold generally have mild throat pain, do not cause fever, pharyngeal exudate, or lymphadenopathy, and have prominent nasal manifestations. GAS may be present with asymptomatic carriage or cause invasive disease. The classic signs of GAS pharyngitis include a tonsillar exudate, tender anterior cervical lymphadenopathy, and fever. Pharyngeal erythema and edema, painful swallowing, and headache are common, whereas cough is not. Gastrointestinal symptoms may be present, especially in children. On the other extreme, patients with GAS pharyngitis may be minimally symptomatic. GAS infection can lead to localized invasive disease, acute rheumatic fever, and glomerulonephritis. Laryngitis, rhinitis, conjunctivitis, and ulcerations should suggest a viral process. It is worth remembering that exudates are not specific for GAS and may also be seen with mononucleosis, herpes simplex virus, diphtheria, other ␤-hemolytic streptococci, anaerobes, arcanobacterium, and adenovirus (see Table 1). Rash may be present with GAS (in the form of scarlet fever), HIV, EBV (especially when ampicillin is administered), and arcanobacterium. 2.2

Diagnosis

The most common diagnostic challenge in caring for a patient with pharyngitis is to establish the correct diagnosis of GAS. Three tools are at the clinician’s disposal: clinical judgment based on the history and physical exam results, the rapid antigen detection test (RADT), and throat culture. Pros and cons exist for each with regard to accuracy, efficiency and cost. Figure 2 displays an algorithm for the management of GAS pharyngitis. Although the throat culture remains the gold standard with a sensitivity and specificity greater than 90%, it is slow (24 to 48 hours) and requires laboratory support and attention to technique. Clinical criteria alone have a diagnostic sensitivity and specificity as high as 75% compared to culture, especially when combined with epidemiological features (winter season, age, exposure to children, outbreaks, and household or dormitory contacts). The RADT gains efficiency at the expense of sensitivity (80% to 90%) and cost. Until newer-generation RADTs achieve the sensitivity of culture, many experts advocate that throat culture be performed when the RADT finding is negative, especially when the pretest probability of GAS is high. GAS serological tests are of no use in the routine management of acute pharyngitis. 2.3

Therapy of Group A Streptococcal Pharyngitis

Group A streptococci remain uniformly susceptible to penicillin. Traditional therapy for GAS pharyngitis has involved either oral or intramuscular penicillin or erythromycin for penicillin-allergic patients. Although erythromycin-resistant GAS has been a problem in some parts of the world, these strains are considered to be uncommon in the United States. First- and second-generation cephalosporins and the newer macrolide antibiotics are also effective, although more expensive and broad-spectrum than is necessary. Oral regimes

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Figure 2 Approach to the patient with a sore throat. The major goals are to diagnose group A Streptococcus sp. infection and initiate therapy as directed by testing with culture or RADT. RADT, rapid antigen detection test.

are typically prescribed for 10 days, whereas a single intramuscular dose of benzathine penicillin is effective. Table 2 provides specific dosing recommendations. Nonspecific symptomatic therapy such as warm saltwater gargles and nonsteroidal antiinflammatory agents may be helpful. Repeat testing after therapy is not routinely indicated, nor is screening of asymptomatic contacts. Symptomatic recurrences with a positive culture or RADT finding should be re-treated; the same regimen may be used since antibiotic resistance is unlikely. If adherence to the oral antibiotic regimen is in doubt, the intramuscular route is preferred. Multiple bouts of GAS pharyngitis suggest either that the patient is being reinfected by a close contact, in which case screening and treating carriers would seem justified, or that the person is simply a GAS carrier and has another cause of sore throat. Throat cultures and RADTs cannot distinguish throat carriage from infection.

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Table 2 Treatment of Group A Streptococcal Pharyngitis Drug Penicillin VK (penicillin V potassium) Benzathine penicillin G Erythromycinb,c Azithromycinc Clarithromycinc Cephalexinc Cefuroxime axetilc

Dose 500 mg qid for 10 days 1.2 million U IM for 1 day 250–500 mg bid–qid for 10 days 500 mg for 1 day then 250 mg/day for 4 days 500 mg bid for 10 days 500 mg qid for 10 days 500 mg bid for 10 days

Costa $3.30 $12.00 $10.00–$53.00 $39.00 $140.00 $40.00 $148.00

a

Average wholesale price, Red Book 2000. Several oral preparations available; see Chapter 3, Table 8. c For penicillin-allergic patients. b

3

OTITIS AND MASTOIDITIS

Acute otitis media (AOM) is defined as an acute, symptomatic, purulent fluid collection in the middle ear. AOM is among the most common ailments of childhood: over twothirds of children are affected by the age of 3 years; as a result millions of office visits are made and billions of dollars spent each year. Although more common in children, otitis can cause significant illness in adults. Chronic otitis media refers to recurrent acute infections or persistent middle ear effusions. Otitis externa, a superficial infection of the external ear, may be acute, chronic, or invasive (‘‘malignant’’). Chronic otitis externa is a localized canal infection often precipitated by injury to the canal’s protective lining from things used to clear the ear (e.g., Q-tips). Mastoiditis is an uncommon pyogenic infection of the mastoid air cells that complicates AOM. The outer ear is composed of the auricle, the external auditory canal, and the most lateral layer of the tympanic membrane (see Figure 3). The cartilage of the outer ear extends one-third of the way into the ear canal. This portion of the canal is responsible for cerumen production. The remaining two-thirds of the ear canal is osseous. The tympanic membrane (TM) forms the lateral border of the middle ear. The drainage system for the mastoid air cells (auditus) extends forward toward the posterior superior aspect of the middle ear space. Inadequate drainage or ventilation of the mastoid air cells can lead to fluid accumulation, secondary bacterial infection leading to mastoiditis, and occasionally retraction of the superior aspect of the eardrum into the mastoid. This reaction can lead to entrapment of squamous epithelium and the development of destructive cholesteatoma. The eustachian tube connects the middle ear and nasal cavity and serves to drain fluid and equalize pressure. Immaturity of the eustachian tube accounts for the higher prevalence of AOM in children than in adults. During infancy, the eustachian tube is at only a 10degree angle, allowing easy reflux of nasopharyngeal secretions into the middle ear. With age, this angle increases to 45 degrees and the cartilage becomes firm and denser. These changes decrease the incidence of nasopharyngeal reflux and subsequent otitis media. The medial wall of the middle ear contains both the round and oval windows. Continuity of the TM with the ossicular chain (the malleus, incus, and stapes) to the oval window is essential to provide adequate amplification for sound production. Any pathological condition of the middle ear such as otitis media or ossicular discontinuity may

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OTITIS Anatomical characteristics (Figure 3) Acute otitis media Acute symptomatic purulent fluid collection in the middle ear most often seen in children Usually follows viral upper respiratory tract infection (URI) S. pneumoniae, nontypable H influenzae, M. catarrhalis most common bacterial causes Otalgia, bulging tympanic membrane that does not move with pneumatic otoscopy, fever Pitfalls in diagnosis (Table 3) Management Treat for 7–10 days with oral antibiotics (Table 4) Perforated tympanic membrane or pressure equalization tube– (PET)-related infection treated with topical agents (Table 5) Blocked PET treated with topical hydrogen peroxide Indications for PET (Table 6) Otitis externa Superficial infection of external canal Localized due to S. aureus or streptococci Diffuse (swimmer’s ear) often due to P. aeruginosa Treatment with topical agents (Table 5) Spreading cellulitis of surrounding tissues treated with oral antibiotics Malignant Suspect in patients with diabetes mellitus, human immunodeficiency virus (HIV), other immune suppressed states with clinically severe external ear infection Invasive necrotizing infection with P. aeruginosa Granulation tissue in posterior/inferior ear canal ENT (ear, nose and throat) referral indicated Mastoiditis Infection of the mastoid air cells that may follow AOM Swelling and tenderness over mastoid Computed tomography (CT) scan to assess for fluid in cells and osteomyelitis Antibiotic similar to acute otitis media (AOM)

affect sound transmission. The major components of the inner ear are the cochlea, utricle, saccule, and the semicircular canals. 3.1.

Microbiological Characteristics

AOM typically follows a viral URI in young children. The most common bacterial causes remain Streptococcus pneumoniae (⬃40%) and nontypable Haemophilus influenzae (⬃30%). Less common causes of AOM include Moraxella catarrhalis (⬃10%), GAS (⬃5%), Staphylococcus aureus, gram-negative rods (GNR), anaerobes, and viruses such as respiratory syncytial virus, rhinovirus, and enterovirus. These uncommon pathogens may be important when considering treatment failures, complications, and chronic infections. As is typical in other URIs, a specific microbiological cause is typically not established. Although AOM is less common in adults, its microbiological features and complications are similar to those in children. Localized acute otitis externa is generally caused by S. aureus and GAS. Diffuse acute otitis externa (‘‘swimmer’s ear’’) is most commonly caused by Pseudomonas

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Figure 3 Anatomical characteristics of the ear. GAS, group A Streptococcus sp.; RADT, rapid antigen detection test.

aeruginosa. Malignant otitis externa is an invasive necrotizing infection seen in patients with diabetes mellitus or immune suppression that can lead to mastoiditis, osteomyelitis, and central nervous system complications. It is most often associated with P. aeruginosa, although fungi have also been implicated in case reports. 3.2

Clinical Manifestations

AOM generally follows a viral URI. Signs and symptoms may include ear pain, an erythematous or bulging tympanic membrane, fever, decreased hearing, irritability, and purulent drainage either from a perforation or via a tube already in place. When it is complicated by mastoiditis, there are edema, erythema, and tenderness over the mastoid, often with a displaced pinna. External otitis is often initiated by excessive moisture. Patients experience itching, otalgia, and ear fullness. In contrast, malignant otitis externa is associated with severe ear

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pain and headache, often with purulent drainage. A clinically severe soft tissue infection of the external ear in a patient with diabetes mellitus, acquired immunodeficiency syndrome (AIDS), or malignancy should raise suspicion of this invasive disorder, which may be fatal when it involves the central nervous system. Mastoiditis can follow AOM because of the spread of pathogens from the middle ear into the mastoid air cells via the auditus. It is characterized by otalgia, fever, decreased hearing and swelling, redness, and tenderness over the mastoid bone. 3.3

Diagnosis

Routine examination of the entire ear including the auricle, external canal, and tympanic membrane should be undertaken for any patient complaining of otalgia. Erythema, swelling, and tenderness of the auricle are manifestations of perichondritis (inflammation of the fibrinous membrane covering the cartilage of the ear). This may be secondary to trauma (including ear piercing) or an external otitis. When examining the ear canal and tympanic membrane, it is important to use the largest-sized speculum possible for best visualization. Occluding cerumen should be removed. Patients with otitis externa have swelling, erythema, and exudate in the external canal. Pain is often present with manipulation of the auricle or placement of the ear speculum. Careful attention should be given to diabetic patients with external otitis because of the increased incidence of necrotizing external otitis (also called malignant external otitis); granulation tissue on the posterior/inferior aspect of the ear canal, at the bonycartilaginous junction, is pathognomonic. Referral to an otolaryngologist is suggested. Patients with temporomandibular joint (TMJ) inflammation may experience otalgia; however, on exam their external canals are normal. Palpation of the TMJ with jaw movement can often reproduce the pain. The diagnosis of AOM can be difficult. Visualization of the tympanic membrane alone is often inaccurate in detecting the presence of middle ear fluid. The absence of movement of the tympanic membrane with pneumatic otoscopy or tympanometry is a much more accurate indicator. A bulging tympanic membrane without movement on pneumatic otoscopy is indicative of AOM with effusion. Chronic otitis media often is manifested by a retracted tympanic membrane, with or without air fluid levels or bubbles. As with AOM, the tympanic membrane does not move with pneumatic otoscopy. It is important to remember that not all middle ear effusions are infected. Common diagnostic pitfalls in the diagnosis of AOM are listed in Table 3.

Table 3 Common Diagnostic Pitfalls with Acute Otitis Mediaa Mistaking the pink or light red blush from crying for TM inflammation. Mistaking the orange appearance of the TM in otitis media with effusion with AOM. Assuming the presence of any TM abnormality indicates AOM. Assuming that all air-fluid levels indicate active infection. Assuming that decreased TM mobility alone indicates AOM. Mistaking increased vascularity after recovery from AOM as a sign of ongoing infection. Failure to remove occluding cerumen prior to a complete examination. a TM, tympanic membrane; AOM, acute otitis media. Source: Professional Communications, Inc., Caddo, OK.

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For patients who have pressure equalization tubes (PETs), documentation of the tube position, patency, and presence of drainage is important. The presence of otorrhea (either purulent or bloody) in a patient with PET or a perforation signifies infection. A blocked PET prevents proper function and should be addressed. Examination of the mastoid for erythema, swelling, and tenderness should always be performed. Plain films or preferably computed axial tomography (CT) scans may reveal fluid in the air cells and associated osteomyelitis. 3.4

Therapy

Management of AOM should begin with prevention. Multiple factors have been found to increase the incidence of AOM such as attendance at day care and smoking in the household. Preventive strategies include breastfeeding infants, reducing day care attendance, eliminating secondhand smoke, and immunization against Pneumococcus sp. and influenza virus. 3.4.1

Systemic

The decision whether to treat AOM with systemic antibiotics is a balance between the fact that many cases are self-limited and the realization that untreated pyogenic infection of the middle ear may lead to invasive complications or long-term sequelae involving hearing, language skills, and behavior. If reliable microbiological data were available without invasive testing, the decision would be easier since some organisms tend to resolve (M. catarrhalis), and others do not (GAS). Unfortunately, the clinical features do not allow one to determine which patients need antibiotics. In the United States, the consensus seems to be to treat all cases of AOM with 7 to 10 days of oral antibiotics, although this practice is quite different in some other countries. Unfortunately, the most common organism, S. pneumoniae, is a moving target with increasing multidrug resistance. Treatment recommendations need to be revised frequently to keep pace with this organism’s evolution. Ideally, one would like adequate coverage for S. pneumoniae, H. influenzae, and perhaps M. catarrhalis for the initial presentation of AOM. Finally, the inevitable discussions about the pharmacokinetics of antibiotics in the middle ear only add to the general sense of doubt. At least 16 different antibiotics have been approved for treating AOM. Table 4 provides some general guidelines. Amoxicillin is the traditional first-line agent. Patients with chronic recurring OM should receive pneumococcal and influenza vaccines. Previously, some experts had advocated antibiotic prophylaxis with amoxicillin or erythromycin with sulfisoxazole for 3 to 6 months though this practice has fallen out of favor and is currently not recommended. Necrotizing otitis externa is treated intravenously for weeks with an antipseudomonal ␤-lactam such as ceftazidime with or without an aminoglycoside. Ciprofloxacin used orally may be an option for susceptible strains. Antibiotics used to treat mastoiditis are the same as for AOM. Surgical de´bridement may be necessary for mastoid abscess. Nasal or oral decongestants and antihistamines have not been proved to be effective. 3.4.2

Local

For patients with persistent AOM despite antibiotic treatment, tympanocentesis (needle aspiration of the middle ear) for Gram stain and culture is warranted. In those patients with AOM with PET or perforation, topical antibiotic drops, rather than oral antibiotics, are the treatments of choice. Common topical antibiotic choices are listed in Table 5.

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Table 4 Oral Antibiotic Treatment of Acute Otitis Media or Sinusitisa,b Drug

Costsc for 10 days

Dose

Amoxicillind Co-trimoxazole Amoxicillin with clavulanic acide Clarithromycin Azithromycin Cephalexin Cefuroxime axetil Cefpodoxime proxetil Ceftriaxone

500 mg tid 1 Double-strength bid 875 mg bid

$2.10 $26.00 $97.00

500 mg bid 500 mg 1 day, then 250 mg/day ⫻ 4 days 500 mg qid 500 mg bid 400 mg bid 1 g IM ⫻ 1 day

$140.00 $39.00 $118.00 $148.00 $146.00 $45.00

a

Typical duration of therapy for oral antibiotic regimens is 7 to 10 days. Drug-resistant strains of S. pneumoniae are common in children, especially those in day care. Oral antibiotics may not achieve adequate levels in the middle ear to eradicate these strains. c Average wholesale price, Red Book 2000. d H. influenzae (30%) and M. Catarrhalis (90%) produce a ␤-lactamase, which will inactivate amoxicillin. e Note the differing ratios of amoxicillin and clavulanic in available preparations, which may not be interchangeable. b

Blocked PETs should be treated with five drops of full-strength hydrogen peroxide for 5–7 days. The drops may be discontinued earlier for increased pain, stinging, or patient ability to taste the drops, as these are indications that the tube has reopened. Successful treatment of external otitis starts with removal of purulence and debris from the canal. This allows for adequate penetration of topical medication. A steroid component can be added to the drops to enhance antiinflammatory effects. Antiseptic drops should be used when a fungal infection is suspected (see Table 6). A wick may be placed to facilitate drop absorption in cases of marked canal swelling. The wick should be changed daily. For cases unresponsive to topical therapy, cultures should be obtained to guide further treatment as oral antibiotics may be needed.

Table 5 Topical Otic Antibiotics Trade name

Drug(s)

Dose

Cipro HC Otic

Ciprofloxacin Hydrocortisone

3 Drops bid for 7 days

Cortisporin Otic suspension

Neomycin Polymyxin B sulfate Hydrocortisone Ofloxacin

3–4 Drops bid for 10 days

Floxin Otic a

Average wholesale price, Red Book 2000.

5 Drops bid for 10 days

Comments

Costsa

Pseudomonas sp. activity Safety in middle ear not proved Possible ototoxicity

$59.00 For 10 ml

$40.00 For 10 ml

Safe in middle ear

$34.00 For 5 ml

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Table 6 Antifungal Topical Therapy Trade name Vo¯Sol HC Otic Cresylate Auro-Dri Dry-ear Gentian violet a b

Drug(s)

Dose

Costsa

Acetic acid Hydrocortisone m-Cresyl acetate 0.25% in alcohol Boric acid solution 2.7%b

3–4 Drops tid ⫻ 10 days 3–4 Drops tid ⫻ 10 days 3–4 Drops tid ⫻ 10 days Apply topically in more severe cases

$59.00 For 10 ml

Gentian violet solution 1 or 2%

$12.00 For 15 ml $3.00 For 30 ml $7.50 For 100 ml

Average wholesale costs. Can also be made by the pharmacist.

3.4.3

Surgical

Referral to an otolaryngologist is indicated for patients with external otitis or otitis media refractory to medical treatment or once the indications for PET placement have been met (see Table 7). Patients with Down syndrome, cleft palate, and HIV infection should have early referral as they are at increased risk of complications. Any concern about necrotizing external otitis or mastoiditis also warrants a referral. A data sheet outlining the number and frequency of the infections, as well as prior treatments, is invaluable to the surgeon during the initial evaluation. Once tubes are placed, they remain for approximately 6 to 12 months. Most children outgrow eustachian tube problems within this time. Twenty percent of patients, however, require a second set of tubes. For patients older than 2 years of age, placement of this second set is often performed with an adenoidectomy as this has been proved to reduce the incidence of further infections. For patients requiring a third set of tubes or those with severe tympanic membrane retraction, long-term tubes may be indicated. These typically remain in place for 3 years. Tonsillectomy has not proved to improve outcome in these patients. 4

SINUSITIS

Sinusitis is an inflammatory process of the sinus cavities. This disorder may be acute or chronic, infectious or noninfectious, and may be caused by a variety of organisms, including viruses, bacteria, and fungi. Some prefer the term rhinosinusitis to stress the importance of coexistent nasal disease. Sinusitis is one of the most common health complaints, generating millions of office visits each year. It shares many of the complexities

Table 7 Criteria for Pressure Equalization Tubes (PET) Persistent acute otitis media (AOM) (failure of three to four sequential antibiotics) Recurrent AOM (more than five or six in 12 months) Chronic otitis media with effusion More than three or four per 6 month period bilaterally More than six per 12-month period unilaterally Special considerations: Down syndrome, cleft palate, human immunodeficiency virus (HIV)

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SINUSITIS Anatomical characteristics (Figure 4) Acute rhinosinusitis most often due to viruses Most commonly involves the maxillary sinus Bacterial sinusitis may follow viral upper respiratory tract infection (URI) Unilateral pain and edema over involved sinus Symptoms persisting >1 week Fever Purulent nasal discharge In sphenoid sinusitis headache referred to occiput Hypogammaglobulinemia, human immunodeficiency virus (HIV) infection, cystic fibrosis suggested by recurrent episodes or chronic sinusitis CT scan best imaging modality Therapy Antibiotic similar to those in acute otitis media (AOM) (Table 4) Short-course (3–5 days) topical decongestants Avoidance of antihistimines Indications for ENT (ear, nose and throat) referral (Table 7) Chronic sinusitis Persistent symptoms despite antibiotic therapy Due to resistant bacteria, chronic sinus ostia obstruction, allergy, immune compromised state Therapy Additional courses of antibiotics, systemic and nasal steriods, and sinus surgery

providers face with otitis media: reliance on a clinical diagnosis, confusing anatomical relationships, increasing antibiotic resistance, tendency of most cases to resolve spontaneously, and rare invasive complications. The function of the nose and paranasal sinuses is to warm and humidify inspired air, to decrease the weight of the skull, and to improve voice resonance. When the nose is viewed via anterior rhinoscopy, the septum and the inferior and middle turbinates can be viewed (see Figure 4). The septum, which lies in the midline, consists of cartilage anteriorly and bone posteriorly. The turbinates are located on the lateral nasal wall. The opening to the nasolacrimal duct is located beneath the inferior turbinate. The middle turbinate is located posterior and superior to the inferior turbinate. The middle meatus contains the drainage system to the maxillary, anterior ethmoid, and frontal sinuses. The meeting point of these drainage sites is known as the osteomeatal complex (OMC). The patency of the OMC is essential for adequate ventilation and health of the respective sinuses. Mucosal and polypoid disease and/or bony abnormalities in the middle meatus may contribute to OMC obstruction and subsequent sinusitis. The superior and supreme turbinates are more posteriorly located and are not visualized in anterior rhinoscopy. The superior meatus contains the drainage site of the posterior ethmoid cells. The largest of the paranasal sinuses is the maxillary sinus, which is located in the body of the maxilla. The ethmoid air cells (usually 10–15) are located medial to the orbits with the sphenoid sinus resting farther posteriorly. The frontal sinuses are located in the frontal bone. These are usually asymmetrical and may be absent unilaterally (12%) or bilaterally (5%).

Figure 4 Anatomical characteristics of the paranasal sinuses.

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Acute rhinosinusitis is most often caused by viruses (rhinoviruses, influenza, and parainfluenza) during an episode of viral URI. The maxillary sinuses are most often involved. The history of a recent ‘‘cold’’ is typical and most of these illnesses are selflimited. Bacterial sinusitis often follows viral infection. The common bacterial causes of sinusitis are S. pneumoniae and nontypable H. influenzae. Less common causes include anaerobes, M. catarrhalis, and GAS. Acute invasive fungal disease, not to be confused with allergic chronic sinusitis, is a disease of immunocompromised hosts. 4.1

Clinical Manifestations

The classic signs and symptoms of acute sinusitis include a nasal discharge, facial pain, and sinus tenderness. These features may accompany those of a typical viral URI with sneezing, nasal obstruction, cough and headache. It is difficult to distinguish viral from bacterial sinusitis. Bacterial sinusitis should be suspected when symptoms persist beyond 1 week, fever is present, discharge becomes purulent, and pain, erythema, tenderness, and/ or edema is localized to one side. Sphenoid sinusitis is characterized by headache that radiates to the occiput. Unusual complications of bacterial sphenoid sinusitis include cavernous sinus or cortical vein thrombosis, orbital cellulitis or abscess, and sensory signs of impingement on the fifth cranial nerve. Frontal sinusitis is characterized by fever and unilateral pain above the orbit. Untreated bacterial frontal sinusitis may progress to subperiosteal abscess formation (Pott puffy tumor). Meningitis and brain abscess, as complications of acute bacterial sinusitis, are unusual in the antibiotic era. 4.2

Diagnosis

Anterior rhinoscopy with excellent illumination is essential in the evaluation of sinus disease. The septum can be examined for deviations that may be contributing to nasal obstruction. The inferior and middle turbinates can be assessed for size and mucosal disease. Application of a topical decongestant (such as phenylephrine hydrochloride [NeoSynephrine]) may be used to improve visualization. The color and thickness of any discharge or the presence of polyps should be noted. The frontal bone, bridge of the nose, and cheekbones should be percussed to assess for localized tenderness. Transillumination of the sinuses is unreliable. Halitosis is one of the most sensitive findings in diagnosing sinusitis in children. The presence of nasal polyposis may be indicative of an underlying allergic process. Allergy testing may be beneficial in these patients. Polyps associated with thick rubbery green or brown mucus are often found with allergic fungal sinusitis. Patients with recurrent sinusitis or chronic sinusitis should also be evaluated for an underlying immunological disorder. Testing for immunoglobulin (and subtype) deficiency, immotile cilia syndrome, HIV infection, and cystic fibrosis should be considered. Immunocompromised patients (especially those with diabetic ketoacidosis, posttransplantation immunosuppression, AIDS, leukemia, and renal disease) deserve special attention. These patients are at higher risk of development of acute fulminant invasive fungal sinusitis (mucormycosis). This is manifested by a dark necrotic septum and turbinates. There is typically granular serosanguinous discharge. Black facial necrosis and septal or palatal perforations may occur. Urgent referral to an otolaryngologist is indicated. Visualizing septate, acute branching hyphae with fungal stains may provide the diagnosis.

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The CT scan provides the best radiological evaluation of sinus infection. Evaluation of the ethmoid air cells with plain films is unreliable, and the presence of mucosal thickening is nonspecific. CT scans provide excellent information about mucosal and bony abnormalities of all the sinuses. Typically coronal studies without contrast should be obtained. Sinus opacification or air fluid levels of the maxillary, sphenoid, and frontal sinuses are diagnostic. In the event of significant disease or in the preoperative setting, additional axial views should be obtained. Indications for referral to an otolaryngologist can be found in Table 8. 4.3 4.3.1

Therapy Local

Although the mainstays of treatment for bacterial sinusitis are antibiotics, some local therapy may hasten sinus drainage and symptom resolution. Oral and topical decongestants decrease edema, thereby improving sinus oxygenation and drainage. Topical decongestant sprays such as phenylephrine hydrochloride (Neo-Synephrine) should be limited to a 3to 5-day course. Extended use of these sprays can lead to rebound nasal congestion (rhinitis medicamentosa). Expectorants such as guaifenesin (200–400 mg qid) may be used, but their usefulness has not been proved. Treatment of allergies and use of humidification and saline solution nasal sprays can also be beneficial. Antihistamines are contraindicated with acute sinusitis because they can thicken secretions and further impede drainage. 4.3.2

Antibiotics

Because most cases of acute rhinosinusitis are viral and self-limited, and establishing a specific bacterial cause requires an invasive procedure, it has been difficult to demonstrate a significant advantage of antibiotics over symptomatic therapy or of one empirical antibiotic regimen over another. Therefore, most experts advocate that when bacterial infection is suspected, inexpensive, narrow-spectrum agents be used first. This strategy decreases cost as well as preventing antibiotic overuse that perpetuates antibiotic resistance. Amoxicillin, doxycycline, or co-trimoxazole administered at standard doses for 10 days has been the standard regimen. As discussed for AOM, the same doubts persist about the impact of drug-resistant S. pneumoniae and ␤-lactamase-producing H. influenzae and M. catarrhalis on the response to these older agents. Second-line, broader-spectrum, and more expensive choices include second- or third-generation oral cephalosporins (cefuroxime axetil and cefpodoxime, among others) and amoxicillin with clavulanic acid (see Table 4). The newer fluoroquinolones can be used but are expensive: levofloxacin 500 mg once daily costs $85.00 and moxifloxacin hydrochloride 400 mg once daily costs $87.00 for a 10-day course (average wholesale).

Table 8 Indications for Referral to Otolaryngology for Sinusitis Recurrent acute sinusitis Three or more episodes in 6 months Four or more episodes in 12 months Chronic sinusitis (3 months or longer) Persistent acute sinusitis despite appropriate antibiotics for minimum 3–4 weeks Persistent sinusitis with acquired immunodeficiency virus (AIDS) Suspicion of acute fulminant invasive sinusitis

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Higher than usual doses of amoxicillin have also been used, as with AOM, in the hope of reaching adequate drug levels within the infected sinus. Patients who do not respond to empirical antibiotic therapy may be candidates for sinus puncture to obtain a sample for culture and sensitivity. 4.3.3

Surgical

Functional endoscopic sinus surgery may be indicated for patients for whom aggressive medical management has failed. The aim of sinus surgery is to increase the patency of the osteomeatal complexes while preserving the normal ciliary drainage patterns. The degree of surgery performed is tailored to an individual’s disease and may include maxillary antrostomy, partial or total ethmoidectomy, sphenoidotomy, and frontal sinusotomy. A septoplasty or turbinate reduction may also be performed to improve nasal airflow or improve surgical assess. 4.4

Chronic Sinusitis

Chronic sinusitis (CS) may be defined as symptomatic sinusitis that lasts for more than 2 weeks or infection that does not respond to empirical antibiotics. CS may be due to the presence of resistant bacteria, chronic sinus ostia obstruction, immune deficiency, or allergy or may be related to nasal and sinus polyposis. Assessment of immune function, CT scan, and allergy testing should be done. Therapy usually involves additional cycles of antibiotics, nasal and systemic corticosteroids, and possibly sinus surgery to relieve obstruction. Referral to an otolaryngologist is suggested. 5

EPIGLOTTITIS

Epiglottitis is an acute cellulitis of the epiglottitis. The location of the epiglottis just superior to the laryngeal inlet is of supreme clinical relevance since even mild edema and EPIGLOTTITIS AND DEEP SPACE INFECTIONS Epiglottitis Life-threatening medical emergency Fever and sore throat progressing to respiratory distress, drooling, stridor Rapid progression, especially in children More subacute disease possible in adults Otolaryngology and anesthesiology consultation Most often due to HIB and S. pneumoniae, viridans streptococci, S. aureus, less often gram-negative rods (GNRs) For children with suspected epiglottitis oropharyngeal examinations contraindicated, though appropriate for adults Intubation in operating room for children with epiglottitis and adults with respiratory compromise Antibiotic management Ceftriaxone for 7–10 days Deep space infections See Table 8 See Chapter 11, Sec. 8

Nose Adenoids Nasopharynx Paranasal sinuses PP

Spread from RP, PP, PV

Penetrating trauma Tuberculosis of the spine (Pott’s)

Parotid Tonsil Odontogenic Spread from M, SM, middle ear (Bezold’s) Odontogenic Salivary gland

Danger

Prevertebral (PV)

Parapharyngeal (PP)

Submandibular (SM)

Source

Retropharyngeal (RP)

Space

CT scan Panorex

Dental infection Brawny edema of upper neck Severe cellulitis Tongue displacement poster-superior Respiratory distressb

Airway maintenance Humidified O2 With or without surgical drainage IV antibiotics Dental evaluation

Airway maintenance Humidified O2 Surgical drainage IV antibiotics

CT scan

Trismus Neck swelling Intraoral bulge of tonsil

Swelling Sore throat Odynophagia Trismus

Severe pain Drooling Trismus Dysphagia, odynophagia Dyspnea

Airway maintenance Humidified O2 Surgical drainage IV antibiotics Spinal stabilization

CT scan

Cervical adenopathy Nuchal rigidity Midline posterior pharyngeal bulge

Airway maintenance Humidified O2 Surgical drainage IV antibiotics

CT scan

Airway maintenance Humidified O2 Surgical drainage IV antibiotics

Treatment

As above

Signs of local infection Mediastinitis

Lateral neck radiography CT scan

Posterior pharyngeal wall bulge Unilateral tilting of head to uninvolved side Cervical adenopathy Nuchal rigidity

Preceding URI Fever Pain Neck swelling Dysphagia, odynophagia

As above Toxic

Tests

Signs

Presentation

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Poor oral hygiene Dehydration

Parotid

b

Pain Swelling of jaw Worse with eating

Trismus Pain Dysphagia Fever Otalgia

Trismus Pain

Airway maintenance Humidified O2 Surgical drainage Oral antibiotics

Hydration, massage, sialogogues, oral hygiene, oral antibiotics

Clinical CT scan

Clinical CT scan

‘‘Hot potato’’ voice Drooling Unilateral swelling of post/lateral soft palate Deviation of uvula to contralateral side Pus via stenson’s duct Swelling of angle of jaw, no trismus

Airway maintenance Humidified O2 Surgical drainage IV antibiotics Dental evaluation

CT scan Panorex

Extreme trismus Swelling in posterior mouth and ramus of mandible

PP, parapharyngeal; RP, retropharyngeal; PV, prevertebral; M, masticator; SM, submandibular; CT, computerized axial tomography; IV, intravenous. Patients with Ludwig’s angina have involvement of the submandibular and sublinqual spaces. These patients are at extreme risk of airway compromise secondary to posterior displacement of the tongue. Control of the airway should be obtained by those specially trained in fiber-optic intubation or tracheostomy.

Tonsils Pharynx

Peritonsillar

a

Odontogenic (molars)

Masticator (M)

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inflammation can cause immediate airway obstruction. Epiglottitis is a potential medical emergency in both young children and adults. The classic bacterial cause of epiglottitis is H. influenzae type b (HIB). With the advent of conjugate vaccines, invasive HIB infections of all kinds including epiglottitis are becoming less common. However, a large number of other organisms have been implicated, including S. pneumoniae, viridans streptococci, S. aureus, and less commonly aerobic GNRs, to name but a few. The differential diagnosis includes diphtheria and retropharyngeal and peritonsillar abscess. Epiglottitis is historically most often seen in children aged 2 to 7; however, the incidence is decreasing secondary to the widespread use of the conjugated H. influenzae vaccine. The typical patient has fever, agitation, sore throat, respiratory distress, and then dysphagia with drooling of secretions. The patient may prefer to sit forward and may have inspiratory strider. A muffled ‘‘hot potato’’ voice and dehydration may be present. The picture is often one of bacterial septicemia with the potential for fulminant progression over a matter of hours to fatal respiratory collapse. In adults, the incidence of acute epiglottitis has been increasing. It can take both an acute and a subacute form. Some appear rapidly, within 8 hours of symptom onset, with throat pain, odynophagia, and drooling. These patients are clinically similar to childhood epiglottitis patients, as described previously. Adults may also have more subacute infection and may not need emergent airway management. Patients suspected of having epiglottitis should be managed with extreme care and urgency. Oral examination with a tongue blade is contraindicated in children since it may precipitate complete airway closure. Adults may be safely examined by indirect laryngoscopy or flexible nasopharyngoscopy as this has not been reported to trigger airway obstruction. In these patients the epiglottis appears markedly swollen with a ‘‘cherry red’’ color. For patients who are in stable condition lateral neck radiography may be performed. This often shows gross enlargement of the epiglottis (‘‘thumbprinting’’) with obliteration of the ventricle. Patients are usually febrile and have a leukocytosis. Chest radiography may demonstrate a concomitant pneumonia. An epiglottitis management team that comprises an otolaryngologist and anesthesiologist should perform a direct examination in the operating room for all patients suspected of having acute epiglottitis. In the presence of epiglottitis, the patient is intubated and cultures are taken of the epiglottis and blood. Preparation for bronchoscopy and/or tracheostomy should be undertaken prior to any airway manipulation in case of a difficult intubation. The clinically stable adult patient without stridor or airway compromise can be treated with antibiotics under close observation. Antibiotic therapy must target ␤-lactamase-producing H. influenzae in addition to streptococci, staphylococci, and GNRs. Therefore, second- or third-generation cephalosporins such as cefuroxime, ceftriaxone, or cefotaxime should be administered intravenously for 7 to 10 days. 6

DEEP SPACE INFECTIONS

The topic of deep space infection is reviewed in Chapter 11, Section 9. A summary of the deep space infections is provided in Table 9. Whenever a deep space infection is suspected, surgical consultation and intravenous antibiotics are urgently indicated. CT scan of the neck from the base of the skull to the superior mediastinum is indicated. In case of suspected odontogenic origin, a panorex or four-view mandibular series should be obtained. A chest radiogram should be obtained to

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evaluate the pleural and mediastinal spaces since these infections may dissect down the open fascial planes. Appropriate empirical antibiotic choice includes use of a third-generation cephalosporin such as ceftriaxone combined with clindamycin, piperacillin with tazobactam, or a carbapenem (meropenem, imipenem with cilastatin) while awaiting culture results. Although frequently infections are polymicrobial, most oral flora involved in odontogenic infections are sensitive to a variety of antibiotics. The prompt empirical administration of intravenous antibiotics in adequate dosage combined with surgical evaluation often proves a more critical aspect than the specific choice of drug. BIBLIOGRAPHY Berman S. Otitis media in children. N Engl J Med 332:1560–1565, 1995. Bisno AL. Acute pharyngitis. N Engl J Med 344:205–211, 2001. Bisno AL, Gerber MA, Gwaltney JM, Kaplan EL, Schwartz RH. Diagnosis and management of group A streptococcal pharyngitis: A practice guideline. Clin Infect Dis 25:574–583, 1997. Block SL, Harrison CJ. Diagnosis and Management of Acute Otitis Media, 1st ed. Professional Communications, 2001. Burns JE, Hendley JO. Epiglottitis. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000, pp 686– 689. Cooper RJ, Hoffman JR, Bartlett JG, Besser RE, Gonzales R, Hickner JM, Sande MA. Principles of appropriate antibiotic use for acute pharyngitis in adults: Background. Ann Intern Med 134:509–517, 2001. Gwaltney JM. Acute community-acquired sinusitis. Clin Infect Dis 23:1209–1223, 1996. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: Background. Ann Intern Med 134:498–505, 2001. Kennedy D. Medical management of sinusitis. Ann Otol Rhinol Laryngol 67:22, 1995. Senior BA, Radkowski D, MacArthur C, Sprecher RC, Jones D. Changing patterns in pediatric supraglottitis: A multiinstitutional review, 1980–1992. Otolaryngol Head Neck Surg 110:203– 210, 1994. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

11 Common Oral Infections H. Charles Hill, II, Thomas W. Connolly, and Susan M. Hill University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Over 500 different microorganisms have been isolated from the human mouth, the site of the greatest variety of bacterial, viral, and fungal flora in the body. The majority of these are commensals and make up the normal oral flora, although it is doubtful that a normal viral flora exists in humans. The normal oral flora is capable of causing local or systemic illness if architectural dental defects occur or immune suppression intervenes. This chapter reviews the more common infections involving the teeth, gums, periodontium, and tongue (see Figure 1). The differential diagnosis and management of patients with oral ulcerations, masses, and plaques are summarized (see Figure 2). Lifethreatening oral infections and those involving the salivary glands are also reviewed. 2

ANATOMICAL AND MICROBIOLOGICAL CHARACTERISTICS

Some of the common oral infections can be distinguished in part on the basis of the location of the lesions. Simple anatomical differentiation among the gingiva, alveolar mucosa, hard and soft palates, and dorsal and ventral surfaces of the tongue can be helpful (see Figure 3). The tooth is held in place by the periodontium or support structures, which include the alveolar bone, periodontal ligament, and gingiva. The gingiva is dense fibrous tissue covered by mucous membranes that surrounds the alveolar bone of the upper and lower jaws and the teeth. The nerve and blood supply of the tooth are centrally located in the pulp. The normal flora of the oral cavity is polymicrobic; the majority of bacteria are anaerobic. Colony counts as high as 2.7 ⫻ 1011 organisms/g can be found in gingival crevices with anaerobes eightfold more common than aerobic or facultative bacteria. The most common bacteria are Streptococcus, Peptostreptococcus, Veillonella, Lactobacillus, Corynebacterium, Actimomyces, Fusobacterium, Porphoromonas, and Prevotella species. Certain viridans streptococci colonize the tooth surface; others colonize the buccal mucosa and tongue. Anaerobes are found more often in gingival crevices. Aerobic gram-negative rods (GNRs) and Staphylococcus aureus are not part of the normal adult oral flora. The mouths of debilitated persons admitted to the hospital often are repopulated by GNRs. Other factors that may alter the normal oral flora include poor nutritional status, smoking, poor oral hygiene, and antibiotic usage. 209

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Figure 1 Algorithmic approach to mouth pain. Mouth pain may be generalized or localized. Generalized pain most often involves the gingiva, oral mucosa, and tongue diffusely. Localized pain can be due to a discrete lesion of the oral mucosa, gingiva, or tooth. ANUG, acute necrotizing ulcerative gingivitis; HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalovirus; MTB, tuberculosis; HPV, human papilloma virus.

3 3.1

TEETH Dental Caries

Dental caries is an infection caused by microorganisms colonizing the exposed surfaces of the tooth. This mass of bacteria adherent to the tooth is called plaque. These microorMOUTH PAIN AND DENTAL INFECTION Approach to the patient with oral pain: Figure 1 Anatomical characteristics of tooth and supporting structures: Figures 3 and 5 Dental caries Increased risk with uncontrolled dietary sugars, poor oral hygiene, reduced salivary flow Bacterial plaque → organic acid by-products → destruction of dental enamel → dental pulp: Figure 4 Pain, cold/hot/sweet sensitivity Dry socket Inflammation 3–5 days after tooth extraction Most common with mandibular molars Localized pain or referred pain to ear

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Figure 2 Algorithmic approach to mouth lesions. Mouth lesions may be categorized as vesicular, ulcerative, or papillary or by their color. ANUG, acute necrotizing ulcerative gingivitis; SLE, systemic lupus erythematosus; HSV, herpes simplex virus; VZV, varicella zoster virus; HPV, human papilloma virus; CMV, cytomegalovirus; MTB, tuberculosis; HIV, human immunodeficiency virus.

ganisms use substrates in the diet, especially refined sugars, to produce organic acid byproducts. The continuous bathing of the tooth’s surface in these acids results in dissolution of the crystalline (hydroxyapatite) portion of the tooth. Different patterns of caries exist and are associated with different organisms: smooth surface caries is often associated with S. mutans, whereas biting surface (pit and fissure) caries is more often due to Lactobacillus spp. or Streptococcus spp. and Lactobacillus spp. Actinomyces spp. more often cause decay of the root of the tooth. Risk factors for dental caries include uncontrolled intake of dietary sugar, poor oral hygiene, and reduced salivary flow. Dental caries appears as white opaque spots on the surface of the enamel. Early carious lesions, particularly those between the teeth, are not easily seen. The decay eventually breaks through the enamel layer, spreads laterally, and penetrates deeper into the tooth. The advancing lesion may darken the tooth. As the enamel is undermined, fractures of portions of the crown of the tooth may appear. As the infection invades the neurovascular bundle in the central pulp of the tooth, symptoms of sensitivity, especially to cold and sweet substances, and pain begin. If unattended, the decay process eventually causes devitalization of the dental pulp. Carious lesions may or may not be evident visually, or the offending tooth may cause referred pain to an alternate location. Systemic signs of infection and intraoral and facial swelling may accompany the infection. Once the pulp is infected, the infection may spread along the length of the root and break through the apex, resulting in the formation of granulomas and abscesses within the alveolar bone (see Figure 4).

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Figure 3 The normal tooth and support structures. The normal tooth situated in the mandibular or maxillary bone. A hardened enamel covers the crown. The nerves and vasculature of the tooth are located centrally. The periodontium are the supporting structures of the teeth, which include the gingiva, periodontal ligament, alveolar bone, and cementum.

These bony lesions may remain localized and asymptomatic or dissect through to the subcutaneous tissue, creating fistulous tracts. The fistula usually appears in the soft tissue at or near the level of the apex of the tooth. In some cases a marked cellulitis develops within various soft tissue spaces of the face and neck (see later discussion and Chapter 10). Once dental caries is observed or suspected, referral to a dentist should be made. In the event that deeper tooth infection (pulpitis, root infection) develops, either root canal therapy or extraction is indicated. If a delay in treatment is likely, antibiotics may be necessary to help contain the infection. The administration of local anesthetics such as bupivacaine injection may provide immediate but temporary pain relief. Prevention of future caries should begin with education and improved oral hygiene. The patient should be encouraged to control exposure to sugars. The frequent application of low-concentration topical fluorides through selected toothpaste, gels, or rinses is valuable. Improved oral hygiene with brushing and flossing disrupts plaque buildup. Dental sealant placement is also helpful. Patients who have received radiation treatment to the head and neck may experience reduced salivary flow. This allows the rapid accumulation of plaque to cause decay, which may progress quickly. Many of these patients are older and suffer from preexisting peri-

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Figure 4 Carious tooth and route of dental infection. After erosion of the enamel and dentin, infection can spread through the dental pulp and break through the apex of the tooth into the alveolar bone to cause an apical root abscess. With worsening periodontitis, the periodontal pocket may deepen, resulting in loss of bone support and eventually tooth loss.

odontal disease that has left the tooth roots exposed. Treating these areas of the tooth, once they are carious, is particularly challenging. Meticulous hygiene and aggressive management through the use of fluoride trays fabricated by a dentist are important. Drugs such as antihistamines and antihypertensives may also reduce salivary gland function. Patients who use these medications on a long-term basis are also at increased risk for the development of dental caries. 3.2

Localized Osteitis (Dry Socket)

Localized inflammation of alveolar bone (osteitis), the most common complication of tooth extraction, occurs after 1%–4% of extractions; 95% of cases involve mandibular posterior teeth, particularly the third molars or wisdom teeth. Predisposing factors include age, impaired blood supply, the length of time required to remove the tooth, the amount of trauma involved in the extraction, and smoking. The onset usually occurs between 3 and 5 days after extraction but on rare occasions may be delayed a week or more. The hallmark of localized osteitis is relentless, almost

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intractable pain. In the mandibular posterior teeth, the pain is frequently referred to the ear, mimicking otitis media, and ear pain may be the presenting complaint. There is frequently a ‘‘metallic’’ taste and the complaint of fetid odor. Examination demonstrates erythema of the gingiva around the tooth socket. The gingiva may be denuded, exposing bone. Irrigation of the socket with tepid water may be required for thorough examination, though this can be very painful. Therapy is supportive in nature. Iodoform dressings impregnated with eugenol (oil of cloves) and zinc oxide or a combination of topical anesthetics provide relief. Nonsteroidal antiinflammatory drugs (NSAIDs) may be helpful. The addition of narcotic analgesics may be required for a limited time. Although histological assessment demonstrates areas of necrotic or inflamed bone, systemic antibiotics are rarely indicated. 4 4.1

PERIODONTIUM Gingivitis

Chronic gingivitis is an asymptomatic inflammatory reaction of the gingiva surrounding the teeth caused by bacterial plaque by-products. Plaque buildup is always present. The gingiva and interdental papilla appear red and swollen (see Figure 5). Mild tenderness may be reported along with toothbrushing-induced bleeding. Although gingivitis may be self-limited, it is often a precursor to destructive periodontal disease. Therapy involves improved oral hygiene and de´bridement of calcified deposits and dental plaque. Patients who have chronic gingivitis should have regular dental care. INFECTIONS OF THE PERIODONTIUM Gingivitis Inflammation of gingiva around teeth: Figure 5 Redness, swelling, tenderness, ready bleeding Acute necrotizing ulcerative gingivitis Necrotic ulcers of interdental gingiva Pain, bleeding, halitosis Fever, lymphadenopathy, headache Increased risk with human immunodeficiency virus (HIV), smoking, alcohol use Treated with de´bridement, Peridex mouthwash, penicillin Periodontitis Infection of gingiva, periodontal ligament, alveolar bone, cementum Insidious, usually asymptomatic May progress to loss of teeth Increased risk with HIV, diabetes Treated with de´bridement, Peridex mouthwash, penicillin, extraction as needed Acute periodontal abscess Localized tender gingival swelling adjacent to tooth Purulent discharge Treated with drainage, Peridex mouthwash, penicillin Pericoronitis Infection of mucosal flap over teeth (usually mandibular molars) Pain, swelling, trismus, lymphadenopathy Treated with de´bridement, Peridex mouthwash, penicillin, debridement

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Figure 5 Teeth and surrounding gingiva. Gingivitis is an infection of the gingiva surrounding the teeth. Plaque buildup is usually present. The gingiva and interdental papilla appear red and swollen.

4.2

Acute Necrotizing Ulcerative Gingivitis (Vincent’s Infection or Trench Mouth)

Acute necrotizing ulcerative gingivitis (ANUG) is most commonly seen in young adults who experience painful necrotic ulcers in the interdental (papilla) gingiva (see Figure 5). Extension of ANUG is usually along the marginal gingiva from tooth to tooth. Patients may complain of excessive salivation, a fetid mouth odor, and spontaneous bleeding from the gingiva. Systemic manifestations often include fever, cervical lymphadenopathy, malaise, and headache. Patients are often very uncomfortable and may avoid eating, drinking, and performing oral hygiene care. ANUG is an anaerobic infection initially thought to be caused by anaerobic spirochetes such as Borrelia vincentii and anaerobic fusiform bacteria. More recently anaerobic GNRs such as Prevotella melaninogenicus and P. intermedia and vibrio species have been associated with the disease. In severe forms of ANUG, cytomegalovirus and other herpesviruses may be contributors. Predisposing factors include poor nutrition, excessive alcohol intake, cigarette smoking, and infection with the human immunodeficiency virus (HIV). Under certain conditions such as severe malnutrition or advanced immune suppression, ANUG can be fulminant with widespread infection of the mouth, face, and neck. Initial treatment includes oral de´bridement, pain control, and counseling related to predisposing factors. The de´bridement is most efficiently accomplished by dental personnel. Frequent mouth rinses with either 3% hydrogen peroxide diluted 50:50 with warm water or chlorhexidine gluconate 0.12% (Peridex) may help relieve symptoms. When discomfort allows, improved oral hygiene with soft toothbrushes and dental floss speeds healing. Patients with signs of systemic involvement should be placed on penicillin (Penicillin VK) 500 mg qid for 10 days. 4.3

Periodontitis

Periodontitis or gum disease is a chronic infection of the tissues surrounding and supporting the teeth (the periodontium) including the gingiva, periodontal ligament, alveolar bone, and cementum. It is usually an insidious, asymptomatic, progressive infection that results in the loss of the connective tissue attachment between the teeth and their supportive bone. Diabetes mellitus and HIV infection may hasten disease progression.

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The inflammatory process is deep within the gingival tissues along the roots of the teeth. Early periodontal disease is similar in appearance to chronic gingivitis. Symptoms of advanced disease may be subtle. The infection is usually painless. Patients may have halitosis and experience cold sensitivity. Once signs and symptoms of chronic periodontal infection occur, though, there is often extensive and irreversible loss of alveolar bone. These changes lead to looseness of teeth, soreness with biting, and spaces between teeth. Definitive diagnosis is made through careful assessment of the bony attachment levels around the teeth through gentle probing between the teeth and the gingiva and with dental radiographs. Therapy includes antibiotics with anaerobic activity such as metronidazole, penicillin, or tetracycline; extraction of teeth that are infected beyond repair; and surgical de´bridement of the remaining lesions. All patients require regular dental maintenance over the lifetime. 4.4

Acute Periodontal Abscess

Acute periodontal abscesses are infections of the periodontal pocket between the tooth surface and gingival tissue. Most periodontal abscesses occur at sites of long-standing chronic periodontal disease. These abscesses most often appear as localized, tender swellings in the gingival tissues between and immediately adjacent to teeth. They may enlarge sufficiently to preclude comfortable biting. Purulent discharge may be evident between the tooth and the gingiva. Periodontal abscesses often drain spontaneously and are self-limiting. If they do not, incision and drainage are warranted. Concomitant use of penicillin may be needed. Definitive cure usually requires surgical elimination of the periodontal pocket. 4.5

Pericoronitis

The infection usually begins in a mucosal flap partially covering an erupting or malposed tooth that allows accumulation of dental plaque or food debris. It is most frequently associated with a partially erupted mandibular third molar. Similar infections occur less frequently in the maxilla. The lesions resemble a necrotizing gingivostomatitis. Pain is present and is often exacerbated by trauma from opposing teeth. Regional lymphadenopathy, trismus, and cellulitis may occur. In immunosuppressed patients, this infection can extend and become a necrotizing gingivostomatitis. Treatment consists of a combination of saline solution rinses with chlorhexidine and de´bridement. Relief from trauma can be provided by reducing an opposing cusp or removing the opposing tooth. Oral antibiotics such as penicillin may be needed. After control of the acute infection, excision of the offending soft tissue or extraction of the offending tooth may be required. 5

TONGUE

Changes on the surface of the tongue are common though infectious causes are not. Isolated irregularities that become indurated or ulcerated or fail to resolve require biopsy. 5.1

Ulcerations

The most common cause of ulceration of the tongue is trauma produced by biting on the lateral margins of the tongue. The patient is often aware of this self-inflicted trauma. If a sharp or fractured tooth or an irregularity in a dental appliance contributes to the trauma,

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TONGUE AND ORAL PATCHES Mouth lesions: Figure 2 Tongue Ulcerations Trauma Aphthous ulcerations (canker sores) Primary herpes simplex virus (HSV) Malignancy, allergy, vitamin deficiency, pemphigus, lichen planus, erythema multiforme Geographic Idiopathic, asymptomatic Asymptomatic, migrating, ulcerative-like lesions Coated Asymptomatic White, yellow, black Increased length of filiform papillae Patches Oral candidiasis Curdlike white or erythematous patches Angular cheilitis Erythema beneath dental appliance Asymptomatic or burning Therapy: Table 1 Unexplained oral Candida spp.: indication for HIV testing Hairy leukoplakia Due to Epstein-Barr virus (EBV) infection Asymptomatic benign white plaques on lateral tongue Treatment generally not needed Indication for HIV testing

reinjury may occur until the irregularity is relieved. Most traumatic ulcers of the tongue heal without intervention, but they may require some care by the patient to prevent persistent reinjury. Aphthous ulcers or canker sores (see Section 7.4) and primary herpes simplex virus infection can cause painful tongue ulcerations (see Section 7.2). Other causes of tongue ulceration include food and drug allergy, vitamin deficiency, lichen planus, pemphigus, erythema multiforme, malignancy, and infections. Allergies cause diffuse mouth ulcerations. Malignant ulcerations are generally seen on the lateral margins of the tongue. In patients who have secondary syphilis, painless mucous patches involving the tongue may develop in addition to the characteristic maculopapular rash. In tuberculosis patients, nonhealing tongue ulcers may develop. 5.2

Geographic Tongue

Geographic tongue or erythema migrans is an idiopathic disorder that mimics ulceration of the tongue’s surface. The precise location and size of the lesions change constantly but are usually limited to the dorsum and lateral borders of the tongue. The central portion of

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the lesion is red as a result of loss of the filiform papillae in this area. The redness is surrounded by a narrow white-yellow zone. Most often the condition is asymptomatic and requires no treatment. 5.3

Coated Tongue

Various colored coatings of the tongue (white, yellow, or black) occur in association with increased length of the filiform papillae on the dorsal surface. Certain foods, use of chemical mouth rinses, and medications such as antimicrobials may contribute to the coating. The condition is asymptomatic. It can be treated by brushing the dorsal surface of the tongue. 5.4

Candida albicans

Infection by Candida albicans is described in Section 6.1. 6 6.1

PATCHES Oral Candidiasis

Oral candidiasis is caused most commonly by C. albicans, a normal commensal of the oral cavity. Alterations in the oral environment due to antibiotics, dentures, decreased salivation, and immune suppression can cause overgrowth of the fungus, leading to clinical infection. In patients using inhaled steroids oral candidiasis also commonly develops. Saliva from the major salivary glands of healthy individuals demonstrates a direct inhibitory effect on the Candida species. Patients who have xerostomia, including those with Sjo¨gren’s syndrome, postirradiation xerostomia, and debilitating disease with dehydration, and those using antisialagogue medications are at risk of development of candidiasis. Neonates and the elderly show an increased incidence of candidiasis, as do patients with insulin-dependent diabetes mellitus. In denture wearers, Candida sp. infection may develop beneath the denture. Immune suppressed patients are most at risk for oral candidiasis. Individuals with moderate to severe infection with human immunodeficiency virus (HIV) (CD4⫹ counts < 500 cells/mm3), patients with cellular or phagocytic defects from systemic chemotherapy or prolonged high-dose (total prednisone dose > 700 mg) steroid use, and those who are immune suppressed after organ transplantation are all at risk. All patients with unexplained oral candidiasis should be tested for HIV infection. Four clinical patterns of infection are recognized. Acute pseudomembranous candidiasis or thrush is characterized by elevated, whitish curdlike plaques found most commonly on the buccal mucosa, tongue, and palate. This material is a mix of tangled hyphae, epithelium, fibrin, bacteria, and necrotic debris. When it is wiped away, there is an underlying erythematous base. There may be gingival ulcerations along with the erythematous lesions. Patients may be asymptomatic or may experience burning and pain. In chronic hyperplastic candidiasis long-standing firm white lesions cannot be easily wiped off the buccal mucosa. They are most often located on the cheeks, lips, and tongue. Because of their similar appearance to hairy leukoplakia (see Section 6.2) and the fact that atypical squamous cells have been isolated from some of these lesions, lesions that do not respond to antifungal therapy require biopsy to exclude malignancy. Chronic atrophic or erythematous candidiasis is the type seen beneath dentures. The somewhat painful, broad-based erythematous lesions follow the outlines of the denture

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and are often accompanied by a hyperplastic papillary component. It is more often seen in patients with poor denture hygiene. Angular cheilitis is manifested by a painful fissure at the corners of the mouth. Lesions crack easily when the person awakens; lesions cause discomfort and occasionally bleed. There may or may not be associated intraoral candidiasis. Diagnosis is usually based on the clinical appearance of the lesion. The presence of hyphae on a wet smear is the simplest confirmatory test result, though this is usually not needed. Although Candida spp. grow on routine blood culture, growth of this organism does not confirm the diagnosis since it can be part of the normal mouth flora. For persistent or undiagnosed lesions, staining of a biopsy specimen with para-aminosalicylic acid (PAS) or methenamine silver may confirm the diagnosis by demonstrating characteristic yeast forms and pseudohyphae. Uncomplicated oral candidiasis can be treated with topical nystatin or clotrimazole troches (see Table 1). For the treatment to be effective, intimate contact between the suspension or troche and the lesions is essential. Therapy should be continued for several days after resolution of symptoms. The use of chlorhexidine rinses in mild uncomplicated cases may be a useful alternative. Systemic treatment with oral fluconazole or itraconazole is indicated in patients who do not respond to topical therapy or who have symptoms of esophageal candidiasis (dysphagia and odynophagia) as well as oral candidiasis. In patients with HIV infection and chronic or recurrent oroesophageal candidiasis, prophylaxis with fluconazole has been used. However, the decision to proceed with prophylactic treatment must be made cautiously since azole-resistant strains are becoming more prevalent in this population. In chronic atrophic candidiasis, treatment may require a combination of topical therapy, surgical recontouring of residual papillary lesions, and refabrication of the denture. 6.2

Hairy Leukoplakia

Hairy leukoplakia (HL) is an adherent white patch most commonly found along the lateral border of the anterior two-thirds of the tongue. It is caused by Epstein-Barr virus (EBV) infection (see Chapter 39). There is a hyperkeratosis of the upper epithelial layer, which causes the characteristic shaggy or ‘‘hairy’’ gross appearance of the lesion. The diagnosis is generally made clinically. Biopsy of the lesions is generally not needed. Unlike with the EBV associated with Burkitt’s lymphoma and nasopharyngeal carcinoma, there is no potential for malignant transformation. HL is highly associated with HIV infection and all persons with HL should be HIV tested. HL is asymptomatic and generally does not require treatment. Treatment with topical retinoids (Retin-A .025% applied tid for 2–3 days) and systemic acyclovir (800 mg 5⫻/day for 2–3 weeks) may be used for cosmetic reasons. Without improvement of the underlying immunosuppression, recurrence is common. 7

ULCERATIONS

Oral ulcerations may be infectious or noninfectious in nature. The most common causes are trauma, herpes simplex infection, and canker sores. Ulceration may also be caused by iron, folate, or vitamin B12 deficiency or Crohn’s or Behc¸et’s disease (see Figure 2). 7.1

Traumatic

Traumatic ulcers are physical injuries to the oral mucosa. They may be found anywhere in the oral cavity, the lips, buccal mucosa, and tongue are the more common sites. Typical

Mycelex troche Sporanox Diflucan

Generic

Itraconazole suspension

Fluconazole

Amphotericin B rinse

Average wholesale price, 2000 Drug Topics Red Book.

Mycolog-II

Nystatin plus triamcinalone acetonide ointment Clotrimazole troche

a

Mycostatin

Trade name

Nystatin suspension

Drug

Table 1 Therapy for Oral Candidiasis

100,00 units/ml Swish and swallow 5 ml tid–qid 100,000 U/mg Apply bid 10 mg Troche Sucked on qid 10 mg/ml solution 100 mg daily orally 100-mg tablets 200 mg on day 1, then 100 mg daily 50 mg in 1000 ml D5W Swish and swallow qid

Dose

For candidiasis resistant to fluconazole or intraconazole

Well tolerated Risk of hepatotoxicity

Well tolerated Safe

Prolonged contact needed Poor taste Safe For angular cheilitis

Comment

1 Liter: $33.00

10 Days: $69.30

150-ml Bottle (14 days): $111.00

10 Days: $52.00

60-g Tube: $54.00

480 ml: $17.00

Costsa

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MOUTH ULCERS Mouth lesions: Figure 2 Trauma Herpes simplex virus (HSV) infection HSV-1 >> HSV-2 Acute primary gingivostomatitis Usually asymptomatic infection of children < 5 years of age Occasionally symptomatic infection in young adults Multiple painful ulcerations throughout oral cavity Oral acyclovir or valacyclovir (may shorten course) Peridex or ‘‘magic mouthwash’’ Recurrent herpes labialis ‘‘Cold sores’’ Recurrent ulcerations around lips Topical penciclovir (may shorten course) Recurrent intraoral stomatitis Less severe than primary infection Zoster Dermatomal distribution of pain and ulcerations Ulcers similar to those of HSV May accompany painful tooth Acyclovir, valacyclovir, famciclovir (may shorten course) Aphthous stomatitis (canker sores) Idiopathic recurrent painful ulcerations Noninfectious Large, chronic, and recurrent ulceration suggestive of underlying malignancy Kenalog in Orabase cream

causes include aggressive toothbrushing, biting oneself, impingement on a sharp tooth surface, and local pressure from an ill-fitting denture. Self-mutilation through intentional body piercing and oral sexual activities can also ulcerate the mucosa, including the ventral surface of the tongue and the floor of the mouth. Size and shape of the ulcer(s) vary considerably. Early lesions tend to be shallow with erythematous borders with superficial, gray or yellow fibrin exudates. More chronic ulcers show a rolled-up, indurated border that can mimic the appearance of oral malignancies. The diagnosis is established by history and examination. Removal of the source of injury along with rinsing and soaking with normal saline solution several times each day are recommended. Antibiotic use is rarely indicated. Lesions that do not significantly improve after a 2-week period should be biopsied. 7.2

Herpes Simplex Virus

Herpes simplex virus 1 (HSV-1) and HSV-2 cause three clinically distinct syndromes: acute herpetic gingivostomatitis (AHGS), recurrent herpes labialis (RHL), and recurrent intraoral herpes stomatitis (RIHS). Although HSV-1 is more common intraorally, HSV-2 causes up to 10%–15% of recurrent oral herpes labialis. The lesions in each disease progress in a predictable manner. They begin as small, discrete vesicles, which coalesce

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and then ulcerate. The ulcers are covered by a yellowish exudate. The duration, symptoms, and severity of the disease depend on the patient’s prior exposure to the virus as well as his or her immunocompetence. More than 90% of adults are seropositive for antibodies against HSV. Patients may shed HSV asymptomatically in their saliva (also see Chapter 20, Sec. 4.3). 7.2.1

Acute Herpetic Gingivostomatitis

AHGS is the primary HSV infection and occurs predominantly in children below 5 years of age. On occasion young adults may have primary oral infection. More than 90% of primary infections are asymptomatic, but when the disease is symptomatic, the patient can be very uncomfortable. The disease presents itself initially as numerous small vesicles on any or all of the soft tissue surfaces of the mouth, nose, tonsils, and pharynx. These shortlived vesicles coalesce, then rupture, leaving painful ulcers surrounded by erythema and edema. The patient’s discomfort is often sufficient to discourage food and fluid intake completely. Fever and malaise may be present during the first several days. Lesions usually resolve within 10–14 days. The disease is contagious. The sharing of eating utensils and toothbrushes should be prevented. Definitive diagnosis in questionable cases can be made with viral culture and Tzanck preparations. 7.2.2

Recurrent Herpes Labialis

RHL or ‘‘cold sores’’ is a cyclical cutaneous condition experienced by 40% of adults. There is often a prodrome of itching and burning. Short-lived vesicles develop immediately around the mouth, then ulcerate, leaving painful shallow ulcers. Recrudescences are less severe than the primary infection. The eruption is self-limited, lasting 7–10 days. 7.2.3

Recurrent Intraoral Herpes Stomatitis

Recurrent intraoral herpes stomatitis can manifest in one of two ways, depending on the immunological health of the patient. In the immunocompetent patient, the lesions are not preceded by prodromal symptoms typical of RHL. Most of the ulcerations are less than 5 mm in diameter and tend to occur on the keratinized soft tissues of the mouth, including the hard palate, gingiva, and dense mucosa covering edentulous ridges. The precipitating factor(s) for the outbreak is generally not obvious though minor trauma may be a risk. Pain is generally mild. In the immunocompromised patient, the ulcers may enlarge, extend along both mucosal and cutaneous surfaces, and cause considerable pain and local tissue destruction. In the debilitated patient, disseminated infection is possible. 7.2.4

Therapy

Treatment for AHGS with oral acyclovir (Zovirax 200 mg 5⫻/day) or valacyclovir (Valtrex 1000 mg bid) shortens the duration of symptoms and viral shedding (see Chapter 20, Table 8). Therapy should be continued for 10–14 days. Topical therapy with penciclovir cream (Denavir 10 mg/g) applied every 2 hours for 5 days may shorten the time to ulcer healing and provide analgesia for patients with RHL, especially if used during the prodromal phase. Pain may be lessened with mouthwashes such as 1 teaspoonful each of table salt and baking soda in a pint of water, Peridex, or a concoction commonly known as ‘‘magic mouthwash’’ (0.5% viscous lidocaine, diphenhydramine hydrochloride, and magnesium containing antacid in a 1:1:1 ratio). The degree of pain relief is correlated with the length of contact time between the ulcer and the agents. Patients should be carefully instructed

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and encouraged to retain the agent in the mouth for a full minute, if possible, before expectorating. 7.3

Zoster

Herpes zoster or shingles is caused by the reactivation of the varicella zoster virus (VZV), the etiological agent of chickenpox (see Chapter 20, Section 4.4.2). It generally effects middle-aged and older patients. Its appearance may suggest an occult immune deficiency such as HIV infection. Zoster presents a prodrome of malaise, fever, and tenderness along the skin in a dermatomal distribution. Within a few days, the characteristic unilateral vesicular eruption on the skin and/or mucous membrane appears. The intraoral ulcers are similar in appearance to HSV, though they tend to be smaller and less painful. Regional lymphadenopathy may accompany the lesions. The acute infection generally lasts a week. In addition to unilateral intraoral vesicles, patients may complain of severe tooth pain. Many patients have undergone serial extraction of otherwise healthy teeth before the diagnosis of shingles was established. VZV is treated with acyclovir (800 mg orally 5⫻/day), famciclovir (Famvir 500 mg tid), or valacyclovir (1000 mg tid) for 7–10 days. In the immune compromised patient, early recognition and aggressive treatment may affect outcome. Perhaps the most debilitating sequela of VZV infection is postherpetic neuralgia. There is some evidence to suggest that early aggressive treatment of the initial vesicles with antiviral therapy may decrease the incidence of postherpetic neuralgia. 7.4

Recurrent Aphthous Stomatitis (Canker Sores)

Recurrent aphthous stomatitis (RAS) occurs singly or in small groups, primarily on the ventral surface of the tongue, floor of the mouth, soft palate, and buccal mucosa. Sores appear as shallow craters that are covered by a whitish membrane surrounded by intense inflammation. These ulcers are very painful and tend to recur. Healing occurs within 7– 10 days without intervention. RAS is not an infection and is not transmissible, though these ulcers are often confused with those caused by HSV. The cause is unknown, though associations with stress, trauma, menstruation, and food allergy have been made. Some patients have associated them with dental procedures. RAS minor, which affects 80% of RAS patients, causes recurrent small (3 mm–1 cm) painful ulcers. There are usually one to five ulcers at a time. In the immunocompetent patient, the ulcers most often occur on the nonkeratinized mucous membranes (lateral and buccal mucosa, maxillary and mandibular sulci, soft palate, and ventral tongue), a feature that helps differentiate RAS from herpes. The lesions heal spontaneously, usually over 5– 10 days. Differentiation from herpes stomatitis can usually be made with viral culture. It must be kept in mind that, in 10% of cases of oral HSV the virus is shed asymptomatically, with a potential to cause a false-positive result for HSV when RAS is the current, active disease. Treatment is palliative: topical triamcinolone acetonide cream 0.1% (Kenalog in Orabase) two to three times daily, Aphthasol (amlexanox 5%) oral paste applied four times daily, chlorhexidine mouthwash, and topical anesthetics such as viscous lidocaine or overthe-counter agents containing benzocaine. In immunocompromised patients RAS major may develop with large (1–3 cm) and numerous (1–10) ulcers that are very debilitating and slow to heal. Nonhealing aphthous lesions may be a clinical sign of undiagnosed immunological disease. In severe cases with extensive ulceration, some trials have shown improved healing with the use of thalidomide

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(Thalomid) 200 mg once a day for 4 weeks. Men and women must use effective birth control during use and for 1 month after cessation of thalidomide. 8

MASSES

Intraoral masses include human papilloma virus (HPV), molluscum cantagiosum, papillary hyperplasia, epidermoid cysts, lymphoma, and squamous cell carcinoma. Intraoral masses and/or nonresolving ulcerations require biopsy to exclude malignancy. HPV is the causative agent of both benign and malignant warts (also see Chapter 16, Section 6; Chapter 17, Section 4; and Chapter 20, Section 4.1). On nonkeratinized surfaces, warts may be flat or verrucous and are generally asymptomatic. In the HIV infected population they may manifest as single, exophytic, cauliflower-like projections that can become quite large. Treatment is not always needed if the warts are asymptomatic. If necessary, warts can be removed with simple excision, electrosurgical excision, or CO2 laser ablation. 9

INFECTIONS OF THE HYPOPHARYNX AND PARAPHARANGEAL SPACES

Dental disease rarely leads to life-threatening infection because of the improvements in dental care and early antibiotic therapy. There are rare occasions when an odontogenic infection may progress rapidly, spread beyond the tooth and surrounding alveolar bone, and become life-threatening (see Figure 3). The fascial planes of the mouth cavity and neck are ‘‘open’’ and provide conduits that can facilitate the spread of infection, potentially leading to abscess formation and necrotizing fasciitis. Infections of the hypopharynx and parapharyngeal spaces are the most common lifethreatening odontogenic infections (see Chapter 10). They most often originate in an inINFECTIONS OF THE HYPOPHARYNX AND SALIVARY GLANDSa Mandibular and submandibular abscesses Originate in apical root abscess of mandibular molars Spread along open fascial planes to submandibular, sublingual, and retropharyngeal spaces May spread down neck to pleura and mediastinum Submandibular, submental, and/or sublingual pain, swelling, and erythema Fever, toxicity CT or MRI scan to help delineate infection and need for drainage Concern for airway obstruction; urgent dental and ENT consultation Treat with penicillin/metronidazole, ampicillin/sulbactam, ceftriaxone/clindamycin, piperacillin/tazobactam Salivary gland infections Parotid > submandibular Often associated with duct obstruction Pain, swelling at mandibular angle or submandible Fever, toxicity Most often due to S. aureus Treat with antibiotic (Keflex or cefazolin) and hydration Sialagogues (after obstruction relieved) a

CT, computed tomography; MRI, magnetic resonance imaging; ENT, ear, nose, and throat.

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fected mandibular molar. Through the roots of the offending tooth, the infection gains access to the mandibular bone, followed by the sublingual and submandibular spaces. From there the infection can spread posteriorly and inferiorly to the submandibular, peritonsillar, parapharyngeal, retropharyngeal, and prevertebral spaces. Occasionally the infection may spread down the neck to the pleural space and mediastinum. Of greatest concern is progression of infection to the sublingual or retropharyngeal ‘‘danger space,’’ which can cause airway obstruction. These infections are polymicrobic, representing the normal oral flora that invade the tissues of the mouth and neck. Anaerobic streptococci, Fusobacterium, Bacteroides, Peptostreptococcus, and Actinomyces species, are often present in addition to aerobic streptococci. Aerobic GNRs and S. aureus are uncommon pathogens in this setting. 9.1

Submandibular Abscess

The most serious extraoral swelling, a submandibular abscess, occurs at the lower border of the mandible, extending posteriorly and obliterating the contour of the mandibular angle. Patients appear acutely ill with jaw, neck, and mouth pain and facial swelling and fever. The swelling and erythema may spread down the neck subcutaneously or along deeper facial planes between the trachea and the anterior border of the sternocleidomastoid muscle. Trismus, interfering with jaw opening, may be present. Examination of the intraoral cavity may reveal a carious lower molar with surrounding erythema and edema, swelling of the peritonsillar tissues extending into the soft palate, and deviation of the uvula away from the side of the infection. The sublingual space may be swollen and tender, causing elevation and deviation of the tongue. The triad of trismus, deviation of the uvula, and elevation of the tongue indicates the need for urgent management, including hospitalization, rehydration, intravenous antibiotics (as suggested in Section 9.3), and airway protection, followed by early extraction and incision and drainage of the infected tooth. 9.2

Ludwig’s Angina

Ludwig’s angina, first described by Wilhelm Frederick von Ludwig in 1836, is a bilateral, rapidly progressing infection that causes swelling of the spaces below the angle of the mandible, inferior to the chin and floor of the mouth. It usually originates from an abscessed second or third mandibular molar. The bilateral submandibular, submental, and sublingual swelling is firm without frank abscess formation. The sublingual swelling may be extensive, pushing the tongue upward toward the roof of the mouth and threatening the airway. The patient may complain of dysphagia, odynophagia, difficulty in speaking with a characteristic ‘‘hot potato’’ voice, and difficulty in managing salivary secretions. Airway obstruction may be imminent. The patient may require rapid oral intubation or tracheostomy. Expeditious consultation of oral surgery and otolaryngology staff is needed. 9.3

Diagnosis and Management

The diagnosis should be suspected on the basis of history and clinical findings. A history of recent odontogenic pain, dental infection, or extraction is often elicited. A full dental examination including radiographs should be done. However, in the presence of severe trismus, intraoral examination and intraoral radiographs may not be possible. A panographic film may be very useful and simple to obtain. Computed axial tomography (CT) or magnetic resonance imaging (MRI) can be used to evaluate the extent of infection, displacement of the trachea, and need for surgical intervention. A chest radiograph to assess for pleural effusions and mediastinal widening should be done.

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Antibiotics with activity against anaerobes and streptococci should be initiated immediately. Such regimens may include parenteral penicillin and metronidazole or broaderspectrum agents such as ceftriaxone and clindamycin, ampicillin/sulbactam (Unasyn), piperacillin/tazobactam sodium (Zosyn), or meropenem (Merrem). 10

SALIVARY GLAND INFECTION

Swellings of the major salivary glands may be the result of infection, obstruction, a combination of the two, or neoplasia. Sudden unilateral swelling associated with meals is usually suggestive of obstruction. Unilateral painful swelling arising over the course of several days in the setting of debilitation, dehydration, or use of antisialagogue medications, such as diuretics, antihistamines, or anticholinergics, is suggestive of infection. The most common salivary gland infection occurs in the parotid. Patients experience acute painful swelling over the angle of the jaw, fever, and systemic toxicity. The submaxillary gland is more susceptible to stone formation; infection is secondary to obstruction. The typical history is one of acute painful swelling beneath the angle of the lower jaw at or around mealtime. In cases of obstruction without infection, the swelling usually decompresses slowly only to recur at succeeding meals. Lingering swelling with increasing pain and onset of fever point to secondary infection. Evaluation of major salivary gland swelling consists of a careful history, gentle but firm palpation of the gland, and an intraoral examination of the duct orifices. Comparison of ducts for the presence of edema, erythema at the orifice, quality and gross quantity of salivary flow, as well as presence of purulence or inspissation is important. Bimanual palpation can sometimes reveal the presence of a sialolith, particularly in the submaxillary gland. Occlusal and panographic radiographs can be useful screening films for stones, although most parotid duct stones are not radiopaque. Treatment includes antibiotics, analgesia, and hydration. Changing medications to nonantisialagogue alternatives is recommended whenever possible. In community acquired parotitis, the most common offending organism is S. aureus. Outpatient antibiotic therapy may include dicloxacillin sodium (Dynapen) or cephalexin (Keflex) 500 mg orally qid. Parenteral agents such as cefazolin 1 g q8h may be used for patients who require hospitalization. Gentle probing and dilation of the duct with a sterile lacrimal duct probe can help relieve obstruction and allow drainage. If salivary flow cannot be elicited, the use of warm packs and a bland diet is suggested. Once salivary flow has been established, the use of sialagogues such as pilocarpine hydrochloride (Salagen) 5 mg qid or sour candies such as lemon drops, in addition to antibiotics and hydration, is recommended. If obstruction persists or if the infection is refractory, a CT scan may be helpful to confirm the diagnosis. Persistent obstruction and chronic infection may require surgical intervention. BIBLIOGRAPHY Eisen D. The clinical characteristics of intraoral herpes simplex virus infection in 52 immunocompetent patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86(4):432–437, 1998. Glick M, Siegal MA. Viral and fungal infections of the oral cavity in immunocompetent patients. Infect Dis Clin North Am 13(4):817–831, 1999. Li X, Kolltveit K, Tronstad L, Olsen I. Systemic diseases caused by oral infection. Clin Microbiol Rev 13(4):547–558, 2000. Wu T et al. Periodontal disease and risk of cerebrovascular disease. Arch Intern Med 160:2749, 2000. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

12 Community-Acquired Pneumonia and Bronchitis John G. Bartlett Johns Hopkins University, Baltimore, Maryland, U.S.A.

Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Pneumonia is the sixth leading cause of death in the United States. It is the primary cause of infection-related mortality. The frequency of community-acquired pneumonia (CAP) in the United States is approximately 2–3 million cases/year with about 600,000 hospitalizations. The inference is that about 75% of patients with CAP are managed as outpatients. Guidelines were published in the summer of 2000 by both the Infectious Diseases Society of America (IDSA) and the Canadian Community Acquired Pneumonia Working Group to aid the practitioner in diagnosis and treatment. Acute bronchitis is the cause of approximately 12 million physician visits annually. Approximately 5% of adults self-report symptoms consistent with acute bronchitis. The vast majority of these persons seek medical attention. Inappropriate antibiotic therapy for this predominantly viral infection is contributing to the growing problem of bacterial resistance. Chronic bronchitis affects 10%–25% of the adult population. Exacerbations of chronic bronchitis contribute to increased hospitalizations and mortality rate. Determining who should be treated symptomatically or with antibiotics is a daily challenge to the primary care provider. The goal of this chapter is to provide guidelines for managing these infections. A summary algorithm of the approach to the patient with cough, concentrating on CAP and bronchitis, is presented in Figure 1. 2

PNEUMONIA

2.1 2.1.1

Evaluation History

Typical clinical features of CAP are cough and fever of acute onset. These symptoms frequently are accompanied by signs and symptoms of a viral-like respiratory tract infec227

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Figure 1 Approach to the patient with pneumonia or bronchitis. Patients who have bronchitis or pneumonia usually report cough. The patient should be assessed by duration of cough and whether the history and examination findings are suggestive of a viral-like upper respiratory tract infection. If pneumonia or bronchitis is suggested, chest radiography is indicated, especially if the patient has abnormal vital signs. Patients who have pneumonia and most who have exacerbations of chronic bronchitis need antibiotic therapy, those who have acute bronchitis generally do not. CBC, complete blood count; LFT, liver function test, e.g., aminotransferase levels; BUN, blood urea nitrogen; HIV, human immunodeficiency virus; AECB, acute exacerbation of chronic bronchitis. 1Temperature

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PNEUMONIAa Approach to the patient with suspected pneumonia (Figure 1) Acute onset of cough and fever associated with abnormal vital signs Chest radiograph often needed to differentiate from bronchitis Risk assessment to estimate potential mortality and need for hospitalization (Table 1) Site of care by risk category (Table 2) Bacteriological characteristics of CAP (Table 3) Concern about increasing resistance to antibiotics (Table 4) Importance of pneumococcal and influenza vaccines Outpatient therapy (Table 5) Doxycycline Macrolide Fluoroquinolone Influenza therapy (Table 6) Reasons for persistent (>5–7 days) fever (Table 7) Patients requiring hospitalization (category 4, 5) ABG or O2 saturation CBC, renal, hepatic function HIV testing Third-generation cephalosporin ⫹ macrolide or fluoroquinolone a

CAP, community acquired pneumonia; ABG, arterial blood gas; CBC, complete blood count; HIV, human immunodeficiency virus.

tion with nasal congestion, pharyngitis, laryngitis, or acute bronchitis. The cough may be accompanied by the production of sputum that may be mucoid or purulent, or may be dry. Pleurisy is sometimes present and may be the major reason for physician consultation. Another feature that sometimes prompts individuals to seek medical attention is hemoptysis, which is most commonly due to acute bronchitis rather than pneumonitis. Many patients have other nonspecific findings such as nausea, vomiting, diarrhea, and headache. Findings suggesting involvement of other organs are found in more than half of cases. Constitutional symptoms that are frequent include fever, malaise, chills, sweats, and fatigue. 2.1.2

Physical Examination

Physical examination almost invariably reveals abnormalities in vital signs with fever, tachypnea, and/or tachycardia. Rales or ‘‘crackles’’ are present in 50%–70% of patients, but this characteristic feature, according to multiple reviews, is not sufficiently sensitive or specific to confirm a diagnosis of pneumonia when compared to radiographic results that demonstrate a pulmonary infiltrate.

>38⬚C, pulse > 100 beats/min, respiratory rate > 24 breaths/min. 2No underlying lung disease, acute onset of symptoms, self-limited, generally viral. 3Exacerbation of chronic bronchitis, FEV1 > 50%, fewer than four exacerbations per year, often bacterial. 4AECB, FEV1 = 5%–65%, advanced age, more than four exacerbations per year, comorbid conditions, often bacterial. 5Patients with suspected pertussis may be treated to reduce transmission.

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Chest Radiograph

The critical test for the diagnosis of pneumonia is a chest radiograph. This virtually always indicates a pulmonary infiltrate. There are four frequently cited reasons for a false-negative chest radiograph finding: Dehydration: This finding does not make sense simply because dehydration does not limit an inflammatory response at other anatomical sites, does not prevent the evolution of a pulmonary infiltrate in experimental animals, and has not been demonstrated to be a limitation in clinical studies. Neutropenia: There is some evidence that profound neutropenia prevents or reduces the evolution of a pulmonary infiltrate, but these studies are limited to a very specific patient population and have not yet been confirmed. Chest radiograph findings that lag behind clinical illness: Classic studies of pneumonia often indicated that the first 24 hours of acute pneumonia was commonly accompanied by the lack of a pulmonary infiltrate. This apparent lag in changes on chest radiography never exceeds 24 hours and is regarded as rare. Pneumonia involving Pneumocystis carinii: P. carinii pneumonia (PCP) continues to be common in patients with human immunodeficiency virus (HIV) infection either because the disease is not controlled in those who are aware of HIV infection or because the individuals affected have not been tested. Chest radiograph results are falsely negative in up to 30% of patients with PCP. 2.1.4

Other Laboratory Tests

The chest radiograph is the only test that is considered routine for virtually all patients with suspected CAP. Other common tests are the complete blood count (CBC) and chemical profile. Anemia specifically suggests an associated comorbid condition, chronic pneumonia or pneumonia due to Mycoplasma pneumoniae. The white blood count (WBC) may be high or low; a low WBC suggests either severe bacterial pneumonia (usually with increased band forms) or a viral infection (usually associated with a right shift). The purpose of the chemical panel is to determine the status of associated conditions, which is particularly important in patients with established chronic diseases such as renal or hepatic failure, diabetes, alcoholism, and other common chronic conditions. 2.2

Differentiating Pneumonia from Bronchitis

The preceding review indicates the critical role of chest radiography in differentiating pneumonia and acute bronchitis since they present similar symptoms. In general, the patient with an acute cough syndrome with a demonstrated infiltrate on chest radiography is a candidate for antibiotic therapy. The same patient with a negative chest radiograph result usually has a viral infection and should not be treated with antibiotics. The use of antibiotics in the latter group accounts for about 10% of all prescriptions for antibiotics and is commonly viewed as a major source of antibiotic abuse. Surveys of physicians and patients indicate that both groups consider antibiotics appropriate for acute bronchitis, and review of outpatient records indicates that antibiotics are prescribed for about 70%–80% of persons with the diagnosis of ‘‘acute bronchitis.’’ These data emphasize the importance of the distinction between acute bronchitis and pneumonitis and the pivotal role of chest radiography in making this distinction. With regard to the chest radiograph, surveys of patients who have an acute cough syndrome have pneumonia in about 5% of cases, asthma accounts for another 5%, and

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most of the rest have symptoms commonly associated with an upper respiratory tract infection (URI), indicating a viral infection. The issue of the necessity of a chest radiograph in all such cases is frequently raised. Prior surveys show that abnormalities in vital signs are a useful clue since these are abnormal in virtually all patients with pneumonitis. Thus, the patient with an acute cough and typical features of a URI does not need a chest radiograph if there are no abnormalities in temperature (<38⬚C), pulse (<90/min), and respiratory rate (<20/min). Some have questioned the necessity of chest radiography even when there are abnormalities in vital signs in patients who have typical symptoms of influenza during influenza epidemics. Many patients with typical symptoms of pneumonia have chronic pulmonary disease such as chronic bronchitis and/or chronic obstructive lung disease (COLD). Patients with exacerbations of chronic bronchitis are exceptions to the admonition to avoid antibiotics in the absence of a pulmonary infiltrate; nevertheless, the utility of antibiotics in exacerbations of chronic bronchitis is quite marginal according to most placebo-controlled trials. 2.3

Human Immunodeficiency Virus Infection

Many patients with HIV infection initially present with pulmonary infections: primarily pneumococcal pneumonia or PCP (also see Chapter 26). This association is important to recognize in order to provide appropriate medical care at a time when advances in medical management have revolutionarily affected the morbidity and mortality rates associated with HIV infection. It is also important for purposes of counseling since these are the patients who are responsible for transmission of HIV infection. Clues to the possibility of HIV infection include the following: most patients are young adults, although any age group can obviously have HIV infection; over 99% of patients have characteristic risk factors, including gay life-style, injection drug use, or sexual contact with someone who is known to have HIV infection or who is in one of these major risk categories. PCP usually presents characteristic symptoms that evolve over a period of weeks: fever, dyspnea, and dry cough. Laboratory clues to this diagnosis include lymphopenia on the CBC with a total lymphocyte count of <1000/mm3. It is probably never wrong to have HIV serological evaluation, but for the young adult with pneumonia in a high-risk category, it is particularly important. This should be done with informed consent, which is required by law in most states. 2.4

Site of Care

The decision for hospitalization is important because of the obvious economic impact. The Pneumonia Patient Outcome Research Team (PORT) has provided guidelines based on a point system that is summarized in Table 1. Patients are placed in five categories according to point totals based on age, sex, associated conditions, physical findings, and laboratory test results (see Table 2). This system was developed with observations of 6000 patients and was then subject to validation with a retrospective analysis of 33,000 patients. The point total correlates with mortality rate. The recommendation is for outpatient management of persons in categories one and two and hospitalization for persons in categories four and five. For category three, hospitalization is considered optional. Many health maintenance organizations (HMOs) and medical institutions now utilize this point system as a guideline, pathway, or performance indicator. Nevertheless, there are two important exceptions. First, some patients require hospitalization because they simply do not have the support mechanism necessary for proper care outside the hospital: compliance with the necessary medication regimen and patient monitoring are inadequate. The second exception is that many patients

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Table 1 Scoring System to Determine Prognosis and Site of Care Risk

Score

Age and residence Men Women Nursing home Comorbidity Cancer/liver disease CHF, renal disease, cerebrovascular disease Physical examination Mental status change Respiratory rate > 20/min, BP < 90 torr Temperature >40⬚C or <35⬚C Pulse > 125/min Laboratory findings Arterial pH < 7.35 BUN .30 mg/dl, Na < 130 mEq/L Glucose > 250 mg/dl, Hct < 30%, pO2 <60 Torr, pleural effusion a

1 Per year of age 1 Per year of age ⫺ 10 Add 10 20 Each 10 Each 20 20 Each 15 10 30 20 10 Each

CHF, congestive heart failure; Hct, hematocrit; BP, blood pressure; BUN, blood urea nitrogen.

with CAP require hospitalization because of the associated condition. Clinical judgment regarding each individual patient is necessary when making these important decisions. 2.5

Microbial Cause

The microbiological characteristics of CAP have been the subject of extensive studies, but even when virtually all reasonable diagnostic testing is done, only about one-half of patients have an established or probable pathogen (Table 3). The frequency of ‘‘enigmatic pneumonia’’ is even higher in outpatients, even when these patients are subjected to the same type of thorough diagnostic testing for an etiological agent. The major pathogens, when a pathogen is found, are Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and viral agents (Table 3). The major pathogens are summarized in the following sections.

Table 2 Site of Care Based on Category and Mortality Points

Mortality (%)

Recommended site of care

I II III

— <70 71–90

0.1 0.6 2.8

IV V

91–130 >130

8.2 29.2

Outpatient Outpatient Outpatient or brief hospitalization Inpatient Inpatient

Category

Source: Fine et al. 1997.

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Table 3 Major Pathogens in Community-Acquired Pneumonia and Method to Establish the Diagnosis Agents

Preferred diagnostic testsa

S. pneumoniae

Blood culture Sputum Gram stain ⫹ culture Urinary antigen Blood culture Sputum Gram stain ⫹ culture Culture empyema fluidb Serological: IgMb Serological: MIFb Urinary antigenc Sputum cultured Rapid sputum assays DFA stainb Cultureb Viral cultureb DFA stainb

H. influenzae Anaerobes M. pneumoniae C. pneumoniae Legionella sp. Influenza virus

Parainfluenza virus Respiratory syncytial virus a

MIF, microimmunofluorescence; DFA, direct fluorescent antibody. Tests usually not done. IgM, immunoglobulin M; MIF, microimmunofluorescence assay; DFA, direct fluorescence assay. c L. pneumophilia type 1 only. d Contact laboratory so specimen is plated on appropriate medium. b

2.5.1 Streptococcus pneumoniae S. pneumoniae has historically been the major identifiable agent of CAP in virtually all studies that have been done. The characteristic clinical features are an abrupt onset of a chill followed by fever, cough, and dyspnea with or without pleurisy. This classic presentation is now thought to be much less frequent, but the disease continues to be abrupt in onset and potentially severe, accounting for about two-thirds of all pneumonia deaths in which an etiological agent is detected. The usual method to establish the diagnosis is with blood culture and/or Gram stain and culture of expectorated sputum. Sputum Gram stains or cultures yield falsely negative results in 50% of patients with bacteremic pneumococcal pneumonia. A new urinary antigen assay that detects pneumococcal polysaccharide antigen has been approved by the Food and Drug Administration. There is substantial interest in S. pneumoniae at present as a result of increasing rates of resistance to penicillin and to other antibiotics as well, as summarized in Table 4. Penicillin resistance has been noted since the 1960s and has been increasing worldwide since then. S. pneumoniae is considered sensitive to penicillin at minimal inhibitory concentration (MIC) ⱕ 0.06 ␮g/ml, intermediately resistant at MIC = 0.1–1.0 ␮g/ml, and resistant at MIC ⱖ 2.0 ␮g/ml. Amoxicillin is somewhat more effective in vitro than penicillin. The distinction between sensitive and intermediately resistant pneumococci is relevant for meningitis since the cerebrospinal fluid level of penicillin is limited and may not be adequate for strains with reduced sensitivity. This is not the case with pneumonic infections since adequate penicillin and other ␤-lactam antibiotic levels that treat both sensitive and intermediately resistant strains of S. pneumoniae are attainable. These intermediately resistant strains can also be treated with third-generation cephalosporins (TGCs) such as ceftriaxone or cefotaxime and newer-generation fluoroquinolones such as levo-

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Table 4 Antibiotic Susceptibility of S. pneumoniaea Agent Penicillin/Amoxicillin Cefuroxime Macrolides Clindamycin Tetracycline Co-trimoxazole Levofloxacin Vancomycin

Resistant, % 12 22 22 6 13 20 0.2 0

a

Based on analysis of 1,601 clinical isolates from 34 U.S. centers, 1997–1998. Source: Doern et al. 1999.

floxacin, moxifloxacin, and gatifloxacin. Pneumococcal pneumonia due to penicillin-resistant (MIC ⱖ 2.0 ␮g/ml) strains can be treated with TGC, fluoroquinolones, or vancomycin. There is also an increasing concern of pneumococcal resistance to cephalosporins. Sensitive strains have a MIC < 0.5 ␮g/ml, intermediately resistant strains have MIC = 1.0 ␮g/ml, and resistant strains have MIC > 2.0 ␮g/ml. Up to 50% of strains that show resistance to penicillins also demonstrate resistance to TGC. Despite this, strains that are intermediately resistant to cephalosporins (and some that are resistant) respond to TGC. For strains highly resistant to penicillins (MIC > 4 ␮g/ml) and cephalosporins (MIC > 8 ␮g/ml) or for a patient who is ␤-lactam–allergic, newer fluoroquinolones, vancomycin, linezolid (Zyvox), or quinupristin-dalfopristin (Synercid) can be used. All persons older than 65 years of age and those younger patients at high risk for pneumococcal pneumonia should be vaccinated (see Chapter 43, Table 1). Revaccination every 5–7 years is recommended. 2.5.2 Mycoplasma pneumoniae Mycoplasma pneumoniae is a relatively common cause of pneumonia in young and previously healthy adults. The infection is characteristically less severe and less abrupt in onset when compared to pneumococcal pneumonia. It is transmitted person to person by aerosol. After an incubation period of 2–4 weeks fever, headache, and pharyngitis develop; they are followed by cough with sputum that is mucoid. The cough may be worse at night. Symptoms can last for 3–4 weeks. A characteristic feature of Mycoplasma sp. infection are its high rates of extrapulmonary complications including rash, aseptic meningitis, hemolytic anemia, hepatitis, and myocarditis. The diagnosis can be made by culture for M. pneumoniae, but virtually no laboratory does this. More practical, but less reliable, are serological tests and the cold agglutinin assay. A cold agglutinin titer >1:64 combined with a complement fixation antibody titer >1:64 is supportive of the diagnosis. Initiation of therapy is most often based on clinical suspicion. 2.5.3 Chlamydia pneumoniae Chlamydia pneumoniae is a relatively newly detected agent of pneumonia that occurs primarily in the same population susceptible to Mycoplasma sp. pulmonary infections:

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young, previously healthy adults. It is estimated that C. pneumoniae causes 5%–15% of CAP. Older patients, however, can become ill with C. pneumoniae, and it is this population who account for most of the hospitalization due to this pathogen. As with Mycoplasma sp., the course is usually benign. Symptoms of upper airway involvement (sore throat, hoarseness, and sinusitis) are the rule. The diagnosis is difficult to confirm. C. pneumoniae can be cultured in tissue cultures, but this is done only in research laboratories. The same applies to serological tests, which are not generally available and are not very accurate when they are. Initiation of therapy is most often based on clinical suspicion. 2.5.4 Legionella pneumophila It is important to recognize L. pneumophila as a cause of pneumonia because legionnaires’ disease is serious and potentially lethal. Initial reports emphasized the frequency of gastrointestinal complications, especially diarrhea and central nervous system (CNS) changes; however, subsequent reports suggest that these symptoms cannot reliably differentiate Legionella sp. from other CAP pathogens. Legionnaires’ disease may occur in epidemics. It is the only important cause of CAP besides S. pneumonia that kills people. Populations at risk include persons over 60 years; those who smoke or who have chronic lung disease; those who have diabetes or renal or hepatic failure; and those who have compromised cell-mediated immunity such as individuals receiving cancer chemotherapy, organ transplantation recipients, those receiving chronic corticosteroid therapy, and persons with human immunodeficiency virus (HIV) infection. There is a common impression that legionnaires’ disease is always sufficiently severe to require hospitalization (it accounts for approximately 2%–6% of patients hospitalized with pneumonia), but there are some recent reports suggesting that at least some ‘‘walking pneumonia’’ is due to Legionella sp. An initial clue to the diagnosis may be a sputum Gram stain result without demonstrable bacteria; although Legionella sp. is a Gram-negative rod, it does not Gram stain well. The diagnosis is preferably made with a urinary antigen assay or culture of respiratory secretions. The urinary antigen assay detects only L. pneumophila serogroup 1 but is a rapid, specific, and sensitive test easily done by most microbiology laboratories, and this strain accounts for about 70% of all cases of legionnaires’ disease. The culture is offered by many laboratories, but most are not very good at it. The laboratory must be informed that Legionella sp. is being sought since special agar (charcoal yeast extract) must be used. 2.5.5 Haemophilus influenzae H. influenzae causes about 3%–15% of CAP, though this may be an underestimation because of the high rate of false-negative sputum culture results. Most cases are seen in persons with underlying COLD. Although most cases of childhood infection with H. influenza have been due to type B, most CAP in adults is due to nontypable strains. Resistance to ampicillin is due to the production of ␤-lactamase. Recent studies suggest that more than 30% of strains are ␤-lactamase producers. If H. influenzae is isolated from sputum or blood, empirical therapy with a TGC or fluoroquinolone is suggested until antibiotic sensitivity results are available. 2.5.6

Influenza Virus

The influenza virus is responsible for about 20,000 deaths/year in the United States, primarily in persons over 65 years and often as a complication of other conditions (see Chapter 14). Primary influenza pneumonia is relatively rare. Most patients with serious disease have bacterial superinfections (most often with S. pneumoniae or Staphylococcus

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aureus) or deterioration of other chronic diseases such as COLD, asthma, diabetes, or hepatic or renal failure. Influenza A generally causes more serious illness than influenza B. There are several rapid diagnostic tests that can be used in office practice, which have a sensitivity of about 70%, cost about $30, and provide results in 15–20 minutes. Clinical studies indicate that a good clinician can make the diagnosis with comparable accuracy on the basis of the presence of an epidemic of influenza and typical flulike symptoms including fever, myalgias, headache, rhinitis, and pharyngitis. The issue of this diagnosis has taken on special importance because of the availability of antiviral agents to treat influenza, including the direct-to-consumer promotion that has magnified patient queries and demands. Nevertheless, it should be emphasized that prevention with vaccination is clearly preferred (see Chapter 43, Table 1). This is due to the fact that even those who are treated often have abnormal pulmonary function test results for several weeks, antiviral agents must be given within 48 hours of the onset of symptoms, and therapeutic trials indicate that the expected benefit is a reduction in acute symptoms of about 1–1.5 days. 2.5.7

Other Viruses

Most patients with viral pneumonia do not have an etiological diagnosis established. Viral infections, though, may account for a substantial number of enigmatic pneumonias when the full menu of diagnostic tests are done. The major agents are influenza virus (discussed previously), parainfluenza virus, and respiratory syncytial virus. These and other respiratory viruses are thought to be common causes of ‘‘benign’’ pneumonitis in young adults. They are, though, an important source of morbidity and mortality in older persons and those with serious underlying conditions. 2.5.8

Anaerobic Bacteria

Aspiration pneumonia is thought to account for about 10% of CAP. It should be suspected in persons who have a predisposition to aspiration that is due to compromised consciousness (alcoholism, anesthesia, or drug abuse) or dysphagia including gastroesophogeal reflux disease (GERD). There are three forms of aspiration pneumonia, which are quite different in terms of pathophysiological characteristics, clinical presentation, and management. Mendelson’s syndrome reflects aspiration of gastric acid, which results in an acute chemical burn of the lung. Most patients have an abrupt onset of symptoms and may be critically ill. This applies to those originally described in 1946 by Mendelson, who had observed aspiration during obstetrical anesthesia. Many now believe that there is a much more subtle form of Mendelson’s syndrome, the so-called mini–Mendelson pneumonia, which only requires supportive care and is probably self-limited. A second form of aspiration pneumonia involves aspiration of foreign material, primarily vegetable material such as peas and beans. If this causes obstruction, there may be atelectasis or ‘‘downstream pneumonia.’’ Removal of the foreign body with bronchoscopy may be necessary. The third and most common form of aspiration pneumonia is infection involving the anaerobic bacteria that predominate as the normal flora in the gingival crevice. The major pathogens are Peptostreptococcus, Fusobacterium, and Prevotella spp. Early signs are a clinically subtle pneumonitis with an infiltrate in a dependent pulmonary segment (usually the superior segment of a lower lobe or posterior segment of an upper lobe) in a patient who is aspiration-prone. Late complications include putrid sputum, cavitation with lung abscess, and/or empyema.

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Etiological Diagnosis

Most patients with CAP who do not require hospitalization do not have diagnostic tests for an etiological agent, in compliance with the recommendations for management of pneumonia of the IDSA and American Thoracic Society. Surveys of office practice indicate that no attempt is made to establish an etiological agent in 90%–95% of cases of CAP; empirical treatment is now well accepted as the standard of care. Nevertheless, the clinician may find benefit in getting a heat-fixed slide of expectorated sputum for subsequent staining in the event that the ‘‘walking pneumonia’’ patient subsequently requires hospitalization. This would represent the pretreatment specimen that is preferred since once antibiotics are given, results of Gram stains and cultures of respiratory secretions are notoriously misleading. It may also be appropriate to confirm the diagnosis of influenza and to distinguish between influenza A and B if antiviral drugs are to be given. The distinction between types is relevant if the preferred agent is rimantadine or amantadine since these drugs are active only against influenza A. By contrast, oseltamivir phosphate and zanamivir have the advantage of activity against both influenza A and influenza B. 2.7

Treatment

The mainstay of therapy for outpatients with CAP is antibiotics. The earlier the antibiotic is started, the better. A retrospective study of 14,069 Medicare patients by Meehan and colleagues showed that mortality rate increased with increasing delay of antibiotic initiation. A delay of 8 hours was associated with a statistically significant increased mortality rate. The favorite drugs for outpatient treatment of CAP are doxycycline, the macrolides, and fluoroquinolones (see Table 5). 2.7.1

Doxycycline

The drug doxycycline is active against the major treatable causes of bacterial pneumonia, including 80%–90% of strains of S. pneumoniae, most H. influenzae, and the atypical agents, M. pneumoniae and C. pneumoniae. It is also active against Legionella sp., but the experience is limited. Advantages of this drug include a long track record with a good safety profile and an extremely low price tag. It also has the advantage of a convenient dosing schedule of twice daily administration. The major disadvantage is the reluctance of some physicians to use a drug that has been around for 20 years, costs 7 cents a pill, and is used primarily for acne. Nevertheless, the experience with doxycycline, which is quite extensive, indicates that doxycycline has good in vitro activity against the likely pathogens of CAP and a lack of significant side effects. The most legitimate concern is the resistance by S. pneumoniae, which averages 10%–20% in most areas but may be substantially higher in others. As noted, side effects are sparse, but the patient should be warned of the possibility of sun sensitivity. Women who are pregnant or breast-feeding should not use the drug because of potential dental discoloration of the child. 2.7.2

Macrolides

The macrolide group includes erythromycin, azithromycin, and clarithromycin. These drugs are active against 70%–85% of strains of S. pneumoniae, although the exact frequency of resistance is controversial. S. pneumoniae may appear resistant to macrolides in routine laboratory testing, although it may well be susceptible in vivo. This distinction between in vitro resistance and in vivo activity can be determined by demonstrating pneumococcal sensitivity to clindamycin. It should be noted that macrolides generally show

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Table 5 Antibiotic Treatment of Community Acquired Pneumonia Agent

Dose (oral)

Costa

Comment

$21b

10%–20% Of S. pneumoniae resistant Active against atypical pathogens Dose-related gastrointestinal toxicity Poor activity vs. H. influenzae Better tolerated than erythromycin

Macrolide class Erythromycin

500 mg qid

Clarithromycin

1 g qd or 500 mg bid 500 mg, then 250 mg/day x 4 days

Azithromycin

Tetracycline class Doxycycline Fluoroquinolone class Levofloxacin

$140 $39c

100 mg bid

$4

500 mg qd

$140

400 mg qd 400 mg qd

$87 $62

Amoxicillin

500 mg tid

$12

Amoxicillinclavulanate Cefpodoxime Cefprozil Cefuroxime Miscellaneous Clindamycin

875 mg bid

$97

Gatifloxacin Moxifloxacin

␤-Lactam class

Co-trimoxazole

400 mg bid 500 mg d day 500 mg bid

$146 $115 $160

300 mg tid

$155

Double strength bid

$26

Better tolerated than erythromycin

10%–20% Of S. pneumoniae resistant Well tolerated Single daily dose Active against atypical pathogens Active against >98% of S. pneumoniae Active against all H. influenzae No activity vs. atypical pathogens Variable activity vs. S. pneumoniae Poor activity vs. H. influenzae Oral ␤-lactam preferred for S. pneumoniae Good activity vs. H. influenzae High rate of diarrhea Preferred cephalosporins for S. pneumoniae Also active vs. H. influenzae Active vs. most S. pneumoniae Good activity vs. anaerobes Poor activity vs. S. pneumoniae

a

Average wholesale price, (2000 Drug Topics, Redbook) for 10 days of therapy. There are many alternative erythromycins (see Chapter 3, Table 8). c Z-pack: 500 mg on day 1 then 250 mg days 2–5. b

‘‘class activity’’ against likely pulmonary pathogens so that strains of S. pneumoniae or S. aureus that are resistant to one tend to be resistant to all three agents in the class. A notable exception is H. influenzae, which is resistant to erythromycin, is probably susceptible to clarithromycin, and is usually susceptible to azithromycin. Macrolides are universally active against atypical agents including M. pneumoniae, C. pneumoniae, and Legionella sp. There are substantial differences in these drugs in terms of cost and tolerance. Erythromycin commonly causes gastric distress. This side effect may lead to dosage noncompliance. Clarithromycin and azithromycin, although better tolerated, are substantially more expensive. The macrolides may cause antibiotic-associated diarrhea, but this is infrequent and is rarely due to C. difficile.

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Fluoroquinolones

The fluoroquinolone drugs are expanding rapidly as a result of the introduction of new agents. They are simultaneously contracting because of the withdrawal of several agents (trovafloxacin, gemifloxacin, and grepafloxacin) because of their side effects. The newer fluoroquinolones, which have enhanced activity against S. pneumoniae, include gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin. These drugs are more active than ciprofloxacin against S. pneumoniae and are consequently favored for infections involving the respiratory tract including pneumonitis. Advantages of this class are the extraordinary activity against S. pneumoniae and good activity against virtually all other treatable bacterial pathogens that cause pneumonia (H. influenzae, M. catarrhalis, most strains of S. aureus, and all three atypical agents). They are given once daily, are well tolerated, and have an extraordinary track record in therapeutic trials. In addition, studies have shown that fluoroquinolones have produced equal, and in some instances better, outcomes for patients hospitalized with CAP when compared to ceftriaxone or combinations of thirdgeneration cephalosporins plus macrolides. There are two potential disadvantages of this class. First, there is concern that excessive use of these drugs will eventually lead to resistance by S. pneumoniae as well as other pathogens. The argument against this concern is that over 200 million persons have received fluoroquinolones and yet S. pneumoniae has retained susceptibility despite very extensive antibiotic pressure. In addition, many believe that the real concern about resistance is related to the use of fluoroquinolones for other respiratory tract infections such as sinusitis, acute bronchitis, and exacerbations of chronic bronchitis, which account for over 50% of all antibiotic prescriptions. By contrast, pneumonitis accounts for less than 1% of prescriptions. Despite these arguments, there has been a slight shift upward in the rate of resistance of S. pneumoniae in recent years, suggesting that the concern is legitimate even though the overall resistance rate remains at less than 2% of strains. The second concern about this class is the cost since the average wholesale price for a course of most fluoroquinolones is $70–$80. Given these issues some authorities prefer to reserve fluoroquinolones for clinical settings in which the patient has a documented lack of response to alternative antibiotics or has intolerance to the alternative drugs. 2.7.4

Other Antibiotics

␤-Lactams are commonly used for pneumonitis. The favored drugs in this class, in terms of activity against S. pneumoniae, are amoxicillin, amoxicillin-clavulanate, cefpodoxime, cefuroxime, and cefprozil. None of these agents has activity against atypical strains so they are generally favored when these agents are considered unlikely. For aspiration pneumonia in outpatients, anaerobic bacteria are the most frequent pathogens, and the preferred drugs are clindamycin and amoxicillin-clavulanate. Clindamycin has the most extensive published experience with anaerobic pulmonary infections. Amoxicillin-clavulanate has a modest and favorable published experience and is active in vitro against nearly all oral anaerobes. Metronidazole should not be used in these infections because it is not active against aerobic and microaerophilic streptococci, which are commonly concurrent pathogens with anaerobes. 2.7.5

Antiviral Agents

As noted, there are now four agents that are effective and Food and Drug Administration (FDA) approved for the treatment of influenza. The relative merits of these drugs are summarized in Table 6. Amantadine and rimantadine are active only against influenza A,

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Table 6 Antibiotic Treatment of Influenzaa

Treatment regimen Influenza activity Efficacy Treatment Must start within 48 hrs Days of symptom reduction Side effects Efficacy Prophylaxis FDA approval for prophylaxis a b

Amantadine

Rimantadine

Zanamivir

Oseltamivir phosphate

100 mg bidb ⫻ 5 days A

100 mg bidb ⫻ 5 days A

10 mg inhaled bid ⫻ 5 days A⫹B

75 mg bid ⫻ 5 days A⫹B

⫹ ⫹ 1–1.5 Days

⫹ ⫹ 1–1.5 Days

⫹ ⫹ 1–1.5 Days

⫹ ⫹ 1–1.5 Days

CNS

CNS

Wheezing

GI intolerance

⫹ ⫹

⫹ ⫹

⫹ ⫺

⫹ ⫺

CNS, central nervous system; GI, gastrointestinal; FDA, U.S. Food and Drug Administration. 100 mg qd for age >65 yrs.

although this agent was responsible for over 95% of all influenza infections from 1997 through 2000. Many authorities prefer rimantadine because of its lower rate of CNS toxicity. Neuraminidase inhibitors, zanamavir and oseltamivir, are relatively new and expensive and have the advantage of activity against both influenza A and influenza B. All four agents appear to have comparable efficacy, with a reduction in the duration of flulike symptoms by 1–1.5 days. They all must be given within 48 hours of the onset of symptoms for demonstrable benefit. Providers must be aware of the differences in these agents in terms of price and side effect profiles (also see Chapter 14, Table 4). They must also be aware that bacterial superinfections are potential problems with influenza. Some patients may require antibacterial agents with attention to the major organisms that cause superinfections in this setting, including S. pneumoniae, followed by S. aureus and H. influenzae.

2.8

Follow-Up

Most patients with CAP respond to antibiotic therapy within 3–5 days with subjective improvement and objective evidence of decrease in fever. Most patients are afebrile by 5–7 days, but the time required for full recovery is often 1–2 months. Patients with influenza generally have abnormal pulmonary function test results for 1–2 months as well. It is appropriate to warn them about this persistence of fatigue and sometimes cough as well. Patients who have persistent fever need to be evaluated for the factors that can explain nonresponse to antibiotic treatment of pneumonia as summarized in Table 7. For patients who respond, the usual duration of antibiotic treatment is 1–2 weeks but may be less with azithromycin because of its long half-life. Follow-up radiographs are advocated for patients who do not respond, for patients who smoke, and for those above 40 years of age. The purpose of this follow-up film is to detect potential underlying lung disease including bronchogenic neoplasms.

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Table 7 Reasons for Antibiotic Failure in Community-Acquired Pneumonia Reason Wrong diagnosis (not pneumonia)

Wrong microbial class

Inadequate host

Noncompliance with medication Wrong antibacterial agent Wrong dose Drainage required Associated condition that confounds response Pulmonary superinfection

Complicated infection with extrapulmonary involvement Complication of antibiotic treatment

2.9

Comment Many other possibilities: Atelectasis Congestive heart failure Bronchiolitis obliterans and organizing pneumonia Wegener’s granulomatosis or vasculitis, Lymphoma Viral Fungal Mycobacterial Most common cause of antibiotic failure; Mortality rate 15%–20% for pneumococcal bacteremia disease despite appropriate antibiotics Mortality rate 15%–30% for legionnaires’ disease despite appropriate antibiotics Primarily among outpatients Many strains of S. pneumoniae now multiply resistant Atypical pathogens not susceptible to ␤-lactams Rare problem except with aminoglycosides Applies to empyemas (noted in about 1% of patients hospitalized for community-acquired pneumonia) Applies primarily to proximal obstruction due to neoplasm, foreign body, or bronchostenosis Infrequent Expectorated sputum culture results often suggestive of ‘‘superinfection’’ because of selective antibiotic pressure Rare but well established complications of pneumococcal pneumonia, e.g., meningitis, septic arthritis, or endocarditis C. difficile–associated colitis Drug fever

Treatment for the Patient Requiring Hospitalization

Patients admitted to a hospital for treatment of CAP generally are older, have more comorbid conditions, and appear more ill at presentation with greater abnormalities of vital signs and initial laboratory test results (see Table 1). In addition to attempting to obtain sputum for Gram stain and culture, two sets of blood cultures should be drawn, and a complete blood count, assessment of renal and hepatic function, and electrolyte and glucose measurements should be done. If the patient has underlying COLD or appears dyspneic, an arterial blood gas specimen should be drawn or oxygen saturation determined. Those patients at potential risk for HIV infection, including all those between the ages of 15 and 54, should have serological testing. Urine for L. pneumophila type 1 antigen should be obtained. If a pleural effusion is present, consideration should be given to performing thoracentesis to rule out an empyema. Pleural fluid should be sent for Gram stain, culture, white blood cell count, and pH. All diagnostic culturing should be performed prior to the initiation of antibiotics.

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For patients admitted to the general medical floor, empirical antibiotic therapy should begin with a TGC such as ceftriaxone 1 g/da and a macrolide. This combination covers penicillin-resistant pneumococci; Haemophilus spp., Moraxella, Legionella, and Chlamydia spp., and the less likely, but possible, aerobic gram-negative rod (GNR) such as Escherichia coli, Klebsiella spp., or Enterobacter spp. Alternatively, a fluoroquinolone such as levofloxacin (Levaquin) can be used as monotherapy. Patients ill enough to be admitted to the intensive care unit should be treated with a third-generation cephalosporin and a macrolide or a combination of a third-generation cephalosporin or ␤-lactam/␤-lactamase inhibitor and a fluoroquinolone. In patients at risk for Pseudomonas sp. infection such as those with frequent hospital admissions for COLD exacerbations, cystic fibrosis, or bronchiectasis, a TGC that has Pseudomonas sp. activity such as ceftazidime should be used. 3

BRONCHITIS

3.1

Acute

Acute bronchitis is an inflammatory condition of the tracheobronchial tree characterized by cough. Acute uncomplicated bronchitis is illness that lasts for less than 3 weeks in otherwise healthy individuals who do not have evidence of chronic pulmonary disease. Acute uncomplicated bronchitis is part of a continuum of viral illnesses that can involve the upper and/or lower respiratory tract systems. Upper respiratory infections (URIs) such as pharyngitis, otitis, and sinusitis are reviewed in Chapter 10; influenza and the common cold are reviewed in Chapter 14. Acute bronchitis is generally a self-limited viral infection BRONCHITIS AND COUGHa Classification, microbiological aspects, and treatment (Table 10) Approach to the patient with pneumonia or bronchitis (Figure 1) Acute Normal host Most common in winter Normal vital signs Viral origin predominant 10% Due to Mycoplasma spp., Chlamydia spp., B. pertussis Diagnostic testing often not needed (Table 8) Antibiotic therapy not needed except for potential influenza or pertussis (Table 9) Chronic Cough > 3 mo/yr for 2 years Often associated with airway obstruction (COLD) AECB often caused by bacteria Severity/risk classification used to judge microbiological features and therapy (Table 10) Cough Differential diagnosis by duration of symptoms (Table 11) Need to consider noninfectious causes, e.g., CHF, asthma, GERD Most common causes of chronic cough in nonsmoker (Table 12) a

COLD, chronic obstructive lung disease; CHF, congestive heart failure; GERD, gastroesophageal feflux disease; AECB, acute exacerbation of chronic bronchitis.

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most commonly seen during the winter months. Despite that fact, up to 70% of patents with acute bronchitis are inappropriately treated with antibiotics. Patients have cough and often other typical coldlike symptoms of rhinitis, hoarseness, and fever. In contrast to that of the common cold, though, cough is the most predominant symptom in acute bronchitis. Although acute bronchitis usually lasts for several weeks, some patients may have symptoms that persist for more than a month. The cough is productive of sputum, which may be purulent, in 50% of patients. Cigarette smokers may have a more prolonged illness with greater amounts of purulent secretions. Fever may be seen in infections due to influenza or adenoviruses but is uncommon with rhinoviruses. Although physical examination may reveal clear lung fields, rales, rhonchi, and wheezing may occasionally be present. The major causes of acute bronchitis are summarized in Table 8. Influenza A virus accounts for the majority of infections. Other viruses include influenza B, adenoviruses, parainfluenza virus, respiratory syncytial virus, and viruses more commonly thought to cause URI such as rhinoviruses, coronaviruses, and coxsackievirus. Bacterial infection by M. pneumoniae, Bordetella pertussis, and C. pneumoniae causes about 5%–10% of acute bronchitis. For patients with cough lasting more than 3 weeks these latter bacteria account for 10%–20% of infections. Although S. pneumoniae, H. influenzae, and M. catarrhalis are able to colonize the upper respiratory tract in normal hosts, there is no evidence that they produce acute bronchitis in adults without underlying lung disease. Special mention of pertussis is warranted. B. pertussis, the etiological agent of whooping cough, is an important consideration in adults with prolonged symptoms. Studies indicate that up to 25% of adults with severe persistent coughing of acute onset have pertussis. Although vaccinated in childhood, most adults are not immune. Whooping cough in the adult is characterized by a severe, persistent cough that begins after an incubation period of 1–3 weeks. Initially patients may report coldlike symptoms of rhinitis, pharyngitis, conjunctivitis, and low-grade fever. Thereafter, the cough worsens to the point that it may induce vomiting. It is characteristically worse at night. In adults the classic ‘‘whoop’’ does not occur.

Table 8 Major Pathogens in Acute Bronchitis and Diagnostic Tests Pathogen Influenza virus

Other viruses Mycoplasma pneumoniae Chlamydia pneumoniae Bordetella pertussis

a

Diagnostic testa Rapid antigen detection tests: 70% sensitivity Clinical criteria: 70% specificity Culture of nasopharyngeal swab: hospitalized patients and epidemiological studies Cultures for parainfluenza and other viruses (rarely done) RSV-DFA test (pediatric only) IgM (diagnostic criteria unclear) MIF with 4-fold rise Calcium alginate nasopharyngeal swabb PCR (experimental) Serologic

RSV, Respiratory syncytial virus; DFA, direct fluorescent antibody; MIF, microimmunofluorescence; PCR, polymerase chain reaction; IgM, immunoglobulin M. b Plate as soon as possible onto Regan-Lowe medium; discuss with the clinical microbiology laboratory.

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The diagnosis of acute bronchitis is a clinical one. Vitals signs are usually normal in these patients. Abnormalities such as heart rate > 100 beats/min, respiratory rate > 24 breaths/min, oral temperature > 38⬚C, or the finding of rales, fremitus, or egophony on physical examination would raise the concern of pneumonia and prompt a chest radiograph. Purulent sputum does not necessarily indicate a bacterial pathogen since both viral and bacterial agents can cause an influx of white blood cells into pulmonary secretions that is that cause of the purulence. Many patients have airway hyperresponsiveness and abnormalities on spirometry. Although these abnormalities usually resolve in 2–3 weeks, they may persist for several months. Laboratory confirmation is usually not indicated for most instances of uncomplicated acute bronchitis (see Table 8). It may be indicated if influenza is suspected, especially if inhalational anthrax is considered in the differential diagnosis or if patients are living in a nursing home. The diagnosis of pertussis should be confirmed prior to treatment. This can be done with nasopharyngeal culture taken with a calcium alginate swab or nasopharyngeal aspiration. The sample should be plated as soon as possible on appropriate medium (consult your clinical microbiology laboratory). B. pertussis is slow growing and may take up to 1 week to grow. Gonzales and associates (2001) have summarized guidelines for managing acute bronchitis from two panels, one representing the Centers for Disease Control and Prevention (CDC) and the other representing the American Chest Physicians/American Society of Internal Medicine (ACP/ASIM). Key points from both groups regarding antibiotic therapy are nearly identical, including a summary of eight clinical trials that did not show any benefit of antibiotic use. Of the nonviral microbial pathogens, C. pneumoniae, M. pneumoniae, and B. pertussis, only B. pertussis requires treatment with antibiotics. Treatment for the great majority of patients with acute bronchitis, therefore, is symptomatic (see Table 9). Antibiotics are rarely indicated. The cough can be treated with nonsteroidal antiinflammatory agents and brompheniramine every 12 hours or with dextromethorphancontaining cough suppressants (e.g., Robitussin DM). Expectorants and inhaled or oral corticosteroids have not been proved to be very helpful. ␤2-adrenergic bronchodilators such as albuterol have been shown to reduce the severity and duration of cough. Influenza A can be treated with amantidine, rimantidine, or the newer neuraminidase inhibitors, as outlined earlier (see Chapter 14, Table 4). These agents can also be used prophylactically to control spread within nursing homes or families for high-risk or nonvaccinated individuals. Pertussis can be treated with erythromycin or co-trimoxazole. Usual

Table 9 Treatment of Acute Bronchitis Cause Influenza Upper respiratory infection

Allergic rhinitis Asthma Pertussis

Treatment Rimantadine, zanamivir, or oseltamivir phosphate (see Table 6) Start within 48 hr of symptom onset Cough medications with codeine or dextromethorphan Dexbrompheniramine ⫹ sedating (first-generation) antihistamine (Actifed, Contac, Dimetapp) Naproxen and/or ipratropium nasal spray Nonsedating antihistamine (second-generation) Inhaled bronchodilator Erythromycin or co-trimoxazole

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therapeutic doses should be given for 2 weeks. Macrolides can also be used prophylactically to prevent spread of pertussis to exposed individuals. Treatment of pertussis does not reduce the duration or severity of illness if initiated after 7–10 days of symptoms but helps reduce transmission to others. There may be great pressure on the provider to prescribe antibiotic therapy by the patient, family, or friend. With direct consumer advertising this demand may increase. It is worthwhile reviewing realistic expectations about the duration of symptoms, the viral nature of the illness, the lack of antibiotic efficacy for the great majority of patients, the concern about adverse drug events, and the growing concern about bacterial resistance in our communities. One study suggested that referring to acute bronchitis as a ‘‘chest cold’’ reduced the patient’s belief that antibiotic therapy was necessary. 3.2

Chronic

The pathophysiological and microbiological characteristics and approach to diagnosis and treatment of chronic bronchitis are very different from those of acute bronchitis. Chronic bronchitis is defined as cough with excessive secretions on most days for at least 3 months of the year for 2 successive years. This clinical syndrome is often associated with airflow obstruction and is referred to as COLD. COLD affects 20% of the population and is the fourth leading cause of death in the United States. Cigarette smoking is the most significant risk factor, though occupational and environmental exposure to dusts and allergens, past childhood respiratory tract infection, and passive exposure to cigarette smoke also contribute. Acute exacerbation of chronic bronchitis (AECB) is episodic worsening of chronic cough, shortness of breath, and/or purulent sputum production without evidence of pneumonia. If underlying lung function is severely compromised, these exacerbations can lead to respiratory failure, need for mechanical ventilation, and prolonged hospitalization. Other risk factors for poor outcomes include age >65 years, need for corticosteroid use, and concomitant cardiac disease. Although bacterial infection is thought to cause 50%–70% of AECB, this topic is much debated. Anthonisen and colleagues (1987) demonstrated in 1986 that antibiotic therapy, in select patients with AECB, leads to improved outcomes. They conducted a double-blind placebo-controlled trial of 362 chronic bronchitis exacerbations. Clinical success occurred in 68% of the antibiotic group, as compared to 55% in the placebo group. This was statistically significant though just barely so. A meta-analysis of nine randomized placebo-controlled trials using antibiotics for AECB by Saint and associates published in 1995 demonstrated a small but statistically significant overall benefit of antibiotic therapy. Defining the bacteriological characteristics of AECB is difficult since the majority of these patients are chronically colonized with S. pneumoniae, H. influenzae, or M. catarrhalis. These same pathogens have been isolated from lower airway secretions with bronchoscopically protected specimen brush techniques, suggesting they are the causative bacterial pathogens in the majority of patients with AECB. Other potential pathogens include H. parainfluenzae, C. pneumoniae, B. pertussis, M. pneumoniae, anaerobes, and Corynebacterium pseudodiphtheriticum. This latter organism has been recently recognized as an important pathogen, especially in immunocompromised patients and those with underlying cardiopulmonary disease. In patients with frequent exacerbations and antibiotic usage, colonization and subsequent infection may occur with aerobic GNRs, including P. aeruginosa. It is important to recognize that viral infection is an important cause of acute exacerbations as it is in acute uncomplicated bronchitis. Because of the difficulty of differentiating colonized patients from those actively infected and the need to identify patients at risk for respiratory failure and to help deter-

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mine who should receive antibiotic therapy, several stratification schemes have been developed to aid the clinician. All schemes utilize severity of underlying lung function, history of recurrent exacerbations, and age to provide an educated guess about the bacteriological features and risk of bacterial resistance and to give the clinician recommendations about empirical antibiotic therapy. Generally, the sicker the patient the more broadspectrum the antibiotic recommendation. None of these schemes has been validated in prospective randomized trials. A recent classification scheme by Ball and associates is summarized in Table 10. For patients with acute exacerbations of chronic bronchitis, antibiotics are frequently recommended. For the patient with good lung function, infrequent exacerbations, and low risk of antibacterial resistance, amoxicillin, doxycycline, or a macrolide can be used as in the treatment of CAP. For patients with more severe lung disease, frequent exacerbations, and increased risk for bacterial resistance, a newer fluoroquinolone such as levofloxacin, gatifloxacin, or moxifloxacin or an oral TGC such as cefixime can be used. If resistant GNR or P. aeruginosa is suspected or documented on culture, ciprofloxacin is a more appropriate choice (see Table 10). Other therapeutic interventions can include a ␤-agonist such as albuterol inhaler, an anticholinergic agent such as ipratropium inhaler (2 puffs qid), and a topical steroid such as triamcinolone inhaler (2–4 bid–qid). For more severe decompensation, oral corticosteroids or leukotriene inhibitors such as montelukast sodium (10 mg/da) or zafirlukast (20 mg bid) can be used. 3.3

Approach to the Patient with Cough

Cough is the most prominent symptom not only of pneumonia and bronchitis but also of myriad other infectious and noninfectious causes. If pneumonia can be excluded by chest radiograph, the differential diagnosis can be approached in terms of the duration of cough, as suggested by Irwin and Madison (2000); acute cough lasts less than 3 weeks, subacute cough lasts 3–8 weeks, and chronic cough lasts >8 weeks. Noninfectious causes such as left ventricular heart failure, asthma, and aspiration should also be considered (see Table 11). The most common cause of acute cough is viral rhinosinusitis. Antibiotics are not indicated. Patients generally respond to symptomatic treatment with dexbrompheniramine maleate; pseudoephedrine sulfate (Drexophed, Dexaphen S.A., Pharmadrine), intranasal ipratropium, or a combination of first-generation (sedating-type) antihistamines and naproxen. Lack of response to symptomatic therapy suggests a bacterial sinusitus, especially if associated with maxillary toothache, purulent nasal secretions, or clinical evidence of sinus consolidation. Indications for antibiotic therapy include bacterial sinusitis, AECB, and pertussis. Subacute cough is most often due to persistence after an acute upper respiratory infection (postinfectious cough), bacterial sinusitis, pertussis, or asthma. Postinfectious cough is due to postnasal drip or persistence of viral rhinitis or tracheobronchitis. It usually resolves spontaneously and antibiotic therapy is not indicated. Evidence of pertussis or sinusitis would warrant the use of antibiotic (see Table 10 and Chapter 10). In cough variant asthma, cough may be the only manifestation of asthma. The vast majority of chronic cough syndromes in immunocompetent persons are due to postnasal drip, asthma, GERD, chronic bronchitis, bronchiectasis, eosinophilic bronchitis, or use of angiotensin-converting enzyme (ACE) inhibitors. Less often lung cancer, sarcoidosis, left ventricular heart failure, or chronic aspiration is the cause. A chest radi-

FEV1 > 50% Increased sputum and purulence Fewer than four exacerbations yearly Same as simple plus FEV1 = 50%–65% Advanced age More than four exacerbations yearly Significant comorbidityg Same as complicated plus Continuous sputum production throughout year

Simple chronic bronchitis

c

Same as complicated bronchitis plus GNRs, including P. aeruginosa

Virale S. pneumoniae H. influenzae M. catarrhalis S. pneumoniaef H. influenzaef M. catarrhalis

Viral, noninfluenza Influenza Mycoplasma Chlamydia Pertussisd

Pathogens

Amoxicillin Macrolide Doxycycline Amoxicillin-clavulanate Levofloxacin Gatifloxacin Moxifloxacin Cefixime Cetibuten Fluoroquinalone Ciprofloxacin Adjustment of antibiotics based on sputum culture

Not indicated See Table 6 Not indicated Not indicated Erythromycinh Co-trimoxazole

Antibiotic treatment

b

FEV1 , forced vital capacity in 1 second; DS, double strength. Costs: see Table 5. c Viral infections account for 90%. d More often recovered (10%–20%) in patients with persistent cough. Therapy does not shorten duration of symptoms but reduces transmission. e Viral infection may precede bacterial. f Concern for bacterial resistance. g Diabetes mellitus, congestive heart failure, chronic renal or liver disease. h There are many alternative erythromycins; see Chapter 3, Table 8. Source: Adapted from Grossman 1997.

a

Chronic bronchial infection

Complicated chronic bronchitis

No underlying structural disease

Risk

Acute bronchitis (self-limited, benign)

Clinical status

Table 10 Classification Scheme and Treatment for Patients with Bronchitisa,b

500 mg tid As above 100 mg bid 875 mg bid 500 mg qd 400 mg qd 400 mg qd 400 mg qd 400 mg bid As above 500 mg bid

400 mg qid Double strength bid

Dose

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Table 11 Differential Diagnosis of Cough Acute Viral upper respiratory tract infection Sinusitis Pertussis Acute exacerbation of chronic bronchitis Rhinitis due to allergy or environmental irritant Left ventricular heart failure Asthma Aspiration Subacute Postinfectious cough Bacterial sinusitis Asthma Pertussis Chronic Postnasal drip Gastroesophageal reflux Chronic bronchitis Bronchiectasis Eosinophilic bronchitis Angiotensin-converting enzyme inhibitors Bronchogenic carcinoma Sarcoidosis Left ventricular heart failure Source: Adapted from Irwin and Madison 2000.

Table 12 Causes of Cough Syndrome in Nonsmoking Patients Condition

Frequency

Diagnosis

Postnasal drip syndrome

40%–50%

Subclinical asthma

20%–25%

Gastroesophageal reflux

20%–25%

Sensation of posterior drainage and frequent clearing of throat Radiographic evidence of sinusitis Nasopharyngeal evidence of mucoid/purulent secretions Episodic wheezing, dyspnea with cough Physical examination with wheezing Pulmonary function test result evidence of reversible airway obstruction Heartburn or sour taste in mouth Reflux demonstrated by radiography, endoscopy, or esophageal monitoring

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ograph can usually exclude carcinoma, pneumonia, and bronchiectasis. A nonsmoking person with a clear chest radiograph finding who is not using an ACE inhibitor most likely has postnasal drip from chronic nasal or sinus abnormalities, asthma, GERD, or eosinophilic bronchitis. Postnasal drip is usually diagnosed by therapeutic trial, treating sinusitis, allergic, or vasomotor rhinitis or removing environmental irritants. Cough variant asthma can be excluded by a negative methacholine challenge test result. GERD can be treated with H2-blockers, proton pump inhibitors, and/or metoclopramide. It is important to recognize, though, that chronic cough can have more than one cause in 18%–93% of cases. Causes and diagnosis of the most common types of cough are summarized in Table 12. BIBLIOGRAPHY Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 106:196, 1987. Bartlett JG. Treatment of community acquired pneumonia. Chemotherapy 46 (suppl 1):24–31, 2000. Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ. Guidelines from the Infectious Diseases Society of America: Practice Guidelines for the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 31:347–382, 2000. Doern G, Brueggman AB, Huynh H, Wingert E. Antimicrobial resistance with Streptococcus pneumoniae in the United States, 1997–1998. Emerg Infect Dis 5:757–765, 1999. Fahey T, Stocks N, Thomas T. Quantitative systemic review of randomized controlled trials comparing antibiotic with placebo for acute cough in adults. Br Med J 316:906, 1998. Fine MJ, Aulde TE, Yearly DM, et al. A prediction rule to identify low risk patients with communityacquired pneumonia. New Engl J Med 336:243, 1997. Gonzales R, Bartlett JG, Besser RE, et al. Principles for appropriate antibiotic use for treatment of uncomplicated acute bronchitis: Background. Ann Intern Med 134:521, 2001. Grossman RF. Guidelines for the Treatment of Acute Exacerbations of Chronic Bronchitis. Chest 112:310S–313S, 1997. Irwin R, Madison JM. The diagnosis and treatment of cough. N Engl J Med 343:1715, 2000. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH et al. Canadian Guidelines for the Initial Management of Community-Acquired Pneumonia: An Evidence based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect Dis 31: 383–421, 2000. Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process and outcomes in elderly patients with pneumonia. J Am Med Assoc 278:2080–2084, 1997. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical exam. JAMA 278:1440, 1997. Saint S, Bent S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstructive pulmonary disease exacerbations: A meta-analysis. JAMA 273:957, 1995. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

13 Tuberculosis C. Fordham von Reyn Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

1

EPIDEMIOLOGICAL CHARACTERISTICS

Tuberculosis is now an uncommon disease in most regions of the United States. As a result, the diagnosis may not be considered promptly and isolation and treatment may be delayed. Early recognition of tuberculosis requires that the clinician know both the disease syndromes and the epidemiological features of tuberculosis, especially groups who are at risk. Stated briefly, most cases of tuberculosis in the United States now occur in older Americans, members of minority groups, foreign-born persons (50% of U.S. cases), institutionalized persons, and those with predisposing disease such as infection with the human immunodeficiency virus (HIV). Table 1 summarizes groups at risk for active tuberculosis in the United States. Rates of active tuberculosis disease are expressed as an annual incidence per 100,000 population. In the United States the rate was 87/100,000 in 1945 and had fallen to 6.4/ 100,000 by 1999. Thus, both active tuberculosis disease (i.e., culture-positive disease) and latent tuberculosis infection (i.e., positive tuberculin skin test result) are more common in Americans who were born when community rates of tuberculosis were higher. In 1945 approximately 50% of Americans had positive tuberculin skin test results. In the year 2000 this figure had fallen to <5%. However, because of waning cellular immunity with age, many persons who had positive tuberculin skin test findings in 1945 would have negative skin test results in 2000, exemplifying the high rate of false-negative tuberculin skin test findings in older populations. In developing countries the annual incidence of tuberculosis disease is often still in the range of 100–400/100,000, and rates of positive skin test results for persons from these regions are expected to be 50%–75%. The most common countries and regions of origin for foreign-born persons with tuberculosis in the United States are provided in Table 1. Rates of tuberculosis in the United States are also high among institutionalized persons, especially those in prisons and homeless shelters, where disease transmission is more common. In addition, persons with certain underlying diseases or risk behavior are at increased risk of tuberculosis. Important examples include persons with HIV infection, injection drug use, alcoholism, silicosis, diabetes mellitus, renal failure, and organ transplantation. In much of the developing world approximately 50%–75% of persons with tuberculosis have HIV infection, whereas in the United States approximately 10%–15% of persons with tuberculosis have underlying HIV infection. 251

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Table 1 Major Risk Groups for Tuberculosis Disease in the United States Foreign-born persons from regions where tuberculosis is endemic Mexico, Philippines, Vietnam, India, China, Haiti, South Korea, Africa Older persons born in the United States Especially those with radiographic findings consistent with prior tuberculosis Persons who reside in institutions Prisons, homeless shelters Persons with chronic underlying disease or risk behavior Human immunodeficiency virus infection, injection drug use, silicosis, weight loss, diabetes mellitus, renal failure, gastrectomy, jejunoileal bypass, solid organ transplantation, carcinoma of head or neck. Recent tuberculosis infection Skin test conversion

Diseases due to nontuberculous mycobacteria (NTM) may sometimes be initially diagnosed as tuberculosis. The clinician should be aware that with the rising incidence of infections due to NTM in the United States (e.g., Mycobacterium avium complex), a patient with acid-fast bacilli (AFB) isolated from pulmonary secretions who is not in one of the defined risk groups for tuberculosis is more likely to have nontuberculous mycobacterial infection or colonization than tuberculosis. 2

CLINICAL SYNDROMES

2.1

Natural History and Definitions of Infection and Disease

A critical feature of the natural history of tuberculosis is the distinction between infection with Mycobacterium tuberculosis (generally detected by a positive tuberculin skin test EPIDEMIOLOGICAL CHARACTERISTICS AND CLINICAL SYNDROMESa Most U.S. cases in elderly, minority, or foreign born population Risk groups for MTB (Table 1) AFB in sputum potentially nontuberculous, especially in low-risk individuals Transmission generally result of prolonged exposure Active tuberculosis in 5%–10% of infected persons, generally as reactivation of latent infection years after exposure Symptoms of pulmonary TB (Table 2) HIV Increases risk of development of active TB Atypical presentations with CD4 count < 200 cells/mm3 Potential extrapulmonary TB manifestations Vertebral osteomyelitis (Pott’s disease) Chronic meningitis Genitourinary disease (sterile pyuria) a

MTB, Mycobacterium tuberculosis; AFB, acid-fast bacillus; TB, tuberculosis; HIV, human immunodeficiency virus.

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result; see later discussion) and disease due to Mycobacterium tuberculosis (detected by a positive stain/culture finding or by a clinical diagnosis of active disease, as discussed later). Mycobacterium tuberculosis (MTB) is transmitted when a person with active MTB pulmonary disease, typically open cavitary disease, coughs and disperses infective droplet nuclei containing MTB. Infection is established when one or more infectious organisms are inhaled and invade the alveoli in a previously uninfected host. The risk of transmission is related to the frequency of cough and to the burden of infection in the index case (AFB smear–positive patients and those with cavitary disease are more likely to transmit disease). Transmission generally requires susceptibility of the exposed person and prolonged respiratory exposure of several hours or more. In approximately 30%–50% of family contacts of active cases infection eventually develops. Each untreated AFB smear–positive index case has been estimated to cause 10 infections per year. In most persons initial infection is contained by a cellular immune response. As a result, a latent infection with MTB is established. In only 5%–10% of persons with latent MTB infection does infection ever progress to active MTB disease. Progression to active disease is most likely in the first 1–2 years after infection but may be delayed until years later (reactivation disease). The most common active disease syndrome is pulmonary tuberculosis followed by various forms of extrapulmonary and disseminated tuberculosis. The pathophysiological events leading to loss of immunological control and active disease are not well understood, but clinical experience has identified conditions that favor the development of active disease. Examples include advanced age, immunosuppression, and HIV infection. 2.2

Primary Infection

In most patients recognizable symptoms do not develop with the acquisition of new tuberculosis infection. A minority of persons with newly acquired infection experience clinical symptoms, including erythema nodosum, constitutional symptoms, hilar adenopathy, and pleurisy with or without pleural effusion. Typically these symptoms resolve spontaneously. In some persons with newly acquired tuberculosis infection progresses directly to active tuberculosis disease (discussed later); this syndrome is known as primary tuberculosis disease and is most common in children and those with HIV infection. 2.3

Latent Tuberculosis Infection

Persons with latent infection with MTB are by definition asymptomatic. They are often identified by skin testing years after primary infection with tuberculosis. Some of these asymptomatic persons may have radiological evidence of a prior inflammatory process in the lung (discussed later). 2.4

Pulmonary Tuberculosis Disease

Most pulmonary tuberculosis results from reactivation of remotely acquired latent infection; less commonly progression is rapid from recently acquired primary infection to active disease. Active pulmonary tuberculosis usually presents with chronic pulmonary or constitutional symptoms, but fulminant presentations may also occur. Typical disease appears insidiously with the development of cough, weight loss, and fever; hemoptysis is reported by a minority of patients (Table 2). Cough and fever that have persisted for 2 weeks may suggest that the patient’s pneumonia is due to tuberculosis. This duration of cough and fever is only noted in 50% and 30% of patients, respectively. Physical findings depend on

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Table 2 Symptoms of Tuberculosis Disease Symptom Cough Weight loss Fever Hemoptysis

Frequency, % 50–80 50–75 30–50 10–25

the duration of disease: wasting and focal pulmonary findings (rales, dullness to percussion) may be present with chronic disease. Lymphadenopathy, hepatosplenomegaly, and clubbing are all uncommon. Laboratory findings may include anemia of chronic disease, elevated erythrocyte sedimentation rate (ESR), hypoalbuminemia, and abnormal liver biochemical findings such as elevations of serum aspartate and alanine aminotransferase. The white blood cell count (WBC) typically demonstrates a mild leukocytosis without a left shift; relative lymphopenia may also be observed. 2.5

Extrapulmonary and Disseminated Tuberculosis Disease

Tuberculosis of the genitourinary tract may cause systemic symptoms and/or sterile pyuria or hematuria. Chronic vertebral osteomyelitis in a person from a country where tuberculosis is endemic is most likely to represent tuberculosis of the spine (Pott’s disease). Tuberculous meningitis is characterized by a subacute clinical course with headache, fever, and, sometimes, cranial nerve signs. Cerebrospinal fluid (CSF) examination reveals a lymphocytic pleocytosis, elevated protein level, and a progressively lower CSF glucose level on repeat lumbar punctures. Patients with disseminated or miliary tuberculosis often have nonfocal systemic symptoms including fever and weight loss and may occasionally have extreme leukocytosis (leukemoid reaction). 2.6

Tuberculosis in Human Immunodeficiency Virus Infection

HIV infection increases the risk that a latent tuberculosis infection will progress to active tuberculosis disease from 10% over a lifetime to 8% per year. Manifestations of tuberculosis in HIV infection depend on the degree of immunodeficiency. HIV-infected persons with CD4 lymphocyte counts of 200 cells/mm3 have clinical features (upper lobe disease and cavitation) similar to those of persons without underlying immunosuppression. Patients with CD4 counts < 200 cells/mm3 may have different clinical patterns of disease. Hilar adenopathy is a more common finding on chest radiograph, and various forms of extrapulmonary tuberculosis are also more common. Bacteremic or disseminated tuberculosis is a common finding in patients with advanced untreated HIV infection from countries where tuberculosis is endemic. 3

DIAGNOSIS

3.1 3.1.1

Latent Tuberculosis Infection Single Tuberculin Skin Testing

Skin testing with tuberculin purified protein derivative (PPD) is the standard method for the diagnosis of latent tuberculosis infection (see Figure 1). Current guidelines emphasize

Tuberculosis

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Figure 1 Approach to the patient with suspected TB. The patient with suspected latent tuberculosis should be assessed for exposure risk and have a PPD planted. Patients with symptoms of active TB should be assessed and isolated. All patients with active TB should be tested for HIV infection. Those with active TB should be treated according to the guidelines in Table 6. PPD, purified protein derivative; HIV, human immunudeficiency virus; TB, tuberculosis; AFB, acid-fast bacillus.

the importance of testing persons at high risk of tuberculosis and deemphasize routine testing of low-risk groups, among whom false positive reactions are more common (Table 3). With such targeted testing of high-risk persons it is no longer necessary to use a 35year-old age cutoff for determining whether the benefits of isoniazid prophylaxis (now called isonicotinic acid hydrazide [INH] treatment of latent tuberculosis) outweigh its risks (see later discussion).

a

All persons

No risk factors Groups

Residents and employees of high-risk congregate settings

Immigrant (<5 years) from high-prevalence country Injection drug users TB laboratory personnel Selected clinical conditions at high risk of tuberculosis

Upper zone fibrosis on radiograph consistent with prior TB Immunosuppression

Recent TB contact

HIV positive

Groups

Important to distinguish between booster phenomenon from remote TB infection and bona fide test conversion from new TB infection (see Figure 2)

Comments

At risk for both HIV and TB. Consideration of BCG immunization warranted Diabetes mellitus, silicosis, chronic renal failure, hematological malignancies, carcinoma of head and neck, 10% weight loss, gastrectomy, jejunoileal bypass Prisons, homeless shelters, HIV residential facilities, nursing homes and long-term facilities for elderly, hospitals, other health care facilities Few TB cases in many U.S. health care institutions; routine employee skin testing likely to yield many false-positive results Testing of persons without risk factors unwarranted

Organ transplantation, other immunosuppression (e.g., ⱖ15 mg prednisone for 1 month) Many U.S. cases of reactivation tuberculosis in this group

CD4 count > 200/mm3: testing generally reliable CD4 count < 200/mm3: false-negative results possible Development of new infections in approximately 30%–50% of family contacts Risk of reactivation 30 times higher with Simon foci

Comments

Groups and cutoffs are from standard recommendations in the United States (American Thoracic Society, 2000). Comments include opinions from the author. PPD, purified protein derivative; HIV, human immunodeficiency virus; TB, tuberculosis; tuberculosis; BCG, bacille Calmette-Guerin.

PPD conversion (10-mm increase within 2 years)

PPD cutoff (two tests)

15 mm

10 mm

5 mm

PPD cutoff (one test)

Table 3 Targeted Tuberculin Skin Testing to Identify Latent Tuberculosis Infectiona

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An intradermal injection of 0.1 ml of PPD is made to produce a tense 5- to 10-mm wheal on the volar surface of the forearm. The skin test is read at 48–72 hours by a trained reader. The area of induration is palpated, measured, and recorded as millimeters in the transverse diameter (perpendicular to the long axis of the forearm). Erythema should be ignored. It is important to note that induration may occur without any attendant erythema. Interpretation of whether a single reaction suggests underlying latent tuberculosis infection is based on results obtained from patients with confirmed tuberculosis disease. Most patients with tuberculosis disease have reactions ⱖ10 mm with an average reaction size in the range of 15 mm. Thus, reactions of 15 mm are considered diagnostic of latent tuberculosis in all persons. Reactions of 10 mm or even 5 mm are considered positive findings in persons at high risk (Table 3). False-negative results occur with malnutrition, aging, immunosuppressive therapy (e.g., 20 mg of prednisone for 2 weeks), and immunodeficiency conditions such as advanced HIV infection (particularly with CD4 cell count < 200/mm3). False-positive results occur in persons with prior infection with nontuberculous mycobacteria and are common when low-risk persons are tested with cutoffs less than 15 mm (e.g., approximately 50% of 10- to 14-mm PPD reactions in health care workers are false-positive). 3.1.2

Sequential Tuberculin Testing: Booster Effect versus True Conversion

An increase of >10 mm between two PPD test results performed within 2 years of each other is considered a PPD conversion and is interpreted as evidence of new infection with M. tuberculosis. When evaluating a change in two skin test results separated in time, several issues must be considered. First, the original PPD may have only been recorded as ‘‘negative’’ without an exact measurement of the size of the PPD in millimeters of induration. This nonspecific ‘‘negative’’ result makes it impossible to determine whether a second positive test result represents a true conversion or not. For example, a 9-mm reaction could be recorded as a negative result for low-risk persons. A subsequent PPD result of 14 mm would be considered a conversion if the actual measurement of the first test were not known (a false-positive result). In fact, the 14-mm result should not be considered a conversion at all since it is less than a 10-mm increase from the original 9-mm reaction. The second is the inherent variability in PPD skin test interpretation. Variations up to 2–5 mm can be seen when two experienced readers measure the same test result. The third is the booster phenomenon. Individuals with prior mycobacterial infection (including immunization with live bacille Calmette-Gue´rin [BCG] or prior asymptomatic infection with nontuberculous mycobacteria) may have a negative result or an insignificant area of induration on initial PPD testing. A second skin test administered within weeks of the first may demonstrate significant induration since the cellular immune response has been ‘‘boosted’’ by the first PPD. Of note, repeated PPD testing does not cause a positive TB test result in persons without prior mycobacterial infection. The second result of this two-step method can be used as a true baseline for comparison in the future, for example, for immunocompromised patients, elderly patients, or health care workers. Without such testing, an initial negative test result that is followed by a positive test result could be misinterpreted as a new conversion. Establishing a true baseline, with two tests for those who have not been tested in recent years, is a key component for interpreting annual tests. Target groups for two-step testing include persons from tuberculosis endemic countries, persons with prior BCG, and older persons. Figure 2 demonstrates how the booster phe-

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Figure 2 For each patient, one with remote TB infection occurring before two annual skin tests (patient 1) and one with TB infection occurring between two annual skin tests (patient 2), the figure shows the results of testing at 0 and 1 week versus testing at 0 week and 1 year. The third test of patient 1 at one year is included to help illustrate the booster effect (since the patient had been shown to be PPD-positive at 1 week, repeat testing would generally not be required). PPD, purified protein derivative; TB, tuberculosis.

nomenon can improve the interpretation of annual PPD testing and how two-step testing can help establish baseline reactivity. Because of the many variables involved in accurate identification of a PPD conversion, practitioners should be conservative about interpreting such results unless the subject is in a high-risk group for tuberculosis. 3.1.3

Chest Radiography

A small proportion of persons with latent tuberculosis have a small calcified granuloma in the lung parenchyma (Ghon focus), sometimes with associated hilar adenopathy and/or calcification (Ranke complex). Other findings may include apical or pleural scarring or calcification and areas of upper zone fibrosis (Simon foci). 3.2 3.2.1

Active Tuberculosis Disease Respiratory Tract Specimens

Testing of expectorated sputum is the most important and expeditious method of supporting and ultimately confirming the diagnosis of pulmonary tuberculosis (see Table 4). Three sputum samples collected on separate days should be sent for stain and culture. The clinician should confirm with the laboratory that each sample is adequate for testing. Several alternative diagnostic approaches are possible when the patient is unable to expectorate sputum or the sample is inadequate. Sputum induction should be attempted first. If this is unsuccessful and the clinical suspicion of tuberculosis remains high, bronchos-

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Table 4 Diagnostic Evaluation for Active Tuberculosis Diseasea HIV-negative (or unknown HIV status) Sputum ⫻ 3 for AFB stain, amplified DNA probe, and culture Chest radiograph PPD skin test HIV ELISA HIV-positive As above, plus Mycobacterial blood culture (lysis-centrifugation or automated) a

HIV, human immunodeficiency virus; AFB, acid-fast bacillus; DNA, deoxyribonucleic acid; PPD, purified protein derivative; ELISA, enzymelinked immunosorbent assay.

copy with bronchoalvelolar lavage should be performed. Transbronchial or percutaneous lung biopsy may be useful in selected cases. Sputum stains for AFB yield positive findings in approximately 40%–50% of patients with pulmonary tuberculosis. A positive AFB stain result supports a diagnosis of tuberculosis but does not confirm it since nontuberculous mycobacteria and some other bacteria (e.g., Nocardia species) may also be acid-fast. Specimens that are AFB-positive can be tested with one of two licensed and highly specific nucleic acid amplification (NAA) tests to determine whether the organism is MTB or another acid-fast organism. NAA testing is available at larger laboratories throughout the United States, and results should be available to the clinician within a few days. AFBnegative sputum samples can also be tested by using one licensed NAA test (Amplified Mycobacterium Tuberculosis Direct Test [MTD], Gen-Probe, San Diego, CA). A positive NAA test result on AFB-negative sputum is highly specific for tuberculosis, but a negative NAA test result on AFB-negative sputum does not exclude the diagnosis of tuberculosis. If a sputum is AFB-negative and NAA-positive, a presumptive diagnosis of tuberculosis is established, but repeat sputum evaluation should be done to confirm the NAA results. Approximately 70% of patients with pulmonary tuberculosis have a positive culture result for MTB. In laboratories that use conventional media, such growth typically occurs at 3 weeks but may take up to 8 weeks. Automated culture systems typically detect MTB in 2 weeks. Susceptibility testing should be performed routinely on all initial isolates of M. tuberculosis. Many AFB-positive, NAA-negative sputum samples from patients in the United States grow a NTM, most commonly organisms of the Mycobacterium avium complex (MAC). Growth of these organisms may be detected at least a week earlier than for MTB. 3.2.2

Sterile Site Culture

Blood cultures for mycobacteria should be obtained from patients with HIV infection, other immunosuppressed patients, and patients with suspected miliary tuberculosis. Special methods are used for mycobacterial blood cultures (e.g., automated, lysis-centrifugation) so the microbiology laboratory should be consulted before the culture is obtained. If focal extrapulmonary tuberculosis is suspected sterile site cultures may be obtained from urine, CSF, and other normally sterile sites (e.g., bone, liver). Polymerase chain reaction (PCR) testing should be considered for patients with suspected tuberculous meningitis, although the sensitivity of such testing is only 50% and test reliability has been shown to vary among laboratories.

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3.2.3

Chest Radiography

Primary disease due to M. tuberculosis may be associated with hilar adenopathy and/or pleural effusion as well as with acute infiltrates. Reactivation disease typically produces infiltrates in the upper lobes or superior segments of the lower lobes. Signs of prior tuberculosis may be evident (see Section 3.1.3). Cavities may also be seen and are typically thin-walled without an associated air fluid level. Miliary tuberculosis usually involves the lung, where the pattern of multiple ‘‘millet seeds’’ produces a diffuse reticulonodular infiltrate.

3.2.4

Other Studies

Chest computer assisted tomography (CT) scans may be used to delineate pulmonary lesions associated with tuberculosis further but are not required for the diagnosis in most cases. CT scans may be useful in distinguishing NTM pulmonary disease from tuberculosis since small nodules (<5 mm) and widespread cylindrical bronchiectasis are more common with Mycobacterium avium complex disease than with tuberculosis. Tissue biopsy may be useful in the diagnosis of pleural tuberculosis, miliary tuberculosis (lung, liver, or bone marrow biopsy), gastrointestinal tuberculosis (small bowel biopsy), Pott’s disease, and meningeal tuberculosis. Both histological evaluation and culture should be performed. PCR of the spinal fluid yields a positive finding in approximately 50% of patients with tuberculosis meningitis and results are typically specific.

DIAGNOSIS AND TREATMENTa Diagnosis Figure 1 Targeted PPD skin testing (Table 3) Importance of recording actual measurement of PPD induration False-negative PPD result possible in elderly, immune suppressed, and malnourished patients False positive result possible in low-risk populations with PPD < 15 mm Interpretation of sequential PPD tests (Figure 2) Booster effect vs. conversion Active TB (Table 4) Treatment Latent TB (Table 5) Active TB (Table 6) Specialty consultation recommended Monthly follow-up Toxicity (Table 6) Response to therapy Importance of compliance: Directly observed therapy a

PPD, purified protein derivative; TB, tuberculosis.

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TREATMENT

4.1

Latent Tuberculosis Infection

Treatment of latent tuberculosis with a one- or two-drug regimen is highly effective in reducing the risk of reactivation tuberculosis (Table 5). Among the four regimens that are currently recommended, the 9-month INH regimen is supported by the best evidence and is the preferred regimen for most patients. Baseline liver biochemical values should be obtained in patients with known or suspected liver disease (e.g., hepatitis B or C virus, alcoholic liver disease), HIV infection, and pregnancy. All patients should be seen monthly to assess compliance and drug side effects. 4.2

Active, Drug Sensitive Tuberculosis Disease

Standard treatment for pulmonary tuberculosis in adults in the United States consists of 6 months of multiple-drug therapy. Multiple drugs are required for two principal reasons: (1) to reduce the likelihood of treatment failure resulting from drug resistance and (2) to inactivate or kill M. tuberculosis in different metabolic states in both intracellular and extracellular environments. As shown in Table 6, most patients should be treated with four drugs for 2 months followed by two drugs for 4 months (6 months total). Initial treatment with only three drugs may be appropriate in selected cases in communities and risk groups with a known low (<4%) rate of TB drug resistance; case by case decisions should be made with a consultant experienced in mycobacterial disease. Compliance with a multiple-drug regimen is critical to the successful outcome of therapy and the prevention of drug resistance. Thus, directly observed therapy (DOT) is generally recommended. With DOT, the patient must be observed by a health care worker as he or she takes each daily dose of medication. State or local health agencies are often able to assist with personnel for home visits or DOT clinics. To reduce the supervisory demands of DOT, twice-weekly regimens may be substituted for traditional daily regimens. An example of such a regimen is isoniazid (INH), rifampin, pyrazinamide, and ethambutol (as in Table 6) daily for 2 weeks followed by the same medications twice per week, though the dose of INH should be increased to 15 mg/kg and pyrazinamide 3–4 g, depending on the weight of the patient.

Table 5 Treatment of Latent Infection with Mycobacterium tuberculosisa Regimen

Dose and duration

Comments b

Isoniazid Isoniazid

300 mg/day ⫻ 9 mo 300 mg/day ⫻ 6 mo

Rifampin and pyrazinamide

600 mg/day ⫻ 2 mo 20 mg/kg ⫻ 2 mo (2 g/day max)

Rifampin

600 mg/day ⫻ 4 mo

Most effective INH duration (use in HIV) More cost-effective than 9 mo of INH but slightly less effective (thus, avoid in HIV-positive cases) Shortest regimen, but fatal hepatitis reported; avoid if any risk factors for liver disease; dispense only 2 week supply at a time; use for contacts of patients with INH-resistant, rifampin-sensitive tuberculosis Third option for patients intolerant of INH or pyrazinamide

a b

Twice-weekly regimens are also available and are most useful in persons for whom DOT is considered advisable. INH, isonicotinic acid hydrazide; HIV, human immunodeficiency virus.

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Table 6 Treatment of Pulmonary Tuberculosis in Adultsa Antimicrobial

Daily dose (oral)

Durationb

Major side effects Hepatitis Neuropathy Hepatitis Allergy/rash Gastrointestinal side effects Drug interactions Hepatitis Rash Arthralgias Gastrointestinal side effects Retinitis

Isoniazid

300 mg

6 Months

Rifampin

600 mg

6 Months

Pyrazinamide

20 mg/kg

2 Months

Ethambutol

15 mg/kg

2 Months

a b

Standard four-drug treatment for drug-sensitive tuberculosis in the United States. This 6-month regimen is standard treatment for drug-sensitive tuberculosis and some forms of extrapulmonary tuberculosis in adults. Twelve months of therapy is recommended for miliary, meningeal, bone, or joint disease.

If formal DOT is not provided, the treating physician should take responsibility for close monitoring of compliance and assessment of side effects. Baseline liver biochemical values should be obtained on all patients. The most common side effects of the four drugs should be regularly reviewed with the patient (Table 6). Patients should be warned that rifampin can turn stool, urine, and tears orange and can stain soft contact lenses. Response to treatment is assessed by repeat sputum cultures at monthly intervals and by follow-up chest radiographs. Drug sensitivities are generally available by 6 or 8 weeks of treatment and should be reviewed for each of the four drugs in the regimen. Patients with resistance to any of the four standard drugs should be referred to a specialist in tuberculosis for further treatment recommendations. For patients with positive culture findings at the outset of treatment and with drug-sensitive organisms, at least 85% should have negative culture results at 2 months. Patients with positive culture results at 4–6 months are defined as treatment failures. Culture-negative patients are best assessed by follow-up chest radiographs; which should show improvement by 3 months. 4.3

Active Drug-Resistant Tuberculosis Disease

For patients with active tuberculosis due to organisms resistant to one or more drugs, therapy must be modified. Among U.S.-born patients, single-drug resistance to isoniazid has been detected in approximately 6% of those with no prior TB and 11% of those with prior TB. Among foreign-born patients, single-drug resistance to isoniazid has been detected in approximately 12% of those with no prior TB and 25% of those with prior TB. When isoniazid resistance is documented, isoniazid should be discontinued and pyrazinamide continued for the entire 6-month regimen. Therapy for other single-drug resistance is more complex. Multiple-drug resistance (MDR) tuberculosis is defined as resistance to at least isoniazid and rifampin. Among U.S.-born patients, MDR tuberculosis has been detected in 2% of those with no prior TB and 4% of those with prior TB. Among foreign-born patients, MDR tuberculosis has been detected in 2% of those with no prior TB and 11% of those with prior TB. These patients must be treated with DOT and with at least three new drugs to which the organism is sensitive. Treatment duration should either be 24 months total

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or 12 months after sputum conversion to negative. A tuberculosis expert should be consulted for these complex patients. 5 5.1

PREVENTION Isolation

Most transmission of tuberculosis occurs prior to confirmation of the diagnosis in the index case. Patients admitted to the hospital with suspected or confirmed pulmonary tuberculosis should be placed on tuberculosis respiratory isolation in a negative-pressure room. An Occupational Safety Health Administration– (OSHA)-approved respiratory device should be used by all persons who enter the room. For drug-sensitive disease, isolation can generally be discontinued after 2 weeks of multiple-drug therapy (even if AFB smear results are still positive). Patients with three negative sputum AFB smear results can also be considered noninfectious. 5.2

Contact Tracing

Household and other close contacts of patients with tuberculosis disease should be located with the assistance of the local health department and skin-tested with PPD. Conversion of the PPD skin test after new infection may take several weeks, so testing of contacts should be performed when the index case is diagnosed and again 8–12 weeks later to exclude transmission. A 5-mm cutoff should be used to define a positive PPD finding in a contact. Children less than 4 years of age who are household contacts of TB cases should be started on one-drug treatment for latent TB regardless of initial skin test result; treatment can be discontinued if the PPD results remain negative at 3 months. Health care workers with respiratory contact with an infectious patient before institution of isolation should also have PPD skin testing performed. PPD skin test conversion (10-mm increase in PPD size within 2 years) results should be treated for latent tuberculosis after active tuberculosis has been excluded. 5.3

Bacille Calmette-Gue´rin Vaccine

BCG is a live vaccine against tuberculosis administered at birth to most children in the world. A vaccine site scar persists over the deltoid, forearm, or hip in most adults. BCG is not routinely indicated for persons living in the United States but should be considered for healthy persons at high risk of TB exposure such as TB laboratory personnel in the United States and medical relief workers who plan to spend a month or more delivering direct care in a country where tuberculosis is endemic. There is considerable resistance to the use of BCG in the United States because the vaccine is associated with a local inflammatory response that persists for several weeks and causes a false-positive PPD skin test (>10 mm) result for several years after administration. These minor disadvantages should not deter use of BCG in the high-risk groups mentioned. BCG is not available in the U.S. for the prevention of tuberculosis but can be obtained in Canada and should be administered 2 months or more before the anticipated high-risk exposure. BCG is contraindicated in persons with immunosuppression and in those with cellular immune deficiency, especially HIV infection, because of the risk of vaccine strain disease. ACKNOWLEDGMENT The author wishes to thank Eero Tala and C. Robert Horsburgh for comments on the manuscript.

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BIBLIOGRAPHY American Thoracic Society. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 161:S221–S247, 2000. American Thoracic Society and Centers for Disease Control and Prevention. Diagnostic standards and classification of tuberculosis in adults and children. Am J Respir Crit Care Med 161: 1376–1395, 2000. Bass JB, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, Snider DE, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 149:1359–1374, 1994. Horsburgh CR, Feldman S, Rizdon R. Practice guidelines for the treatment of tuberculosis. Clin Infect Dis 31:633–639, 2000. Iseman MD. A Clinician’s Guide to Tuberculosis. Philadelphia: Lippincott, Williams & Wilkins, 2000. Jones BE, Young SMM, Antoniskis D, Davidson PT, Kramer F, Barnes PF. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148:1292–1297, 1993. Miller LG, Asch SM, Yu EI, Knowles L, Gelberg L, Davidson P. A population based survey of tuberculosis symptoms: how atypical are atypical presentations? Clin Infect Dis 30:293–299, 2000. Snider GL. Tuberculosis then and now: A personal perspective on the last 50 years. Ann Intern Med 126:237–243, 1997. Talbot EA, Moore M, McCray E, Binkin NJ. Tuberculosis among foreign-born persons in the United States, 1993–1998. JAMA 284:2894–2900, 2000. von Reyn CF, Williams D, Horsburgh CR, Jaeger AS, Marsh BJ, Haslov K, Magnusson M. Dual skin testing with Mycobacterium avium sensitin and purified protein derivative to discriminate pulmonary disease due to M. avium complex from pulmonary disease due to Mycobacterium tuberculosis. J Infect Dis 177:730–736, 1998.

14 Common Cold and Influenza Sherif B. Mossad Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

1 1.1

COMMON COLD Introduction

The nasal congestion, sneezing, and scratchy throat of the common cold are well known to us all. Although the cold is a well recognized as a single clinical entity, there are hundreds of different viral pathogens responsible. It is this large number of pathogens and perhaps limited protective immunity that account for the frequent recurrence of these infections. They are the most common reason for physician visits in the United States and contribute greatly to missed work and school. The resultant absenteeism and disruption of family schedules have substantial financial and social consequences. In addition, adults may lose workdays when they have to stay home with sick children. Less commonly, colds may be complicated by more serious bacterial superinfections, including sinusitis, otitis media, and bronchitis, or exacerbate underlying medical conditions such as congestive heart failure and chronic obstructive pulmonary disease. The common cold is also the most common cause of antibiotic misuse. 1.2

Epidemiological Characteristics

Since the common cold is usually a self-limited illness, the exact number of infections that occur yearly is not known. Most healthy adults suffer two to four colds per year; children may suffer up to six to eight colds per year. There are no data to suggest that immunocompromised patients suffer more colds, but they do suffer more of the resultant COMMON COLD Rhinitis, nasal congestion, sneezing, sore throat Viral cause most common (Table 1) Need to exclude S. pyogenes pharyngitis, allergic rhinitis, and, if symptoms severe, influenza and bacterial sinusitis Antibiotics not indicated Treatment symptomatic (Table 2)

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complications. The exact mechanism of transmission of the causative agents is not clear. Most likely the viruses are transmitted through inhalation of aerosolized droplet nuclei or larger particulate matter from the infected person. Transmission of virus may occur by direct close contact (hand or environment) of infectious secretions. Most colds occur during the fall and winter months; the same seasonal increase is seen for influenza. The reasons for this peak in seasonal incidence likely include closer indoor quarters, more contact of children during school hours, and lower relative humidity during cold weather, which may enhance survival of enveloped viruses. 1.3

Causative Organisms

Large epidemiological studies conducted in the 1960s showed that viruses are the causative agents in most cases of the common cold. Most colds are caused by one of five viral families (see Table 1). Rhinoviruses account for approximately 50% of colds. The major obstacle to the development of a specific therapy and an adequate vaccine for rhinovirus infections is that over 100 antigenic serotypes must be included in such an endeavor. In addition, reinfection with the same virus type is not uncommon. Rhinoviruses are predominant in the early autumn and spring. Other viruses account for approximately 20% of colds. These include coronavirus; parainfluenza viruses 1, 2, and 3; influenza viruses A, B, and C; adenovirus; respiratory syncytial virus; and enteroviruses. Most of these viruses are more common in the colder months, with the exception of enterovirus, which occurs predominantly in the summer months. Other yet unidentified viruses are believed to be the causative agents in 30% of cases. Rarely do bacteria, such as Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, and Chlamydia pneumoniae, cause coldlike illnesses. 1.4

Clinical Illness

The onset of a cold usually begins after an incubation of 12–72 hours. The characteristic constellation of symptoms, including nasal drainage and congestion, sore throat, sneezing,

Table 1 Causes of the Common Cold Viral family

Specific viruses

Colds, % 40–50

Orthomyxoviridae

Rhinovirus Enterovirus Coronavirus Parainfluenza 1, 2, 3 Respiratory syncytial virus Influenza A, B, and C

Adenoviridae

Adenovirus

3–5

Bacteria

S. pyogenes

5

Picornaviridae Coronaviridae Paramyxoviridae

Unknown

10 10–15 5–10 5–10

20–25

Comment Most common

Can cause upper and lower respiratory tract symptoms Upper and lower respiratory tract symptoms Can be more severe with fever, pharyngeal erythema, and conjunctivitis Diagnosis by culture or rapid Streptococcus sp. screen

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headache, and low-grade fever, is sufficient for diagnosis. On examination, the pharyngeal and nasal mucosa may be erythematous, but the physical findings are frequently less impressive than the presenting symptoms. The alae nasi may become macerated from severe rhinorrhea and a nasal tone of voice may develop with nasal obstruction. Conjunctivitis is not a feature of the common cold except in cases caused by adenovirus. The average duration of a cold is about 1 week, but a small proportion of patients may have an illness lasting up to 2 weeks. Adenovirus may cause a more severe cold with fever, increased pharyngeal erythema, and occasionally bronchitis. The diagnosis of the common cold is a clinical one. Viral cultures, nucleic acid probes, polymerase chain reaction, and serological diagnosis have no place in clinical practice. Bacterial cultures to detect superimposed infections occurring as a complication of colds are indicated when conditions such as sinusitis or otitis media are clinically suspected. 1.5

Differential Diagnosis

Streptococcal pharyngitis is a common and eminently treatable infection that should be differentiated from common cold. These patients are more likely to have fever, pharyngeal exudate, and enlarged, tender cervical lymph nodes. However, in many cases, it may be impossible to sort out these two conditions without microbiological investigation. For patients with sore throat or pharyngeal exudate predominating their clinical picture or pharyngeal exudate, a culture or rapid antigen test to detect GABHS is appropriate (see Chapter 10). Allergic rhinitis, in addition to the nasal symptoms, is usually accompanied by itchy eyes or excessive lacrimation. It is often exacerbated in certain seasons, or after certain exposures. A personal or family history of atopy may be present. Influenza is usually a more severe illness, with higher temperatures and more systemic symptoms such as malaise and myalgias. Occasionally a milder case of influenza may be mistaken for a rhinovirus-like cold. Paranasal sinusitis should be thought of when a cold lasts more than 2 weeks and is accompanied by headache and purulent nasal or postnasal drainage. 1.6

Treatment

When patients seek medical attention for what is most likely a common cold, health care providers should emphasize education. Distinction from illnesses that would need different treatments (S. pyogenes pharyngitis, allergic rhinitis, influenza, bacterial sinusitis, and otitis media) should be reviewed. The proper use of over-the-counter (OTC) medication, if any is indicated, should be explained. There is a plethora of OTC products available for the treatment of the common cold. Many of these products are combinations of several drugs. Their active ingredients can be grouped into four major categories: symptomatic measures, pharmacological blockers, specific antiviral agents, and other miscellaneous agents (see Table 2). It is safe to say that none of the available agents has proved to be the long awaited ‘‘cure for the common cold.’’ 1.6.1

Symptomatic Measures

␣-Adrenergic Agonists. Traditionally known as decongestants, the ␣-adrenergic agents exert their vasoconstricitive action by their sympathomimetic effects on intranasal blood vessels. They are especially useful early on in the illness when rhinorrhea is most

? Efficacy, good safety record ? Efficacy

2–4 g/day, May reduce symptoms, diarrhea ? Efficacy, nausea, altered taste, ? lipid alteration ? Efficacy, anaphylaxis in patients with atopy Overuse, antimicrobial resistance Systemic side effects Cosmetically unappealing, systemic toxicity if ingested

Fever, myalgia, pain Sore throat Histamine block Stopping of viral replication

Antioxidant

NSAIDs Steam inhalation Pharmacolgical blockers Mast cell stabilizers

a

? Action Bacterial infection Antiinflammatory ? Prevention of transmission

Echinacea

Antibiotics Glucocorticoids Aqueous iodine

NSAIDs, nonsteroidal antiinflammatory drugs; ICAM-1, intracellular adhesion molecule 1; GI, gastrointestinal.

? Blocking of ICAM-1

Zinc

Antiviral agents Tremacamra Pleconaril Interferon Vitamin C

GI irritation and bleeding ? Efficacy

Drying nasal secretions Cough suppression, secretion removal

Antihistamines Antitussives and expectorants

Topical, excess drying, high blood pressure exacerbation Drowsiness, ? effect Sedating, can cause constipation

Drying nasal secretions

Anticholinergics

Topical and oral, excess drying, high blood pressure exacerbation

Comments

Drying nasal secretions

Desired effect

␣-Adrenergic agonists (decongestants)

Symptomatic relief

Table 2 Therapy for the Common Colda

Cold Eeez

Cromolyn sodium nedocromil sodium None FDA approved

Phenylephrine, oxymetazoline, pseudoephedrine Ipratropium bromide, atropine methonitrate Chlorpheniramine Dextromothorphan, codeine, hydrocodone Guaifenesin Ibuprofen Camphor, menthol

Examples

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prominent. Excessive application of these agents may cause nasal dryness and a rebound phenomenon known as rhinitis medicamentosa after their discontinuation. Most package inserts of these agents warn patients receiving antihypertensive medications of the potential for worsening of hypertension during their use. They are available in both oral and intranasal formulations. Phenylephrine (Neo-Synephrine), oxymetazoline (Afrin), and pseudoephedrine (Sudafed) are widely used examples. They are also effective in treating other causes of increased nasal drainage. Anticholinergics. The anticholinergic compounds exert their effect through their parasympatholytic activity. They are mainly applied locally intranasally for the same purpose as ␣-adrenergic agonists and have similar side effects. Agents such as ipratropium bromide (Atrovent) and atropine methonitrate are effective but have short half-lives, making frequent applications necessary. Antihistamines. Frequently used for the treatment of nasal allergies of various causes, the antihistamine agents have been extensively studied for the treatment of the common cold. However, the pathophysiological rationale for their use in this illness is controversial. The sedating effect of first-generation antihistamines, such as chlorpheniramine (Alka-Seltzer Plus) and clemastine fumarate (Tavist-1), may actually be of value when taken at bedtime to help ill people fall asleep. Sedation is obviously a hazard for people driving cars or operating any type of heavy machinery. Second-generation antihistamines, such as fexofenadine (Allegra) and cetrizine (Zyrtec), are selective for blocking H1 receptors and thus are much less sedating. However, their anticholinergic activity is also less potent than that of the first-generation agents. Antitussives and Expectorants. Dextromothoraphan (Contac, Smithkline Beecham), codeine, and hydrocodone are examples of antitussives. Guaifenesin (Triaminic, Novartis) is used as an expectorant. Both types of drugs are frequently included in many combinations of cold remedies. ␤-Agonists, such as albuterol (Proventil, Schering-Plough), have been shown to decrease the duration of cough during acute bronchitis. Controlled studies have not shown an overall large benefit from these drugs in the common cold. Nonsteroidal Antiinflammatory Drugs. Symptomatic relief of headache, malaise, and fever can be attained by using any of the nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen (Motrin), because of their antiprostaglandin effects. Some studies have raised the concern that these agents may prolong viral shedding, though other studies have not confirmed these findings. Gastrointestinal irritation associated with these agents is usually mild if used only for the duration of the cold and in moderate doses. Steam Inhalation. A soothing effect on the irritated nasopharynx may be expected from inhaling heated vapor. However, studies have so far been controversial. Agents such as camphor (Vicks Vaposteam) and menthol (Cepacol) have been used in various concentrations for the temporary relief of sore throat, cough, and nasal congestion. This is a relatively benign intervention but further studies are needed to confirm its benefits. 1.6.2

Pharmacological Blockers

Mast Cell Stabilizers. Agents such as cromolyn sodium (Gastrocrom) and nedocromil sodium (Tilade) are effective in preventing asthma attacks because they prevent release of histamine and other chemical mediators of inflammation. Large trials utilizing these agents for treatment of colds have not been conducted, but preliminary studies suggested they may be effective. If an effect is proved, they may be a very appealing option, given their excellent safety profile.

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1.6.3

Mossad

Antiviral Agents

The main obstacle in developing a specific therapy for the common cold is the wide variety of offending viruses. In addition, any self-limited illness such as a cold should be treated with a very safe and easy to administer drug. Several compounds have been studied over the years, none of which has been proved to be clinically effective. Tremacamra, a soluble intracellular adhesion molecule 1 (ICAM-1), has been shown to reduce the severity of experimentally induced rhinovirus colds, but the clinical effectiveness of this compound has not been shown yet. Pleconaril, a viral capsid inhibitor with activity against both enteroviruses and rhinoviruses, has also been shown in one large study to shorten the symptoms of naturally acquired colds by 1 to 2 days. Neither of these compounds is currently available on the market. Interferon is a powerful antiviral drug with established efficacy in other viral infections including hepatitis B and C. Its efficacy in the prevention or treatment of the common cold has not been established. Administered to volunteers prior to the onset of symptoms in experimental rhinovirus infection models, it has had some success. Intranasal administration has been associated with nasal dryness and bleeding. 1.6.4

Other Agents

Vitamin C. Controversy surrounding the value of vitamin C for treatment of the common cold continues. Its effect is thought to be due to its antioxidant activities in activated leukocytes. A recent review of the literature suggested that the optimal dose may be 1–4 g/day. However, the maximal recommended daily intake for healthy adults is 2 g/day. Doses in excess of 4 g/day have been associated with diarrhea. Studies of patients with the common cold, though, have shown that doses up to 30 g/day have been well tolerated for at least the few days of the illness. The average benefit in all studies using 2–4 g/day has been a decrement of about 30% in the severity of illness. Zinc Salts. Similarly, studies using zinc salts (Cold Eeez) for the treatment of the common cold have shown different benefits, or lack thereof, depending on the formulation and dose utilized. Doses well above the minimal daily requirements are needed to show any effect and the benefit is seen mainly when started within 24 hours of the onset of illness. The mechanism of action is unclear, but blockage of ICAM-1 is thought to be an important factor. Side effects include nausea and altered mouth taste. Long-term safety has not been established; altered lipid metabolism, immunological responses, and copper deficiency are possible concerns. Echinacea. Clinical trials using echinacea have varied in clinical design and the formulation of echinacea used. Therefore, the claims of some studies that echinacea may be useful for treatment of colds need to be viewed cautiously. Currently no recommendation can be given regarding its use. Unfortunately, large studies may never be done because echinacea is not patentable nor U.S. Food and Drug Administration (FDA)-regulated. Producers may not take on the risk or expense of performing well-designed clinical trials. Moreover, reports of anaphylaxis from echinacea in patients with history of atopy have raised concern about using it in such patients. Antibiotics. Even though almost all colds are not caused by bacteria, antibiotics continue to be prescribed for this illness. About one-fifth of all antibiotic prescriptions given for adults in the United States are for upper respiratory tract infections. A subset of patients with colds who harbor Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the oropharynx may benefit from antibiotics, but there is no easy

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way to identify these patients on clinical grounds. With the widespread problem of antimicrobial resistance and their potential side effects, antibiotics should not be recommended for patients with uncomplicated colds. Surveys of patients who consulted their family physician for colds suggest that their satisfaction did not depend on receiving a prescription for treating their illness. Glucocorticoids. Despite their antiinflammatory properties, glucocorticoids have not been shown to be of value in the treatment of colds. They are associated with considerable systemic side effects and should not be used for the treatment of such benign illness. Aqueous Iodine. Aqueous iodine may prevent transmission of viruses on the hands of patients with colds. However, it is cosmetically unsightly and may be associated with systemic toxicity if ingested. 1.7

Advice on Management

Educating patients about their illness, its natural course and potential complications, as well as the benefits and limitations of the various treatment modalities for the common cold, is extremely important. Excluding GABHS pharyngitis when clinically suspected is reasonable. Symptomatic measures including bed rest and fluids can be advised as needed. ␣-Adrenergic agonists, anticholinergics, and antihistamines are useful during the initial stages of illness, when rhinorrhea is common. Antitussives and expectorants are expected to be of value later on when cough may be a prominent symptom. Analgesics and NSAIDs are effective for headaches, fevers, and body aches. Inhalation of steam is a simple measure that may help soothe a sore throat. Vitamin C supplements in doses ranging from 2 to 4 g/day and zinc salts taken within 24 hours of the onset of illness may be considered. Limited data supporting their efficacy need to be weighed against the toxicities of these agents. Long-term administration of either of these agents should not be recommended at this time without further research regarding their safety and long-term benefits. 2 2.1

INFLUENZA Introduction

Influenza is a systemic viral infection characterized by the sudden onset of fever, myalgia, and cough. Although generally self-limited in younger healthy persons, it is associated with significant morbidity and mortality rates in the elderly and debilitated populations. Influenza epidemics (regional or countrywide outbreaks) occur annually between the months of November and March in the Northern Hemisphere and between May and SepINFLUENZA Epidemic and seasonal incidence Sudden onset of fever, myalgia, and cough Complications in high-risk groups (Table 3) Diagnosis clinical; confirmation by viral culture or antigen detection Symptomatic treatment (Table 2) Antiviral agents effective for prophylaxis and therapy (Table 4) Vaccination of paramount importance (Table 5)

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tember in the Southern Hemisphere. Three worldwide outbreaks of more virulent mutated viral strains occurred in the 20th century (1918, 1957, and 1968). These pandemics claimed the lives of more than 21 million people. Each year in the United States, 20,000 to 40,000 people die as a result of influenza and pneumonia complications, making influenza and pneumonia the sixth leading causes of death in this country and the most common cause of death due to infection. Two to 4 million people in the United States are infected with influenza annually, causing approximately 300,000 hospitalizations. Almost one-third of wintertime hospitalizations in children are related to influenza. Most epidemics are thought to spread from schoolchildren to their families. The economic impact resulting from lost workdays and medical care is estimated to be $12 million yearly. It is projected that the next pandemic will cost the United States $70 to $160 billion. 2.2

Cause and Pathogenesis

Influenza is an enveloped virus of the Orthomyxoviridae family with a single ribonucleic acid (RNA) strand for its genetic core. There are three types of influenza, referred to as A, B, and C. Influenza virus has two surface glycoproteins protruding through the lipid envelope: the hemagglutinin (HA) and neuraminidase (NA). There are 15 HA and 9 NA subtypes for influenza A but only 1 of each for influenza B. The viral HA binds to sialic acid on the surface of respiratory epithelial cells, allowing viral entry and replication in the infected cell. Through action of the viral NA, newly generated virus is cleaved from epithelial sialic acid, allowing viral release. These progeny viruses then go on to infect other respiratory epithelial cells. An internal or matrix protein, M1, serves as a skeleton for the virus, providing its stability. A second type of surface protein, M2, is responsible for early viral replication. Nomenclature of influenza viruses depends on the virus subtype, its geographic origin, the strain sequence number, and the year of isolation. For example, A(H1N1)/Sydney/5/93 is an influenza A virus discovered in Sydney, Australia, in 1993 that has a type 1 HA and a type 1 NA and given the strain sequence number 5. Both the NA and HA can undergo genetic changes that result in alterations of the amino acid (antigen) sequences. Small changes (altering the amino acid by <1%) are referred to as antigenic drifts; major changes are antigenic shifts. Annual epidemics occur as a result of antigenic drift, which is a slow process affecting both influenza A and B. Pandemics, on the other hand, are caused by antigenic shift, which produces a major change in the viral antigenic composition. The change in glycoprotein structure allows the virus to evade immunological protection built up from previous native infections or immunizations, allowing more severe clinical illness. The larger the change (for example, from influenza A H3N2 to influenza A H1N1), the larger percentage of the population will not be immune and the greater the risk for a more severe global pandemic infection. The epidemic or pandemic spread results from transmission of a new influenza virus from other species, such as birds (commonly passing through other intermediate hosts such as pigs), followed by either genetic reassortment with circulating human influenza viruses or direct transmission to humans. Recently a new strain of virus (H5N1) was transmitted from birds to people in Hong Kong, causing clinical illness. Fortunately there was no documented person-to-person spread. Most influenza epidemics in the 20th century were due to influenza A but a few were due to influenza B. The former usually causes more severe illness and can infect humans as well as birds, swine, and other mammals. All three pandemics in the 20th century were caused by influenza A. In contrast, infection with influenza C virus is commonly asymptomatic or causes a very mild illness. There is not the characteristic seasonality seen with influenza A or B.

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Transmission is by small particle aerosol from an infected person. After an incubation of 1–2 days, clinical illness sets in. Viral shedding from the infected person peaks within 2 to 3 days of infection but may last for 1 week or more. The resultant virally induced cell injury of respiratory epithelium leads to inflammation of the larynx, trachea, bronchi, and occasionally alveoli. 2.3

Clinical Manifestations

Influenza appears suddenly with headache, myalgia, dry cough, and fever and is commonly accompanied by chills, rigors, and sweats. Headaches are diffuse, and throbbing and myalgias can be incapacitating. Sore throat and rhinorrhea may occur but are usually not prominent during the initial stages of illness. Some patients may complain of substernal pain due to an accompanying tracheitis. On exam, the patient is ill appearing with pharyngeal erythema and occasionally scattered rhonchi or rales. The elderly may experience confusion and somnolence. Convalescence may take 2 to 3 weeks. In contrast, common colds are usually more gradual in onset, fevers are uncommon or low-grade, and myalgias are mild or absent. Rhinorrhea and sore throat predominate. Symptoms rarely last more than 1 week. Complications of influenza can be severe and account for the increased wintertime mortality rate due to influenza and pneumonia (see Table 3). Those at most risk for these complications include patients with cardiovascular and chronic pulmonary disease, diabetes, renal insufficiency, hemoglobinopathies, and immune compromised states. Complications can include sinusitis, bronchitis, otitis media, and pneumonia, either primary viral or secondary bacterial. Primary viral pneumonia directly follows the acute febrile phase of influenza, manifested by increasing cough and shortness of breath. The chest radiograph shows diffuse bilateral adult respiratory disease syndrome–like abnormalities and a leu-

Table 3 Increased Morbidity and Mortality Rates of Influenza Risk patients Cardiovascular disease Chronic pulmonary disease Renal insufficiency Diabetes Hemoglobinopathies Immunocompromised Complications Exacerbations of asthma, chronic bronchitis, and congestive heart failure Otitis media, sinusitis Viral pneumonia Bacterial superinfection Myositis Myocarditis and pericarditis Toxic shock–like illness Reye’s syndrome Guillain-Barre´ syndrome Transverse myelitis, encephalitis

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kocytosis is present. The mortality rate is high. In contrast, secondary bacterial superinfection appears in a biphasic manner. Initially the influenza symptoms clear. Bacterial pneumonia, usually from Streptococcus pneumoniae, Haemophilus influenzae, or Staphylococcus aureus, follows after several days to weeks with recurrence of fever and cough. The chest radiograph generally shows focal consolidation. Prognosis is better than for primary influenza pneumonia. Systemic complications include myopericarditis and myositis; exacerbation of chronic bronchitis, asthma, and congestive heart failure; a toxic shock–like illness; myelitis; encephalitis; and Reye’s syndrome. The latter syndrome is an encephalopathy seen in children who are on long-term aspirin therapy. 2.4

Diagnosis

The diagnosis of influenza can be made clinically or serologically or by viral identification. Specific diagnosis of influenza is important when considering antiviral therapy. It is also important epidemiologically to identify the type of influenza virus prevalent in the community for future vaccine preparation. When surveillance data confirm the presence of influenza in a community, the constellation of fever, myalgia, and dry cough is 85% accurate in predicting the diagnosis of influenza. Viral culture is accurate but expensive and time-consuming. Viral growth usually takes 3–7 days. Use of the shell vial technique can speed up detection time to 1–2 days. Several rapid diagnostic tests have been developed, including direct fluorescent antigen detection, enzyme immunoassay, and optical immunoassay. These are less costly (between $15 and $20) and have a rapid turn-around time (between 15 and 30 minutes). Depending on type of sample (nasal wash is better than throat swab), the sensitivity and specificity can vary from 60% to 90%. These rapid tests do not differentiate influenza A from B; the distinction may have important therapeutic implications. Serological diagnosis is not useful in office practice. 2.5

Treatment

Symptomatic measures similar to those used for the common cold have been the mainstay of treatment for influenza for years (Table 2). Four agents that have been shown to shorten clinical illness and reduce viral shedding have been released (see Table 4). In the 1960s, amantadine, a drug used for the treatment of parkinsonism, was found to be effective in shortening the duration of influenza A. It reduced symptoms by 1 to 2 days in 70% to 90% of cases if started within 48 hours of the onset of illness. Unfortunately, amantadine has been associated with significant central nervous system (CNS) side effects, drug interactions, and rapid development of viral resistance in up to 30% of patients. In the early 1990s, rimantadine was found to be as effective as amantadine and to have fewer side effects. Viral cross-resistance with amantadine did occur. Both of these agents block the M2 envelope protein, thus interfering with early viral replication. In 1999, two agents that block the action of viral NA, zanamivir and oseltamivir, were FDA approved. Both are sialic acid analogs that interfere with the action of the NA, blocking viral release from infected respiratory epithelial cells. They have been found to be as effective as amantadine and rimantadine but have three main advantages: activity against both influenza A and B, fewer side effects, and much lower potential for inducing viral resistance. Fortunately, both amantadine- and rimantadine-resistant influenza strains remain susceptible to the neuraminidase inhibitors (NAIs). In most studies, these NAIs were associated with reduction in the amount and duration of viral shedding and in intranasal cytokine levels, which are responsible for the systemic symptoms of influenza.

b

a

Rimantadine (Flumadine) Zanamivir (Relenza)

Oseltamivir (Tamiflu)

$3.50

Tablets and syrup $9.15

Inhaled powder $50.40

Tablets and suspension $63.10

Block M2 ion channels, prevent HA cleavage, block Inhibit viral NA, prevent sialic acid cleavage from HA, trap RNA encoding, inhibit early viral replication virus inside cells, prevent epithelial spread Influenza A only Influenza A and B Good Poor Good 67% 40% None Minimal None Hepatic None Hepatic Renal (not removed by hemodialysis) Renal and stool Renal None (so far) ⇑ CNS toxicity: antihistamines, ⇓ peak levels: ASA and acetaminophen anticholinergics, CNS ⇓ renal clearance: stimulants cimetidine ⇓ renal clearance: TMP-SMX, triamterene, HCTZ, quinine, and quinidine CNS (5%–30%): drowsiness, CNS (<6%) Bronchospasm in patients Nausea and vomiting (8%– confusion, seizures with reactive airway 14%); ⇓ when taken with GI upset disease food Category C, i.e., administer only if benefits outweigh risks to the fetus 200 mg/day, or 100 mg bid 10 mg bid via a 75 mg bid diskhaler; requires motor coordination Yes No Yes

Amantadine (Symmetrel)

RNA, ribonucleic acid; CNS, central nervous system; TMP-SMX, trimethoprim and sulfamethoxazole; HCTZ, hydrochlorothiazide; ASA, acetylsalicylic acid. Cost based on actual wholesale price as listed in 2002 Drug Topics Red Book.

Dose adjustment >65 years and in renal dysfunction Formulation Cost (5-day course)b

Safety in pregnancy Dose in adults

Side effects

Spectrum Oral bioavailability Plasma protein binding Metabolism Excretion Drug interactions

Mechanism of action

Drug (trade name)

Table 4 Antiviral Agents for Treatment and Prevention of Influenza in 2000a

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Several other clinically significant benefits were found in these studies, including reduction in the number of nights of disturbed sleep, reduced need for symptomatic relief medications, decreased time to return to normal activities, and reduced bacterial complications such as otitis media and sinusitis. Viral resistance to the NAIs is rare because viruses with NA mutations are less fit for replication. Cross-resistance between zanamivir and oseltamivir is thought to be unlikely because of slightly different configurations and site of attachment. Zanamivir is administered intranasally and oseltamivir orally. Both agents need to be given within 24–48 hours of the onset of clinical illness to be effective. During an influenza epidemic, if a patient presents classic symptoms of influenza, it is reasonable to perform one of the rapid influenza detection tests and start antiviral therapy. If surveillance data suggest that influenza B is the predominant virus, then using one of the NAIs is advisable. If influenza A is diagnosed, the choice among the four drugs depends on the patient’s age, concomitant medications, other underlying diseases, and insurance coverage. In addition, if one contracts influenza A from a patient who is receiving amantadine or rimantidine it makes more sense to use a NAI. None of these medications is indicated for mild or nonfebrile influenza-like illnesses. The earlier any of these agents is started, the greater the benefit achieved. There are no data on the efficacy of treating influenza pneumonia or the use of these agents in the immunocompromised influenza patient. 2.6 2.6.1

Prevention Vaccination

Vaccinating people at high risk for influenza-related complications and their close contacts is our best preventive measure against influenza. About one-third of the population of the United States, 70 to 75 million people, is considered at risk. The Centers for Disease Control and Prevention (CDC) recommends the inactivated trivalent influenza vaccine for these high-risk patients (Table 5). In 2000, CDC changed the lower age limit for vaccine recommendation from 65 to 50 years. Only about one-third of patients younger than 65 years who were at high risk for influenza-related complications were actually being immunized. Other groups of people who should consider vaccination include those providing essential community services, students and staff at schools and colleges, travelers to the

Table 5 Target Groups for Influenza Immunization All persons aged 50 years or older All residents of long-term care facilities regardless of age Adults and children with chronic cardiac or pulmonary disorders Adults and children with other chronic medical problems such as diabetes mellitus Immunosuppressed individuals, as a result of disease or medications Children receiving long-term aspirin therapy to reduce the risk of development of Reye’s syndrome Women in the second or third trimester of pregnancy during the influenza season Health-care providers Household members of persons at high risk for influenza Travelers to areas with known epidemics Source: Adapted from Centers for Disease Control and Prevention 2000.

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Southern Hemisphere between April and September, travelers to the tropics at any time, and anyone who wishes to decrease the chance of contracting influenza during epidemics. The ‘‘flu shot’’ is a trivalent vaccine composed of two strains of influenza A (H1N1 and H3N2) and one strain of influenza B. Selection of strains for the next year’s vaccine is based on the viral types expected to predominate in the forthcoming epidemic. The vaccine is updated yearly and annual vaccinations are recommended. The vaccine is administered intramuscularly (45 ␮g in 0.5 cc) in the deltoid. It should be provided from mid-October. Unvaccinated persons can receive the vaccine through February. Adults need only one dose of the vaccine yearly. Unvaccinated children less than 9 years of age should be given two doses, one month apart. The protective effect of the vaccine takes about 3 weeks to develop and usually wanes by the end of the flu season. Since the vaccine is grown in eggs, those with serious egg allergy should not be vaccinated. Minor respiratory tract infections are not contraindications to vaccination. Local injection-related side effects are the main complication of immunization. Systemic reactions such as fever and malaise may develop in about 10% of adults, especially in those who were never vaccinated before. In 1976, the swine influenza vaccine was associated with increased frequency of Guillain-Barre´ syndrome (GBS), but this association has not been observed since with subsequent vaccine preparations. There has been no causal relation between vaccination and GBS indicated in several investigations. The benefits of vaccination clearly outweigh the remote potential risk of GBS. Influenza vaccine can be given at the same time as other vaccines including pneumococcal vaccine. During pregnancy, administration of the vaccine after 14 weeks of gestation may be preferable. Several studies in healthy working adults, elderly nursing home residents, health care providers, and several other populations have confirmed the efficacy and cost-effectiveness of influenza immunization. Vaccination reduces the incidence of influenza-like illness by 70% to 90%. The risk of hospitalization for influenza-related pneumonia and exacerbation of congestive heart failure (CHF) or chronic bronchitis is diminished by 30% to 70%. Allcause mortality rate is lessened by about 80%. In addition, people who contract influenza despite having the vaccine often have a milder illness than unvaccinated individuals. Vaccination rates are less than optimal in the United States. Physicians need to educate their patients about the value of immunization and address some of the misconceptions surrounding the flu shot. It needs to be reinforced that vaccination will not (1) cause flu, since the administered vaccine is inactivated, and (2) prevent all respiratory tract illnesses. Vaccination rates may be improved by several measures, including educational programs for the public, easier access to vaccination in medical or public health settings, and automatic reminders to patients and health care providers that vaccination is due. Scheduling routine office visits to those at risk during the early fall may also increase the rate of vaccination. The implementation of Medicare reimbursement since 1993 has improved the vaccination rate in people 65 years or more. A live-attenuated, cold-adapted intranasal trivalent influenza vaccine has been developed and studied in both adults and children. It has been found to be as effective as the current inactivated intramuscular vaccine. The local injection side effects are mitigated, but transient rhinorrhea and sore throat may occur. It is not yet available commercially. 2.6.2

Antiviral Drugs

Amantadine and rimantadine are approved for prophylaxis during influenza A outbreaks in persons at high risk for complications if they are not vaccinated. Both are 70% to 90% effective in preventing influenza A when given for 10 to 14 days after exposure. Mass

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chemoprophylaxis with these agents during epidemics is not recommended because of excessive costs, toxicities, and concerns about viral resistance. They have been effective in reducing the spread of nosocomial influenza. The prophylactic dose for adults for either agent is 200 mg/day orally or 100 mg twice a day. Dose reduction to 100 mg/day is needed in the elderly and those with renal dysfunction. Zanamivir and oseltamivir have also been studied as prophylactic agents in several settings, including community and nursing home outbreaks, and for family contacts. They have been found to be as effective as amantadine and rimantadine. Oseltamivir was recently approved by the Food and Drug Administration for prophylaxis during outbreaks and zanamivir is also approved for this indication. Chemoprophylaxis with any of the antiinfluenza drugs does not interfere with the antibody response to the vaccine and should not be considered as a substitute for vaccination. BIBLIOGRAPHY Centers for Disease Control and Prevention. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 49(RR03):1–38, 2000. English JA, Mauman KA. Evidence-based management of upper respiratory infection in a family practice teaching clinic. Fam Med 29:38–41, 1997. Gubareva LV, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet 355:827–835, 2000. Long JK, Mossad SB, Goldman MP. Antiviral agents for treating influenza. Clev Clin J Med 67: 92–95, 2000. Mossad SB. Fortnightly review: Treatment of the common cold. Br Med J 317:33–36, 1998. Roberts CR, Imrey PB, Turner JD, Hosokawa MC, Alster JM. Reducing physician visits for colds through consumer education. JAMA 250:1986–1989, 1983. Smith MB, Feldman W. Over-the-counter cold medications: A critical review of clinical trials between 1950 and 1991. JAMA 269:2258–2263, 1993. Sperber SJ, Hayden FG. Minireview: Chemotherapy of rhinovirus colds. Antimicrob Agents Chemother 32:409–419, 1988. Sullivan KM. Health impact of influenza in the United States. Pharmaco Economics 9:26–33, 1996. 2002 Drug Topics Red Book. Montvale, NJ: Medical Economics, pp. 193, 519, 522, 552.

15 Urinary Tract Infections Kevin D. Dieckhaus University of Connecticut Health Center, Farmington, Connecticut, U.S.A.

1

INTRODUCTION

Acute symptomatic infection of the genitourinary tract is one of the most common infectious syndromes that the medical care provider encounters in the outpatient setting. Urinary tract infections (UTIs) and their subsequent complications lead to over 8 million office visits and 1 million hospitalizations per year in the United States, where annual costs of medical care related to UTIs have been estimated at over $1 billion. Urinary infection disproportionately affects women. Approximately 40%–80% of otherwise healthy women experience a UTI at some point in life. The vast majority of these episodes are uncomplicated and resolve with appropriately targeted antibiotic therapy. Although most infections of the lower urinary tract may not be serious or life-threatening, infection frequently causes local irritative symptoms that are quite severe and disturbing to the patient. Up to 50% of women who experience a single episode of UTI may suffer from recurrent infection. Certain populations have a high risk of UTI. Institutionalized elderly populations may have incidences of bacteriuria approaching 30% in men and 50% in women. Instrumentation of the urinary tract, particularly the use of chronic indwelling urethral drainage, leads to its rapid colonization. The risk of development of bacteriuria with the use of an indwelling urinary catheter increases from approximately 5% per day for the first few days of instrumentation to nearly 100% by 4 weeks. Although the vast majority of episodes of UTI in otherwise healthy hosts are relieved with relatively few interventions, acute urinary infection either recognized or unrecognized may occasionally progress to more serious upper urinary tract involvement leading to acute pyelonephritis, perinephric abscess, and bacteremia. The emergence of resistance to commonly prescribed antimicrobial agents has caused particular concern.

2

PATHOPHYSIOLOGICAL CHARACTERISTICS

The bladder is generally considered to be a sterile space; however, small numbers of bacteria have occasionally been demonstrated in the urine of clinically uninfected patients as documented by the use of suprapubic puncture techniques. The bladder environment resists bacterial invasion through a variety of mechanisms. Low urine pH and extremes 279

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of osmolality inhibit bacterial growth. Urine lacks several nutrients required for optimal bacterial growth. Prostatic secretions in men contain prostatic antibacterial factor, which is inhibitory to urinary pathogens. Perhaps the most important defense, however, are the hydrodynamic properties of the urinary system. Urine flow and intermittent micturation produce an intrinsic flushing mechanism that clears the bladder of pathogens. Incomplete voiding due to urinary retention results in reduced bacterial clearance and increased risk of cystitis. In established infection, the local immune system responds at all levels with secretory immunoglobulin A (IgA), inflammatory cytokines, cellular immunity, and systemic antibody production. The vast majority of infections of the lower urinary tract are due to microorganisms’ ascending the urethra to gain access to the bladder. The introital, perianal, and vulvovaginal areas of the female have been demonstrated to serve as a reservoir of microorganisms that may traverse the urethra to cause infection. The use of the spermicide nonoxynol-9 preferentially inhibits lactobacilli in the vaginal microenvironment and may also increase the adherence of Escherichia coli to vaginal epithelium. A comparatively shorter urethra, which lies in close proximity to these potential areas of bacterial colonization, explains the higher incidence of uncomplicated UTI in women than in men. Sexual intercourse has been demonstrated to force bacteria into the bladder, leading to single or recurrent bouts of UTI, known as ‘‘honeymoon cystitis.’’ Condom use may increase this effect. In the presence of a urethral drainage system, bacteria may gain entry to the bladder extraluminally in the mucus sheath that surrounds the catheter. Once established in the urinary bladder, bacteria may multiply and invade the bladder wall, leading to acute symptoms of cystitis. The presence of vesicular-ureteral reflux facilitates the progression of infection to the kidney and collecting system and may lead to pyelonephritis, renal or perinephric abscess, and bacteremia. Urinary tract infections are the most common source of bacteremia with gram-negative bacilli in adults. Men are less likely than women to experience symptomatic UTI for several reasons. The long male urethra, decreased bacterial colonization of the urethral meatus, and prostatic secretions all limit the potential for bacteria to ascend through the urethra to the bladder proper. Each of these protective mechanisms may be abrogated. Chronic prostatitis may decrease the production of prostatic antibacterial factor. Urethral instrumentation or drainage may allow direct access to the bladder, bypassing the urethra and prostate. Condom catheters prevent this process but have been associated with increased meatal colonization with uropathogens and subsequent increased risk of UTI. Although less common than infection caused by ascending routes of infection, hematogenous infection of the urinary system may occur. Bacteria present in the bloodstream as a result of a variety of conditions often lead to clinically apparent infection of the kidney parenchyma, surrounding soft tissue, collecting, or drainage systems. For this reason, the urinary system is frequently involved in cases of endocarditis. This involvement may be manifested by asymptomatic bacteriuria, pyuria, clinically apparent cystitis, or complicated upper tract disease with pyelonephritis and/or abscesses. The majority of UTIs are due to Escherichia coli, though only a few serotypes are responsible for the majority of infections. Uropathogenic E. coli isolates may exhibit type 1 fimbriae, which bind mannose epitopes in urinary glycopeptides such as the TammHorsfall protein or other ligands. E. coli strains expressing type 1 fimbriae or P fimbriae class III are associated with acute cystitis in women and children. The increased adherence properties of the organism may hinder the mechanical elimination of organisms through urinary flow and micturation, leading to recurrent infections with the same bacterial strain. E. coli expressing P fimbriae class II exhibit increased propensity to upper urinary tract

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infections and subsequent bacteremia. Expression of Dr antigen on E. coli leads to persistence of E. coli in chronic pyelonephritis. The P fimbriae of uropathogenic E. coli have been demonstrated to facilitate colonization of the colon and perineum, thus predisposing to recurrent infection as well. 3

BACTERIOLOGICAL CHARACTERISTICS

The bacterial flora of UTI varies according to the clinical scenario (Table 1). Of infections in uncomplicated cystitis 80% are due to E. coli. Uncomplicated infection may occasionally be due to Staphylococcus saprophyticus in otherwise healthy young women. Other bacteria such as Klebsiella, Enterobacter, Proteus, and Pseudomonas species; staphylococci; and enterococci occasionally cause disease. The presence of structural abnormalities of the urinary system such as strictures, calculi, congenital anomalies, and fistulae increases the likelihood of these more unusual isolates or mixed infections. Patients living in extended care facilities or requiring mechanical urinary drainage are likewise more likely to harbor isolates other than E. coli. Prior antibiotic use in this population often leads to antibiotic resistance in these strains.

Table 1 Flora of Urinary Tract Infections Uncomplicated infection Gram-negative bacilli: Escherichia coli a Klebsiella spp. Enterobacter spp. Proteus spp. Gram-positive cocci Staphylococcus saprophyticus Staphylococcus aureus Group B streptococci Enterococci Complicated infection Gram-negative bacilli Escherichia coli Other Enterobacteriaceae (Enterobacter, Klebsiella, Morganella, Proteus spp.) Pseudomonas spp. Acinetobacter spp. Citrobacter Gram-positive cocci Coagulase-negative staphylococci Staphylococcus aureus Group B streptococci Enterococci Yeast Candida albicans Other Candida species a

In >80% of cases.

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CLINICAL MANIFESTATIONS

The primary presenting symptoms of infection of the lower urinary tract are due to local irritative symptoms. Inflammation of the urethra and bladder may cause urinary frequency and dysuria. The urine may be dark, blood-tinged, cloudy, or foul-smelling. The patient may describe suprapubic heaviness or pain. Urinary urgency, described as a need for immediate micturation, may be present. Fever is less common. Bladder pain on palpation above the symphysis pubis may be present on abdominal examination. Occasionally, patients may notice pneumaturia described as frothy urine or a flatulant sound with mictuyration. Although possibly due to a standard bacterial infection, pneumaturia may be due to vesicovaginal or vesicoenteric fistulae or bacterial fermentation of urinary glucose in the diabetic patient. Young, otherwise healthy women frequently experience multiple symptoms referable to the lower urinary tract. Elderly or otherwise compromised patients, however, may not experience discomfort per se and may only report new or increased urge incontinence or foul-smelling urine. It is important to recognize that infections other than UTIs may cause local irritative symptoms. In women, vaginal infection may mimic UTI. An appropriate history and pelvic exam must be performed if vaginal infection with Candida sp., bacterial vaginosis, trichomonas, or sexually transmitted diseases is suspected. In men, a history of dysuria or urethral discharge with an appropriate risk exposure history should prompt an evaluation for gonorrhea, chlamydia, and other sexually transmitted diseases (STDs). In a patient with risk factors for STDs, particularly a change in sexual partner, a pelvic examination with appropriate cultures should be obtained. STDs are discussed in detail in Chapters 16 and 17. The patient with pyelonephritis classically experiences fever, chills, and flank pain, along with symptoms of cystitis and urethritis. Flank tenderness may be elicited by palpation of the costovertebral angle. However, symptoms vary widely from patient to patient. The patient with upper tract disease may have only lower tract irritative symptoms and no symptoms referable to the kidney or ureter. Pain from pyelonephritis may occasionally mimic that of appendicitis or acute cholecystitis. Unilateral severe flank pain extending to the groin is suggestive of renal calculi. Deep-seated pyogenic infections such as nephric or perinephric abscesses can cause abdominal or back pain, fever, and leukocytosis. Occasionally there may be no focal symptoms of pyelonephritis and diagnostic imaging is required for diagnosis. UTI in the elderly may be asymptomatic. Furthermore, older individuals are more prone to urinary urgency, frequency, and incontinence without infection, making the diagnosis of infection difficult on clinical grounds alone. Nevertheless, a change of longterm urinary characteristics frequently heralds infection. Individuals who have indwelling catheters or who require intermittent catheterization may have no symptoms or may note only changes in urine characteristics.

5

LABORATORY DIAGNOSIS

Although UTI is frequently suspected on clinical grounds, its diagnosis requires confirmatory laboratory evaluation. This generally involves microscopic evaluation of a urine sample with or without microbiological culture. The collection of an appropriate urine specimen may be problematic and operator-dependent.

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283

Urine Collection and Transport

The urethra and meatus may be colonized with a variety of uropathogens that can affect microbiological culture results. Patients must be carefully instructed on how to obtain an appropriate urine specimen to reduce the likelihood of contamination from periurethral sites. Commercial kits facilitate appropriate collection techniques. Men should cleanse the meatus with gauze soaked in detergent solution. The foreskin, if present, should be retracted. The procedure is technically more difficult with women. The labia should be separated and the urethral meatus should be cleaned with gauze soaked in detergent solution. A small amount of urine should be voided and discarded; a midstream collection may be placed in the collection cup. A true ‘‘clean-catch’’ urine specimen may be difficult or impossible to obtain in obese women or patients with physical disabilities, altered sensorium, or inability to void. In these situations, bladder catheterization using a catheter inserted through the urethra is required. Careful attention to aseptic technique and topical decontamination with povidone iodine are required to prevent introduction of organisms into the bladder. Suprapubic bladder puncture is generally not required except in special circumstances. In patients with chronic indwelling urethral drainage, a urine sample may be obtained by placing a needle into the sampling port located on the catheter after topical application of disinfectant solution. Urine from the drainage bag or collection system must not be used as results often do not correlate with that of the bladder. Bacteria may continue to replicate in the urine medium between the time of collection and processing, altering the concentration of bacteria in the sample. Because of this, the sample should be stored in a refrigerator at 4⬚C until processing within 24 hours. Alternatively, commercial dip agar transport kits are available for immediate plating of the sample onto the nutrient medium in the office. 5.2

Urinalysis

The urinalysis is an important tool for the establishment of a diagnosis of UTI in the outpatient setting. Microscopic examination of an unspun specimen may demonstrate pyuria and/or bacteriuria. Observation of leukocytes on an unspun specimen or ⱖ2–5 polymorphonuclear leukocytes (PMNs) per high-power field on a centrifuged specimen corresponds to ⱖ8 PMNs/mm3 on urinalysis and suggests a pyogenic inflammatory process. The majority of patients with UTI have pyuria; however, it a nonspecific finding. The finding of pyuria without significant bacteriuria should prompt an evaluation for other causes of sterile pyuria (see Table 2). The presence of white cell casts suggests pyelonephritis, although the lack of white cell casts does not rule out upper tract disease. Urinalysis frequently demonstrates microscopic hematuria in patients with UTI, although this is a finding with low specificity. A microscopic examination of urine for the presence of bacteria is a simple and inexpensive tool for rapid diagnosis. Gram stain or methylene blue may be used to evaluate a midstream clean-catch urine sample. Urine samples demonstrating one bacterium or more per high-power field generally correspond to a bacterial concentration of 105 organisms/mm3. This cutoff is generally considered significant bacteriuria. Lack of organisms on several fields indicates fewer than 104 organisms/mm3. Analysis for nitrites, the product of gram-negative rod (GNR) reduction of nitrates found in urine, may be used as a chemical surrogate for the presence of GNRs. The nitrite test has both a low sensitivity and specificity; a urinary pH > 7 suggests infection with a ureasplitting organism such as Proteus or Klebsiella spp. The reliability of the microscopic

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Table 2 Causes of Sterile Pyuria Infectious Sexually transmitted diseases Fungal infection Genitourinary tuberculosis Leptospirosis Viral cystitis Low-titer bacterial UTI (<105 organisms/ml)a Peritoneal or pelvic infections (appendicitis, diverticulitis) Prostatitis Partially treated UTI Noninfectious Contamination with vaginal or foreskin secretions Renal calculi Tumor Tubulointerstitial nephritis or glomerulonephritis a

UTI, urinary tract infection.

examination or urinalysis result is directly dependent on the quality of the sample. A sample showing squamous epithelial cells indicates contamination of the specimen. A repeat specimen should be obtained. Examination of the urine by means of a multitest dipstick is a simple, inexpensive, and practical tool for the office practice, particularly where microscopic urine examination or obtaining urinalysis results rapidly is impractical. Dipstick leukocyte esterase tests have sensitivities of 74%–96% and specificities of 94%–98% for the detection of pyuria. Rapid evaluation for nitrites and microscopic hematuria can also be performed. A patient with symptoms suggestive of UTI and a negative dipstick evaluation finding should be referred for formal urinalysis with or without bacterial culture. 5.3

Culture

Direct culture of urine is the gold standard for the diagnosis of UTI. Interpretation of bacterial counts can be difficult and must be considered in light of the patient’s risk factors and symptoms. The generally recognized cutoff for significant bacteriuria is more than 105 organisms/mm3 of urine. Demonstration of 103 organisms/mm3 of urine in men is considered significant by some. These break points have been established primarily for enteric gram-negative bacilli. Other organisms such as gram-positive bacteria and fungi may cause significant infection yet have colony counts below these levels on culture. Furthermore, in certain situations, as when young women have symptoms of cystitis, lower numbers of organisms (102 to 104/mm3) can be significant. In addition to establishing a diagnosis, results of the urine culture may also define appropriate medical therapy by indicating patterns of bacterial sensitivity to antimicrobial agents. Urine culture has several limitations. Contamination of the urine culture specimen with urethral or perineal organisms is common. In this situation, the bacterial count is generally less than 105 organisms/mm3 and may consist of several different isolates, of

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which some may be recognized skin surface colonizers. False-negative culture results may be caused by prior antimicrobial use, dilution of urine through forced fluids or diuresis, ureteral obstruction below the level of infection, or unusual organisms requiring special growth media. Additionally, a patient may have significant bacteriuria in the absence of discernible symptoms of UTI or evidence of pyuria. 6

IMAGING STUDIES

Diagnostic imaging should be pursued in the setting of UTI when an underlying structural abnormality of the urinary tract is suspected. The goal of imaging studies is to identify lesions such as renal calculi, strictures, obstruction, or focal abscess that may require surgical or urological intervention. Adult women with uncomplicated lower or upper tract infections usually do not require imaging studies. However, patients who do not respond to antibiotic therapy, have obstructive symptoms, or have multiple episodes of pyelonephritis should be investigated for potentially treatable abnormalities. Clinicians should be alert to the potential renal calculi in UTI caused by urea-splitting organisms such as Proteus sp. Additionally, many would recommend further evaluation for men who have UTI or pyelonephritis. Evaluation of the urinary tract should generally begin with a plain film of the abdomen, which may identify urinary calculi, soft tissue gas, calcification, or masses. Ultrasonography is useful for detecting renal calculi, obstruction with hydronephrosis, and nephric and perinephric abscesses. An intravenous pyelogram can provide a functional evaluation of the renal parenchyma and is perhaps the most sensitive test for detecting abnormalities of the renal collecting system. Contrast-enhanced computer assisted tomography (CT) is also highly sensitive in evaluating kidney parenchyma and surrounding soft tissue. CT scanning with spiral technology improves the sensitivity of the test in detecting ureteral calculi. A voiding cystourethrogram evaluates abnormalities of the bladder outlet and urethra. 7

THERAPUETIC APPROACHES

It is important to identify infections complicated by pyelonephritis, calculi, obstruction, or abscesses as these may suggest the need for urological or surgical intervention and longer courses of antimicrobial therapy. 7.1

Antibiotics

The choice of antibiotic for outpatient management of UTI requires a drug with good oral absorption or ease of parenteral administration, achievable bactericidal concentrations in the urine, and favorable toxicity profile. A list of commonly used antimicrobial agents for the outpatient management of UTI, doses, and costs is given in Table 3. Empirical antibiotics should be based on the likely pathogen and its anticipated resistance profile. Antibiotic therapy should be modified when necessary after results of microbiological culture and sensitivity testing are available. In addition to eradicating pathogenic bacteria from the urine and vaginal, perineal, and bowel reservoirs, antibiotic administration may also deplete vaginal populations of Lactobacillus sp. and anaerobic bacteria. These bacteria are important in competitively inhibiting pathogenic gram-negative bacteria and Candida spp. Thus, treatment with antibiotics may increase the risk for colonization with resistant bacterial strains. Perhaps

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Table 3 Antimicrobial Agents for Outpatient Management of Urinary Tract Infection Agent Trimethoprim Sulfamethoxazole Trimethoprimsulfamethoxazole Nitrofurantoin

Usual dose 100–200 mg bid 2-g load, then 1 g qd One double strength tablet (160 TMP/ 800 SMZ) bid 100 mg bid

Costs for a 3-day coursea $1.00–$2.00 $4.00 $7.80

$9.00b

Norfloxacin Ciprofloxacin Ofloxacin Enoxacin Amoxicillin Amoxicillin/ clavulanate Cephalexin

400 mg bid 250–500 mg bid 400 mg bid 400 mg qd 250 mg tid 250/125 mg tid

$24.00 $12.50–$25.00 $30.00 $20.60 $1.90 $14.50

500 mg qid

$13.40

Ceftriaxone Cefpodoxime

1–2 g IV/IM qd 100–200 mg bid

a b

$135.00–$270.00 $18.00–$36.00

Comment Reduced urine concentration in renal failure, rash Rash

Reduced urine concentration in creatinine clerance <40, pulmonary fibrosis Expensive, reserved for complicated infections

70% E. coli resistant to ampicillin No activity against enterococci No Pseudomonas spp. activity

Average wholesale price (2000 Drug Topics, Redbook). Most experts recommend 7 days of therapy with nitrofurantoin instead of 3 days.

more clinically important is the frequent induction of candidal vaginitis after initiation of therapy for UTI. Antibiotics vary in their ability to penetrate the bacterial reservoir sites of the bowel, perineum, and vagina as well as their activity against local mucosal protective flora. Nitrofurantoin is concentrated in the urine and has little effect on vaginal and bowel microflora; however, it may not eliminate perineal colonization with urotropic GNRs because of poor penetration into these tissues. Trimethoprim and the fluoroquinolones penetrate these mucosal sites much more readily, providing good bactericidal activity against urotropic gram-negative bacteria, and do not significantly alter vaginal Lactobacillus sp. or anaerobic bacterial concentrations. Treatment with doxycycline or ␤-lactam agents, particularly aminopenicillins, alters the endogenous microflora most. The clinician should avoid these agents if possible for patients who have a history of recent or recurrent vaginal yeast infection. The patient should be counseled in how to differentiate a vaginal yeast infection from a relapse of the UTI and advised on how to initiate self-treatment with anticandidal agents, usually topical or low-dose systemic azole antifungal agents. 7.1.1 Folic Acid Inhibitors Both trimethoprim and sulfonamide agents interfere with bacterial synthesis of folic acid. The antibacterial spectrum covers E. coli, Klebsiella sp., Proteus sp., and S. saprophyticus, which are responsible for most cases of uncomplicated cystitis. The combination of trimethoprim with sulfamethoxazole is synergistic and is available in a fixed-dose tablet. There may be several reasons to consider trimethoprim (TMP) without sulfamethoxizole (SMX). Trimethoprim alone reaches adequate urinary concentrations for bacterial inhibi-

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tion and has been shown to be as effective as TMP-SMZ in uncomplicated UTI. TMPSMX penetrates well into prostatic tissue and is useful for management of UTI associated with prostatitis (discussed in Chapter 17). Sulfamethoxazole can be associated with severe dermatological allergic reactions and may not reach adequate urine concentrations for some causes of uncomplicated UTI. Patients who have glucose-6-phosphate dehydrogenase (G6-PD) deficiency may experience hemolytic anemia. Recently there has been increasing resistance to TMP-SMZ demonstrated in E. coli urinary isolates. From 1992 to 1996 resistance to TMP-SMX increased from 8% to 16%, to amoxicillin from 29% to 36%, and to cephalothin from 20% to 28% in the Seattle, Washington, area. Nevertheless, the combination tablet is inexpensive and is the drug of choice in areas where resistance to TMPSMX is <10%–20%. 7.1.2

Nitrofurantoin

Nitrofurantoin (Macrodantin, Macrobid, Furadantin) is generally used in macrocrystalline form and can attain bactericidal concentrations in the urine for most isolates of E. coli, Citrobacter spp., S. saprophyticus, and Enterococcus faecalis. Activity against Enterobacter spp., Enterococcus faecium, and Klebsiella spp. is more variable. These agents have been used successfully for management of cystitis and chronic suppressive therapy. Urinary excretion is decreased with even minimal degrees of renal dysfunction. For this reason, nitrofurantoin should not be used by patients who have creatinine clearance of <40 ml/ min. Gastrointestinal side effects are common in the microcrystalline formulation, but less apparent in the macrocrystalline preparation. Acute or chronic pulmonary hypersensitivity is observed in <1000 treatment courses. It may progress to pulmonary fibrosis, particularly in long-term suppressive therapy. 7.1.3

Quinolones

Fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin, enoxacin) interfere with bacterial deoxyribonucleic acid (DNA) gyrase. They have activity against Enterobacteriaceae, Enterococcus spp., Staphylococcus spp., and Pseudomonas spp. Oral fluoroquinolones attain very high urinary concentrations, allowing renal parenchymal penetration. They may therefore be used for upper and lower urinary tract infections complicated by anatomic abnormalities, calculi, or device-related infections, as these tend to be associated with more antibiotic-resistant organisms and/or tissue penetration of infection. Oral fluoroquinolones attain excellent prostatic as well as serum concentrations. However, the achievable urine concentration may be marginal for some S. saprophyticus isolates. Quinolone resistance may emerge during therapy of complicated UTI with Pseudomonas spp. or Enterococcus faecalis. Quinolones may increase serum levels of concomitantly administered theophylline, coumadin, or digoxin and may decrease levels of phenytoin. 7.1.4 ␤-Lactam Agents The ␤-lactam agents interfere with bacterial cell wall synthesis. Aminopenicillins, such as ampicillin and amoxicillin, provide good activity against most enteric GNRs as well as enterococci. There has been a rapid emergence of resistance to these agents, however; over one-third of urinary E. coli isolates demonstrate resistance. The addition of ␤-lactamase inhibitors such as clavulanate to amoxicillin (Augmentin) increases the antimicrobial spectrum of this class and reduces the potential for resistance. This combination is expensive, can cause diarrhea, and should be considered a second-line agent. The first-generation cephalosporins, cephalexin (Keflex) and cefadroxil (Duricef), have some activity against most isolates of E. coli, Klebsiella spp., and Proteus spp. The

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third-generation cephalosporin ceftriaxone (Rocephin) offers expanded coverage of gramnegative bacilli including resistant Enterobacteriaceae but not Pseudomonas sp. It must be administered either intravenously or intramuscularly but because of its favorable pharmacokinetic profile it can be administered in a once-daily dosage. Thus, this agent has been useful for management of UTI in extended care facilities for patients who have altered sensorium, are otherwise unable to swallow pills, or have unpredictable gastrointestinal absorption. Cefpodoxime (Vantin), an oral third-generation cephalosporin, has limited activity against resistant Enterobacteriaceae and no activity against Pseudomonas spp. The high cost of these agents should preclude their use except in cases of documented intolerance to other less costly antimicrobials, antibiotic resistance, or, in the case of ceftriaxone, the need for outpatient parenteral therapy. Enterococcus spp. are resistant to all cephalosporins. 7.1.5

Fosfomycin Tromethamine

Fosfomycin (Monurol), a new antimicrobial agent, is a derivative of phosphonic acid that inhibits cell wall synthesis. It is well absorbed orally. It has activity against most aerobic GNRs except Pseudomonas spp. and enterococcus. It is generally well tolerated but very expensive. It can be used as single-dose therapy for uncomplicated UTI. 7.2

Nonspecific Measures

Increasing oral fluid intake in order to increase urinary flow has been advocated by some and is a commonly touted practice among laypeople. Forced diuresis enhances the urodynamic properties of the urinary collecting system in eliminating the buildup of bacteria in the bladder. The patient is advised to drink fluids and to void frequently and completely. The increased fluid may dilute the bacterial counts in residual urine. This intervention has been little studied, but there have been anecdotal reports of clearance of UTI symptoms with forced diuresis alone. Hydration may also dilute the acidic and osmotic properties of the urine and decrease antibiotic concentrations. Increased urinary flow may increase the risk of vesiculoureteral reflux. Forced diuresis does not appear to improve outcome more than antibiotic therapy alone. Acidification of the urine may augment the antibacterial properties of urine but is difficult to achieve. The major effect of urinary acid is potentiation of pH-dependent action of urea and osmolality. Ingestion of over-the-counter ascorbic acid, methionine, or juices, e.g., cranberry juice, has only a very mild effect on urinary acidity except in large amounts. Cranberry juice exerts its antibacterial effect in urine by increasing hippuric acid production from precursors present in the berry. Cranberry and blueberry juices contain lectins that bind type I fimbriae, but the clinical significance of this is unknown. It is difficult to acidify the urine of patients adequately with urea-splitting organisms such as Proteus sp. and some Klebsiella sp. infections. Adequate urinary pH is difficult to attain and may be potentially harmful. Patients with renal tubular acidosis may not be able to excrete the acid load, leading to systemic acidosis. A decrease in urinary pH may also precipitate uric acid calculi. Furthermore, ascorbic acid administration may lead to urinary calcluli with oxalate, a major metabolite. Thus acidification of the urine cannot be recommended as part of routine clinical management of UTI. Analgesia with phenazopyridine hydrochloride (Pyridium), given at a dose of 100– 200 mg tid with food, is occasionally useful for symptomatic management of dysuria associated with UTI. However, appropriate antimicrobial therapy without urinary analgesia frequently leads to rapid resolution of symptoms. The patient should be warned that this agent causes reddish orange discoloration of the urine and can likewise permanently stain soft contact lenses.

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UNCOMPLICATED URINARY TRACT INFECTIONa (see Figure 1) Young healthy women Confirmation of pyuria with urinalysis Consideration of STD in the differential diagnosis Bacteriological evaluation result predictable (Table 1) No need for culture 1 vs. 3 Days of antibiotics (Table 4) Trimethoprim, TMP-SMX, quinolone (Table 3) No need for follow-up culture Forced diuresis and urine acidification not helpful a

8 8.1

STD, sexually transmitted disease; TMP-SMX, trimethoprim and sulfamethoxazole.

CLINICAL SYNDROMES Uncomplicated Urinary Tract Infection in Women

An uncomplicated UTI is defined as an infection of the bladder that occurs in a young healthy woman with a structurally and neurologically normal urinary tract without evidence of obstruction or kidney involvement. The onset of symptoms is generally acute, with dysuria, urinary frequency, and urgency. Infection rarely leads to renal parenchymal damage. When an otherwise healthy woman is first evaluated for symptoms consistent with a UTI, a stepwise approach to office management is appropriate (Figure 1). Urinalysis should be performed to document pyuria. Obtaining a urine culture is not mandatory since the bacteriological characteristics are predictable (see Table 1). Common agents used for empirical therapy for outpatient-acquired uncomplicated UTI include trimethoprim, TMP-SMX, norfloxacin, and other quinolones (see Table 3). Amoxicillin and the first-generation cephalosporins are less efficacious and should not be used as first-line drugs. The duration of antibiotic therapy required to eradicate urinary tract infection has been the subject of much debate. Traditionally patients have received 7–10 days of therapy. More recent data have shown that a 3-day course of antibiotic is as effective and less toxic than longer courses. Single high-dose therapy has also met with success though it is less effective than 3-day therapy. The preferred length of treatment for most patients with uncomplicated UTI is currently 3 days (see Table 4). Several agents known to yield high concentrations in the urinary tract have been evaluated for use in a one-time oral or parenteral dose (see Table 5). Single-dose therapy offers the advantage of improved adherence with supervised administration, fewer side effects, less expense, reduced potential for emergence of resistant bacterial strains, and perhaps less alteration of the perineal, vaginal, and rectal microflora. Single-dose observed therapy may be useful for uncomplicated UTI in adolescent girls, women, and pregnant women when given shortly after the onset of symptoms. It is less effective than longer courses of antimicrobials for patients who delay seeking medical care or for infections caused by S. saprophyticus. Additionally, patients with unrecognized upper tract infection or complicated UTI are unlikely to respond to single-dose therapy. In fact, failure of singledose therapy should prompt consideration of the diagnosis of pyelonephritis, nephrolithiasis, or structural anatomical abnormalities.

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Figure 1 Management of dysuria and pyuria. Asymptomatic patients generally do not need treatment. For women with uncomplicated cystitis a urine culture is not needed and 3 days of therapy is adequate. Patients with complicated cystitis should have cultures performed and be treated with 7–10 days of therapy. Patients with frequent recurrences should be evaluated with genitourinary imaging, treated for 2–6 weeks, and considered for chronic prophylaxis. SDT, single-dose therapy; GU, genitourinary; STD, sexually transmitted disease.

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Table 4 Duration of Antibiotic Therapy Percent eradication Agent TMP-SMX TMP Norfloxacin Ciprofloxacin Ofloxacin Amoxicillin Cefadroxil Nitrofurantoin Fosfomycin Pros

Cons

Single dose

3 Days

ⱖ3 Days

87 83 82 89

94 93 95–97 95 95 88

94 88 95–98 95–99

a

100

a

a

a

a

More efficacious Less recurrence

Better for complicated UTI

More expensive More toxicity

More expensive More toxicity Greater alteration of bowel flora

a a

57 77–82 97 Less expense Less toxicity Less alteration of normal bowel flora Less effective Increase recurrences

a a

a

Inadequate data from large well-designed studies. TMP-SMX, trimethoprim and sulfamethoxazole; UTI, urinary tract infection. Source: Warrens et al. 1999.

Table 5 Agents Evaluated for Single-Dose Antimicrobial Urinary Tract Infection Therapy Dose

Cost per coursea

3g 2g 1–2 double-strength tablets

$0.84 $1.30–$2.60 $0.30–$0.60

200–400 mg 200 mg

$3.00 $4.90

Oral agents Amoxicillin Sulfasoxizole Trimethoprim and sulfamethoxazole (TMP-SMZ) Trimethoprim Nitrofurantoin (Macrodantin) Fluoroquinolones Norfloxacin Ofloxacin Ciprofloxacin Tetracycline Fosfomycin

800 mg 400 mg 500 mg 2g 3g

$8.00 $4.90 $4.00 $0.45 $27.90

500 mg IM

$22.50

Parenteral agents Ceftriaxone a

Average wholesale price (2000 Drug Topics, Redbook).

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Response of uncomplicated UTI to antimicrobial therapy is usually evident by a reduction in symptoms within 12–48 hours. No specific follow-up is required if the patient responds appropriately. The clinician should counsel the patients treated with single-dose therapy that they may continue to experience symptoms of dysuria, urgency, and frequency for a few days despite bacteriological cure. If symptoms fail to abate or recur after initial improvement, a urine culture should be obtained to guide further antimicrobial therapy. Other causes of urinary symptoms in the absence of significant colony counts on standard culture media include infection with atypical pathogens such as Ureaplasma spp., Mycoplasma spp., or anaerobes; cystitis with urinary bacterial concentrations below 105 organisms/ml; interstitial cystitis; or the trigonitis/urethral syndrome. 8.2

Recurrent Urinary Tract Infection

Recurrent infection after treatment for an initial UTI is fairly common; up to 20% to 50% of women report recurrent infection during their lifetime. Women with a single episode of UTI have greater than a 1 in 4 chance of development of a recurrent infection within 6 months. An important distinction in recurrent urinary tract infections is that between relapse and reinfection. 8.2.1

Relapse

Relapse of infection implies a recurrent infection of the urinary system shortly after completion of therapy with the same organism that caused the initial infection. Relapse usually occurs within 2 weeks of treatment for UTI. If a pretreatment urine culture is available, the urine culture obtained at the time of recurrent symptoms demonstrates an organism identical to the original isolate. Given that >80% of episodes of UTI are due to E. coli, COMPLICATED AND RECURRENT URINARY TRACT INFECTIONa (see Figure 1) Complicated UTI GU structural abnormalities, older women, men, immunocompromised, recurrent UTI, symptoms >7 days Urinalysis and culture Bacteria generally more resistant Treatment for 7–10 days (Table 3) TMP-SMX, quinolone Yogurt, acidophilus-containing milk products not helpful Follow-up culture after treatment Recurrent UTI Occur in 20%–50% of women who have UTI Recurrence Relapse of partially treated infection Acquisition of new infection Removal of risks if possible (Table 6) GU imaging and urological consultation potentially necessary Antibiotic prophylaxis potentially indicated for repeated recurrences (Table 7) a

UTI, urinary tract infection; GU, genitourinary; TMP-SMX, trimethoprim and sulfamethoxazole.

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one should also evaluate the antibiotic susceptibility patterns to compare organisms isolated before and after antibiotic treatment. More sophisticated testing of urinary isolates with restriction-fragment-length polymorphism (RFLP) or pulsed-field gradient-gel electrophoresis (PFGE) may precisely determine clonality of the infecting organism. However, these are available only in specialized research laboratories and are generally unnecessary in clinical practice. Relapse of UTI may be due to a persistent nidus of infection such as an anatomical abnormality, undiagnosed upper tract disease, abscess, calculi, or prostatitis. Physiological obstruction in postmenopausal women may result from cystoceles, pelvic tumors, or prolapse of pelvic structures. A relapse of infection due to structural abnormalities or renal parenchymal involvement is more likely to result in renal functional impairment or bloodstream infection. Therefore, identification of structural abnormalities in this setting should be pursued with diagnostic imaging studies. Patients should be offered 10–14 days of antibiotics, with decisions about more aggressive diagnostic evaluation predicated on the response from the second course. Antimicrobial therapy for relapsed UTI requires longer courses of therapy for eradication of the infecting organism. If no obvious nidus of infection is identified or an apparent nidus is not correctable, a 2-week course of antimicrobial therapy should be attempted. A urine culture with antimicrobial sensitivity testing should be obtained prior to the initiation of empirical antibiotics. The choice of antimicrobial agent should be modified once the susceptibility pattern of the infecting organism is known. Some patients relapse after 2 weeks of therapy, and repeated 2-week courses or longer courses of therapy (4 to 6 weeks) have been suggested for these patients. 8.2.2

Reinfection

Reinfection implies successful sterilization of the urinary system with antimicrobial therapy followed by reintroduction of microorganisms, leading to repeated episodes of infection. These organisms may be of the same species as the original isolate or different species. In fact, many of these second isolates are identical to the original isolate by RFLP or PFGE and are thought to involve reinfections emanating from bacterial reservoirs present in the bowel, perineum, and vagina. Reinfection of the urinary system may be associated with several factors (see Table 6). Identification and correction of any potential causes of recurrent infection are critical prior to embarking on long-term antibiotic use. Recurrent infection shows a seasonal pattern and is more common in the summer months. Mechanical causes such as sexual in-

Table 6 Factors Associated with Recurrent Urinary Tract Infection Risk factor Diaphragm use Estrogen deficiency Family history Secretor status Sexual intercourse Spermicide use

Potential intervention Avoidance of use Topical or systemic estrogen replacement None None Postcoital micturation, prophylactic antibiotics Avoidance of use

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tercourse may force bacteria from the perineum through the urethra and have been implicated as a cause of recurrent UTI in some women. Use of a diaphragm for birth control may in some women contribute to physiological obstruction of the urethra. Differences in toileting habits (e.g., direction of wiping after bowel movements) are often cited as a precipitant for UTI in women but have not been conclusively proved to be. Likewise, other behavioral risk factors such as bicycle riding, ingestion of coffee or tea, use of tampons, and wearing of pantyhose have been implicated but have not been borne out in careful studies. Disruption in the vaginal ecology is often an important factor in recurrent infection. Colonization and persistence of urotropic bacterial isolates in the bowel and pelvic areas may serve as a reservoir for recurrent infections. Recent antibiotic use can increase the incidence of UTI as a result of deleterious effects on vaginal lactobacilli. Spermicide use also decreases the population of vaginal lactobacilli and has been associated with increased rates of E. coli colonization and subsequent UTI. Nonoxynol-9, the most commonly employed spermicide, preferentially inhibits lactobacilli and has little effect on enteric GNRs. Spermicide use has also been implicated in increasing adherence of E. coli to vaginal epithelial cells. Women with repeated episodes of UTI may have a history of childhood UTI or a maternal history of UTI, suggesting a genetic predisposition. Blood group antigen secretor status has been associated with recurrent infection. Women who are of positive secretor status may have higher-affinity binding sites on vaginal epithelial cells for urotropic E. coli. Estrogen deficiency in postmenopausal women is associated with decreased numbers of vaginal lactobacilli, increased pH, and increased colonization with GNRs. A search for modifiable risk factors for recurrent UTI should be undertaken prior to antibiotic therapy. In postmenopausal women, estrogen replacement therapy may be offered unless there is a documented contraindication. Topical intravaginal estrogen appears to be more effective in reducing UTI incidence than systemic estrogen replacement therapy alone. The ingestion of yogurt, acidophilus-containing milk products, and other natural remedies has also been suggested as a method to normalize vaginal ecological characteristics. These methods, however, have not been conclusively demonstrated to have any impact on incidence of recurrent infection. Sexually active women using diaphragms and/ or spermicide for contraception can be encouraged to use an alternative method. If development of recurrent UTI is temporally associated with sexual activity, the woman should be encouraged to empty her bladder immediately after intercourse. This mechanically clears bacteria that may have been introduced to the bladder and may decrease the frequency of symptomatic infection in some women. 8.2.3

Antibiotic Prophylaxis

Many women either do not have modifiable risk factors or continue to have recurrent symptomatic infections despite appropriate behavioral and nonantibiotic interventions. In choosing to employ suppressive antibiotics for prevention of recurrent infection the clinician should weigh the decreased infection rate against the risks of long-term toxicities of antibiotic therapy. These may include the development of antibiotic resistance, Clostridium difficile enterocolitis, allergy, and nitrofurantoin-induced pulmonary fibrosis. Suppressive antibiotics may be warranted for patients with frequent episodes, with prolonged or severe symptoms, or risk of renal parenchymal involvement from recurrent infection. This latter group may comprise patients with underlying structural or functional abnormalities such as calcluli or vesiculoureteral reflux who may be asymptomatic but are nevertheless at high risk of renal damage from bacteriuria. Suppressive antibiotics may decrease the frequency but rarely entirely eliminate the risk of recurrent infection. Anti-

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biotic prescribing methods generally employ one of three strategies: (1) event-associated chemoprophylaxis, (2) patient-initiated early intervention, or (3) chronic suppressive therapy. Event-associated prophylaxis is most commonly employed when there is a strong association of UTI with sexual activity. The woman is given a supply of antibiotic and instructed to take a single dose either just before or immediately after coitus. Full therapeutic doses are not required (see Table 7). Adherence to this method is usually good. There is no need to administer more than a single dose in a 24-hour period. For patients who have three or fewer infections per year, patient-initiated therapy should be attempted. The patient is given a prescription for a small supply of appropriate antibiotics to have available at home. When the patient first notices the symptoms of recurrent UTI, she may begin the dosage herself and continue antibiotic therapy for 3 days. Because the goal of this approach is to treat an infection after it has already been established, the standard treatment dose of antimicrobials should be given, usually for a 3-day course. The patient may also be given material for a clean-catch urine specimen that can be refrigerated and taken to the office within 24 hours for confirmatory urinalysis and/or urine culture. This specimen should be obtained prior to initiation of antibiotics. This method does not eliminate the development of UTI symptoms as prophylaxis does, yet it does have the advantages of decreased overall antibiotic use, lower costs, potential for less development of resistance, and improved compliance when compared to that of chronic suppressive antimicrobial administration. Patient-initiated antimicrobial therapy allows for decreased patient frustration and more rapid initiation of treatment by eliminating the time delays inherent in obtaining a medical appointment and waiting for prescriptions to be filled. The sensitivity of the experienced patient in making a self-diagnosis of recurrent UTI is high: approximately 85%–95% of treatment courses are confirmed by urine culture. Patients whose symptoms continue beyond 3 days should seek evaluation of other causes of urinary symptoms. Continuous antimicrobial prophylaxis may be considered for some patients with frequent recurrences of infection. This may include women with multiple recurrent episodes of symptomatic UTI or patients with known obstruction or calculi not amenable to definitive intervention. Because the vaginal, rectal, and perineal microflora is an important reservoir for the urotropic bacteria that lead to recurrent UTI, agents that penetrate these compartments but do not alter endogenous microflora are preferred. For this reason, fluo-

Table 7 Antimicrobial Agents Used for Urinary Tract Infection Prophylaxis Daily dosea

Costs per dosea

100 mg Single-strength tablet or double-strength tablet qod

$0.15 $0.65

50 mg 100 mg 200 mg 250 mg

$0.75 $2.00 $3.90 $0.60

Agent Trimethoprim Trimethoprim and sulfamethoxazole (TMP-SMX) Nitrofurantoin Ciprofloxacin Ofloxacin Cephalexin a

Average wholesale price (2000 Drug Topics, Redbook).

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roquinolones or trimethoprim alone or in TMP-SMX combination is often employed in this setting. Nitrofurantoin is concentrated in the urine and may be used for long-term prophylaxis. It does not penetrate these compartments and therefore has little effect on either the protective resident microflora or reservoirs of urotropic GNRs. The antimicrobial doses administered for continuous prophylaxis are typically lower than therapeutic doses (Table 7) and can be given every day to every other day. When first initiated, continuous prophylaxis should be given for 6 months, then discontinued. Unfortunately in up to 60% of women recurrent UTI develops within a few months of stopping of prophylaxis. This event requires treatment of the acute infection followed by reinitiation of longer-term continuous prophylaxis. Some patients who have particularly frequent recurrences without antibiotics require reinitiation of prophylactic antibiotics for years at a time. Continuous antibiotic use may lead to infection with antibiotic-resistant organisms. If a UTI develops during continuous prophylaxis, a urine culture should be obtained prior to treatment. Empirical therapy should generally involve a change to a different antimicrobial agent. Antibiotics should then be tailored to the susceptibility pattern of the infecting organism once this information is available. 8.3

Complicated Urinary Tract Infection

A complicated infection is characterized by underlying functional or structural abnormalities of the urinary tract in the setting of infection. Complications may be due to renal calculi, anatomical abnormalities, or immune deficiency. Renal transplantation recipients and the elderly may also experience complicated UTI. Many consider any UTI in a man ‘‘complicated’’ (see Figure 1). Complicated infections are often due to more resistant organisms such as enterococci; S. saprophyticus; Pseudomonas, Acinetobacter, Klebsiella, or Proteus spp.; and other GNRs. Prior to initiation of therapy, a urine culture should be obtained. Empirical initial therapy may include TMP-SMX, trimethoprim, or a fluoroquinolone. Nitrofurantoin and ␤-lactam antibiotics should be avoided by this group of patients. Typically, a 7- to 10-day course of antibiotic therapy is prescribed. Antibiotics should be adjusted on the basis of the results of the urine culture. Urinalysis and culture should be obtained at the conclusion of therapy. For the patient who relapses after a 7- to 10-day course of antibiotics, longer courses of antibiotics, of 2–6 weeks, may be needed. Patients with frequent recurrences may require chronic suppressive antibiotic therapy. If an anatomical abnormality is identified, the patient should be referred for urological evaluation. Physical obstruction of the urinary system should be relieved by the removal of calculi. If infection above the level of obstruction is suspected, percutaneous drainage may be required. Abscesses should be drained when possible. A possible exception is the presence of intrarenal abscess, which may respond to longer courses of antibiotics. Urine stasis resulting from a neurogenic bladder or prostate enlargement may require periodic straight catheterizations or continuous urinary drainage during the acute infection, followed by medical or surgical intervention once bacteriuria has cleared. 8.4

UTI During Pregnancy

The topic of UTI during pregnancy is reviewed in Chapter 33. 8.5

Fungal Urinary Tract Infection

The vast majority of fungal infections of the urinary tract are due to Candida spp. Fungal UTIs occur most often in hospitalized patients or those living in nursing homes who have

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FUNGAL URINARY TRACT INFECTION AND PYELONEPHRITISa Fungal UTI Nosocomial or nursing home–related Increased with Foley catheters and antibiotic use Most due to Candida albicans, but increasing amount of fluconazole-resistant Candida species Removal of catheter generally effective in clearing of yeast Fungal pyelonephritis and/or fungus ball uncommon even in high-risk patients, e.g., those with GU abnormalities or immune compromise Treatment with oral fluconazole or amphotericin B bladder wash for cystitis; intravenous fluconazole or amphotericin B for systemic illness Pyelonephritis Bacteriological characteristics same as those of cystitis (Table 1) Oral therapy for 7–14 days for healthy young women with mild to moderate illness (Table 3) Admission and intravenous therapy for more severe illness, immune compromised host, elderly TMP-SMX or quinolone a

UTI, urinary tract infection; GU, genitourinary; TMP-SMX, trimethoprim and sulfamethoxazole.

indwelling Foley catheter. Candida spp. are now the cause of 25% of nosocomial UTIs. There is an increased risk in patients who have diabetes mellitus or receiving antibiotics even without the presence of a Foley catheter. With the increasing use of urinary drainage systems in nonhospitalized patients, candidal UTI is becoming a more common occurrence in the outpatient setting. The microbiological diagnosis of candidal UTI can be difficult. Candida spp. often colonize the urinary tract of patients who have indwelling catheters. Furthermore, acute symptomatic UTI is frequently associated with only 103 –105 organisms/ml of urine. Candida spp. isolated from the urine may represent bladder colonization or infection. Most patients with fungal bladder infections are asymptomatic. Most colonizations and asymptomatic infections resolve spontaneously, particularly if a causative Foley catheter can be removed. Risks for upper tract involvement or dissemination include urological abnormalities, obstruction, and immunosuppression. Even in these populations, though, fungal pyelonephritis or obstructing fungal ball (bezoar) is rare. There is an increasing incidence of nonalbicans candidal infections, with C. glabrata, C. tropicalis, and C. parapsilosis. Whereas most C. albicans organisms are sensitive to azole antifungal agents, the sensitivities of other candidal species are less predictable. There are several options for treating symptomatic fungal UTI, including systemic amphotericin B, bladder irrigation with amphotericin B, and oral therapy with azole antifungal agents. Removal or replacement of urinary catheters should be performed whenever possible. Single-dose intravenous amphotericin B 0.3 mg/kg is effective and may be used for patients in appropriate facilities or in cases of azole resistance. Continuous bladder irrigation with amphotericin B 50–100 mg/L dextrose (D-5-W) through a multilumen urethral catheter may be given for 5 days. Fluconazole 100 mg/day is generally given for 7 days for cystitis. Reductions in glomerular filtration rate result in decreased urinary fluconazole levels. Therefore, in cases of acute or chronic renal failure, the dose of flu-

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ASYMPTOMATIC AND CATHETER-RELATED URINARY TRACT INFECTIONa Asymptomatic Generally does not require treatment (Figure 1) Treatment for Pregnant women Renal transplantation recipients Preceding urological procedures After removal of Foley catheter Common in elderly nursing home patients: No treatment If treatment is started Treatment for 7–10 days TMP-SMX or quinolone Antibiotic adjustment based on culture results GU catheter–related Colonization in all patients with Foley catheters No treatment of asymptomatic infection or colonization All positive urine culture results not to be treated If treatment started Treatment for 7–10 days TMP-SMX or quinolone Antibiotic adjustment based on culture results a

TMP-SMX, trimethoprim and sulfamethoxazole; GU, genitourinary.

conazole should be increased rather than decreased. For upper tract involvement or dissemination, fluconazole 400 mg intravenously should be used. 8.6

Catheter-Associated Urinary Tract Infection

The presence of urinary drainage catheters is increasing in the outpatient setting and presents a special challenge to care providers. All patients with indwelling catheters eventually become colonized. If the patient has asymptomatic bacteriuria, even with associated pyuria, no therapy is needed. Treatment of these patients exposes them to antibiotic toxicity and breeds bacterial resistance. Treatment should be reserved for symptomatic patients. A urine culture should be obtained prior to the initiation of therapy; 7–10 days of therapy should be adequate. The temptation to treat all positive culture results should be strongly resisted. Because the catheter often serves as a nidus of infection, it should be removed if possible or at least replaced. 8.7

Asymptomatic Bacteriuria

Asymptomatic bacteriuria in otherwise healthy adults and elderly adults does not alter mortality rate and generally should not be treated. Treatment for asymptomatic bacteriuria should be offered to patients at high risk of infectious complications such as those who are pregnant, have documented vesiculoureteral reflux, are renal transplantation recipients, or are planning to undergo urological surgery. Bacteriuria noted after removal of a urethral catheter often leads to symptomatic UTI, which can be prevented by a short course of

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antimicrobial therapy. Isolation of diphtheroids, lactobacilli, anaerobes, and coagulasenegative staphylococci (other than S. saprophyticus) generally indicates contaminants and treatment is not indicated. 8.8

Acute Pyelonephritis

Acute pyelonephritis typically causes fever, dysuria, and flank pain. Nausea and vomiting may be present. Abdominal and costovertebral angle tenderness may be present. The microbes that cause lower tract infections are responsible for the majority of cases of pyelonephritis as well. Young, otherwise healthy women with mild illness and little or no nausea may respond well to outpatient oral antibiotics for 14 days. For otherwise healthy women with mild to moderate pyelonephritis a 7-day course of a highly active agent may suffice. Other patients such as men, the elderly, or women with more severe presentations should be hospitalized. Patients with nausea and emesis may require intravenous antibiotics until they are able to take oral antimicrobial therapy. Antimicrobial therapy should be tailored to the results of urine culture and sensitivity testing. Gram stain of the urine at the time of presentation may help dictate appropriate empirical therapy. Empirical treatment should employ TMP-SMX, if the resistance rates are low in the community, or ciprofloxacin. If gram-positive cocci are seen on Gram stain or enterococci isolated from culture from the urine, ampicillin or vancomycin should be used. Antibiotic management should be adjusted on the basis of urine culture results. Patients usually improve within 2–3 days of therapy. If there has been no response (e.g., decrease in temperature and WBC and improved sense of well-being and appetite) by the third day of antimicrobial therapy, diagnostic imaging should be considered to rule out nephrolithiasis, obstruction, or abscess. Follow-up urine culture after successful resolution of symptoms is not necessary in the majority of cases but should be performed for pregnant women and those with a history of repeated UTI. BIBLIOGRAPHY Dieckhaus KD, Garibaldi RA: Prevention of catheter-associated urinary tract infections. In: Abrutyn E, Goldmann DA, Scheckler WE, eds. The Saunders Infection Control Reference Service. 2nd ed. Philadelphia: WB Saunders, 2001, pp 257–267. Fischer JF. Candiduria: When and how to treat it. Cur Infect Dis Rep 2:523–530, 2000. Kunin CM: Urinary Tract Infections, Detection, Prevention, and Management, 5th ed. Baltimore: Williams & Wilkins, 1997. Warrens JW, Abrutyn EA, Hebel JR: Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin Infect Dis 29:745–758, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

16 Gynecological Infections Rebecca A. Clark Louisiana State University Health Sciences Center, New Orleans, Louisiana, U.S.A.

1

INTRODUCTION

This chapter reviews causes of common gynecological presentations observed in outpatient settings such as vaginal discharge or genital ulcer disease and other gynecological conditions including human papillomavirus (HPV) disease, acute urethral syndrome, bartholinitis, intrauterine device– (IUD)-related infections, and Fitz-Hugh–Curtis syndrome. For each infection, the presenting symptoms, differential diagnoses, diagnostic methods, and management strategies are discussed. Tables addressing treatment options are adapted from the Centers for Disease Control and Prevention 1998 Guidelines for treatment of sexually transmitted diseases as published in the Morbidity and Mortality Weekly Report. The costs of specific therapies, a vital component in determining treatment options, are incorporated into all drug therapy tables. The costs for drugs are the least expensive average wholesale price listed in the 2000 Drug Topics Red Book. Screening recommendations for human immunodeficiency virus (HIV) testing and cervical disease are also outlined. Although the gynecological infections covered in the chapter can be managed by a general primary care provider, there are specific complications that should prompt a referral to a gynecologist. These include pelvic inflammatory disease (PID) requiring hospitalization, severe genital warts, and HPV cervical disease meeting criteria for colposcopy.

2

VULVOVAGINITIS AND VAGINOSIS

Vulvovaginitis and vaginosis are common medical problems, accounting for approximately 5 to 10 million office visits per year. The majority of cases have three infectious causes: bacterial vaginosis (40%–50%), vulvovaginal candidiasis (20%–25%), and trichomonas vulvovaginitis (15%–20%). Table 1 summarizes the different findings on physical examination and microscopy of vaginosis of various causes. 2.1

Bacterial Vaginosis

Bacterial vaginosis (BV) is the most common cause of abnormal vaginal discharge in women of childbearing age. The term vaginosis is used because of the superficial nature 301

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VAGINAL DISCHARGE Vaginal discharge can be caused by vulvovaginitis/vaginosis (Table 1), mucopurulent cervicitis, pelvic inflammatory disease (Table 7), and genital ulcer disease (Table 9). To determine the cause(s) of vaginal discharge, the clinician should perform external, speculum, and bimanual examinations and obtain vaginal secretions for microscopic examination and endocervical or urine specimens for Neisseria gonorrhoeae and Chlamydia sp. identification. Recurrent vulvovaginal candidiasis is an indication for human immunodeficiency virus (HIV) testing. See the following tables for treatments: Table 2: bacterial vaginosis Table 3: vulvovaginal candidiasis Table 4: trichomonal vaginitis Table 5: Chlamydia trachomatis cervicitis Table 6: Neisseria gonorrhoeae cervicitis Table 8: Pelvic inflammatory disease

of the infection. Generally there is not an increase in the number of polymorphonuclear neutrophils (PMNs) on the saline solution wet mount of vaginal secretions, and if there is an increase, a coinfection should be considered. Although many women are unaware of an abnormal discharge, they usually do note a strong fishy vaginal odor. The discharge is generally described as homogeneous and gray to white in color. BV represents a change in the vaginal microflora. There are a reduction of hydrogen peroxide–producing lactobacilli and an increase in the prevalence and concentration of Gardnerella vaginalis, anaerobic bacteria (e.g., Prevotella species and Mobiluncus species), and genital mycoplasmas. Gardnerella species may adhere to squamous epithelial cells, forming ‘‘clue cells’’ with the cell borders obscured by adherent bacteria. The change in bacterial flora seen with BV is accompanied by a rise in pH to as high as 7.0. BV is diagnosed by identifying three or four of the following criteria: (1) presence of clue cells, (2) pH greater than 4.5, (3) thin homogeneous vaginal discharge, and (4) a fishy odor most pronounced with mixing vaginal fluid with the 10% potassium hydroxide

Table 1 Vaginosis and Vulvovaginitis: Findings on Physical Examination and Microscopy Bacterial vaginosis Physical finding

Fishy odor

Discharge appearance Saline solution wet mount preparation Vaginal pH

Gray-white, homogeneous Clue cells >4.5

Vulvovaginal candidiasis

Vulvovaginal trichomoniasis

Noninfectious vaginitis

Erythema, labial fissures ‘‘Cottage cheese’’– like Budding yeast, hyphae <4.5

Strawberry cervix Frothy, watery, yellow-green Trichomonads

Irritated or atrophic vagina

Negative result

>4.5

>5.0

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(KOH) preparation. By using these criteria, in more than 90% of patients BV can be diagnosed. Vaginal culturing for Gardnerella species is not helpful since these organisms may be detected in 50%–60% of healthy asymptomatic women. Treatment for BV is outlined in Table 2. When treating BV, the early cure rates using oral metronidazole (500 mg bid ⫻ 1 week) are 90% at 1 week and 80% at 4 weeks. A single oral dose of metronidazole (2 g) has similar early response rates but higher rates of relapse. Topical vaginal therapy with clindamycin cream or metronidazole gel is as effective as oral metronidazole. Unfortunately, regardless of the treatment option, as many as 30% of women with bacterial vaginosis experience relapse within a month. There is no role for treating partners. Treatment of bacterial vaginosis in patients with prior preterm births has been shown to reduce prematurity (18% vs. 39%) and premature rupture of membranes (5% vs. 33%). Postpartum endometritis following cesarean section also occurs at five times the rate in women with bacterial vaginosis when compared to that in women without this diagnosis. Because of these associated complications, screening and treatment should be considered for women with previous preterm births and prior to pelvic surgery. Routine treatment of asymptomatic disease is not otherwise recommended. 2.2

Vulvovaginal Candidiasis

The most common cause of vaginitis is the yeast species Candida; C. albicans causes 80%–95% of infections. Risk factors for vaginal candiasis include antibiotic use, diabetes mellitus, and pregnancy. Women with vulvovaginal candidiasis often experience pruritus,

Table 2 Treatments for Bacterial Vaginosis Recommended options Nonpregnant women Metronidazoleb 500 mg PO bid ⫻ 7 days Clindamycinc,f cream 2%, one full applicator (5 g) intravaginally at bedtime ⫻ 7 days Metronidazole gel 0.75%, one full applicator (5 g) intravaginally bid ⫻ 5 days Pregnant women Metronidazoleb,d,e 250 mg PO tid ⫻ 7 days Alternative options for nonpregnant women Metronidazoleb 2 g PO ⫻ 1 dose Clindamycin 300 mg PO bid ⫻ 7 days Alternative options for pregnant women Metronidazoleb 2 g ⫻ 1 dose Clindamycin 300 mg BID ⫻ 7 days a

Costsa $2.45 $33.90 $24.25 $2.38 $1.86 $35.51 $1.86 $35.51

2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company. Women should be advised to avoid consuming alcohol during treatment with metronidazole and for 24 hours thereafter. c Clindamycin cream is oil-based and may weaken latex condoms and diaphragms. d Metronidazole gel 0.75% intravaginally bid ⫻ 5 days is also an alternative for low-risk pregnant women who have not had a premature delivery. e Lower doses of metronidazole during pregnancy are recommended to limit the exposure of the fetus to medication. f The use of clindamycin vaginal cream during pregnancy is not recommended because it may increase the risk for preterm deliveries among pregnant women. b

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burning, irritation, soreness, dysuria, and dyspareunia. Signs on examination include erythema, edema, excoriation, and labial fissures. There can be adherent vaginal discharge described as ‘‘cottage cheese–like’’ in the vaginal canal. On both the saline solution wet mount and KOH preparation, hyphae and budding yeast may be visualized on microscopy in most women with vulvovaginal candidiasis. However, false-negative study results may occur in 10%–30% of women. Although fungal cultures should not routinely be performed, these cultures may be helpful in situations in which the signs and symptoms suggest vulvovaginal candidiasis but the microscopy finding is negative. A positive vaginal yeast culture result may be found in 10%–15% of asymptomatic healthy women at any time and does not indicate vulvovaginal candidiasis without the typical signs and symptoms. A negative culture finding virtually excludes the possibility that a woman has vulvovaginal candidiasis. Treatment is outlined in Table 3. Topical antifungal drugs and oral azole agents such as fluconazole achieve cure rates in over 80%. Complicated vulvovaginitis and non–C. albicans species infection (5%–20%) are more difficult to treat and generally require 10–14 days of therapy. Only topical azole therapies should be used to treat pregnant women. The most effective are butoconazole, clotrimazole, miconazole, and terconazole. Most experts recommend 7 days of therapy during pregnancy. Recurrent vulvovaginitis, defined as at least four episodes per year, occurs in less than 5% of otherwise healthy women. In these women, maintenance suppressive therapy may be considered for 6 months after the initial induction regimen has resulted in negative culture findings. Regimens include ketoconazole (100 mg/day), itraconazole (50–100 mg/ day), fluconazole (100 mg/day), and clotrimazole vaginal suppositories (500 mg). Testing for HIV infection should be considered for women with recurrent vulvovaginitis since this manifestation has been shown to be a frequent presenting complaint. 2.3

Trichomonal Vaginitis

Trichomonas vaginalis is a protozoon with worldwide distribution that causes venereal vaginitis and urethritis. Vaginal T. vaginalis infection ranges from asymptomatic to a severe and acute inflammatory process. Women with trichomonal vaginitis generally present a profuse, frothy, watery green or yellow discharge. Pruritus may be noted but is less frequently seen than in patients with vulvovaginal candidiasis. Examination may show the characteristic ‘‘strawberry cervix’’ caused by intraepithelial hemorrhages, though this is seen in only 5%–10% of patients. The saline solution wet mount yields a positive result for motile trichomonads in only 50%–70% of the culture-confirmed cases, although PMNs are generally always noted. Trichomonads may also be visualized on Papanicolaou smears, but the sensitivity is only 60%–70%. The most sensitive diagnostic modality is a trichomonas culture, but this is not performed by most laboratories. Treatment is outlined in Table 4. Cure rates with metronidazole as a single 2-g oral dose or a 7-day course of 500 mg bid are 82%–88% and 85%–90%, respectively. The cure rate increases to more than 90% when sexual partners are treated simultaneously. Patients allergic to metronidazole should be desensitized. Women should be advised to avoid consuming alcohol during treatment with metronidazole and for 24 hours thereafter. Some patients may have trichomonas strains resistant to metronidazole and appear to have refractory infections. In such patients, the maximal tolerated dose of metronidazole (2–4 g orally daily for 10–14 days or 500 mg IV q6–8 h ⫻ 3 days) can be tried.

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Table 3 Treatments for Candidal Vulvovaginosis Nonprescription treatment options Butoconazole nitrate (Femstat) 2% cream 5 g/day ⫻ 3 days Clotrimazole (Gyne-Lotrimin) 1% cream 5 g/day ⫻ 7–14 days, 45-g cream Mycelex-7, 100-mg vaginal tablet 1/day ⫻ 7 days or Mycelex 3, 20-mg vaginal tablet 1 bid ⫻ 3 days Miconazole (Monistat) 2% cream 5 g/day ⫻ 7 days or 100 mg/day vaginal suppository ⫻ 7 days Tioconazole (Vagistat-1) 6.5% cream 5 g ⫻ 1 dose Prescription vaginal preparation options Clotrimazole (Mycelex) 500-mg vaginal tablet ⫻ 1 dose Miconazole (Monistat) 200-mg/day vaginal suppository ⫻ 3 days Terconazole (Terazol) 0.4% cream 5 g/day ⫻ 7 days or 0.8% cream 5 g/day ⫻ 3 days or 80-mg vaginal suppository/day ⫻ 3 days Nystatin (Mycostatin) 100,000-U vaginal tablet/day ⫻ 14 days Prescription oral regimen Fluconazole (Diflucan) 150 mg ⫻ 1 dose

Costsa $14.08 $15.99 $12.00 $9.41 $10.98 $11.57 $14.39 $13.88 $25.40 $23.25 $5.17 $26.22 $5.50 $11.15

a

2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company.

Concurrent vaginal metronidazole by suppository 500 mg/day ⫻ 5 days has also been effective. Topical paromomycin (250 mg/day for 2 weeks) can also be considered in patients who still do not respond. Tinidazole, available in Canada and Europe, can achieve cure in some cases because cross-resistance with metronidazole is incomplete. 2.4

Noninfectious Causes of Vulvovaginitis

Sometimes patients with symptomatic vaginitis have negative microscopy findings, negative yeast culture results, and a normal pH. In these cases, noninfectious causes of vaginitis should be considered. Causes may include soaps, deodorants, underwear, detergents, sanitary napkins, spermicides, douching, vaginal lubricants, exposure to hot tubs, chlorinated pools, and local application of selected medications including azole antifungals. Postmenopausal women may also suffer from vaginal atrophy and atrophic vaginitis. Common vaginal symptoms in this population include vaginal dryness, itching, vulvar pruritus, urinary symptoms (urgency, frequency, incontinence), burning, and dyspareunia. Women with vaginal atrophy generally have pale, smooth, shiny, dry-appearing tissue.

Table 4 Treatments for Trichomonas vaginitis Recommended options for pregnant and nonpregnant women

Costsa

Metronidazole 2 g PO ⫻ 1 dose Metronidazole 500 mg bid PO ⫻ 7 days

$1.86 $2.45

a

2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company.

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There can also be signs of inflammation such as patchy erythema, petechiae, increased vascularity, friability, bleeding, and discharge. Vaginal pH is commonly greater than 5.0. 3

MUCOPURULENT CERVICITIS

Although mucopurulent cervicitis is not a reportable disease in the United States, it is believed to be one of the most frequent genital infections in women. There are no standardized diagnostic criteria for mucopurulent cervicitis. Women generally have an inflamed endocervix with purulent discharge (at least 30 PMNs per 400⫻ microscopic field), edema and erythema of the zone of ectopy (area of columnar epithelium extending from the endocervix to the exocervix), and readily induced endocervical bleeding. Neisseria gonorrhoeae and Chlamydia trachomatis are the causes of mucopurulent cervicitis. Not all women, though, with N. gonorrhoeae or C. trachomatis cervical infections have abnormal findings on examination. A substantial number of women are asymptomatic and have a completely normal cervix on examination. Therefore, a normal physical examination result cannot exclude a cervical infection with these organisms. Diagnosis is generally made by culture of the endocervical canal for N. gonorrhoeae and C. trachomatis. Enriched and selective culture media (such as modified Thayer Martin medium) should be used for N. gonorrhoeae, and tissue cultures are required for C. trachomatis. However, the technical difficulty and cost of chlamydia cultures have limited their availability, and most laboratories utilize either enzyme-linked immunoassay (ELISA) or direct immunofluorescence staining techniques of cervical smears. One advantage to obtaining N. gonorrhoeae cultures is the ability to determine antimicrobial sensitivities. Gram staining the cervical discharge may also be useful in detecting N. gonorrhoeae and can provide immediate diagnostic feedback. In recent years, several nucleic acid amplification tests to diagnose both N. gonorrhoeae and C. trachomatis have been introduced. These tests are extremely sensitive, in fact nearly as sensitive as cultures, and it is possible to screen for both N. gonorrhoeae and C. trachomatis through urine testing. Therapy for mucopurulent cervicitis is outlined in Tables 5 and 6. Women infected with N. gonorrhoeae are often coinfected with C. trachomatis (and vice versa) and should be treated for both. A sample empirical regimen may include a single oral dose of cefixime 400 mg and azithromycin 1 g. A management challenge for N. gonorrhoeae infection has been the emergence of resistance, particularly to penicillins and now more recently to the quinolones. Tetracyclines and quinolones are contraindicated in pregnant or lactating women. Quinolones should not be used in women <18 years of age. The safety and efficacy of azithromycin in pregnant or lactating women have not yet been established. A test of cure 3 weeks after completion of treatment ideally should be performed particularly for women who received erythromycin, since this regimen is not highly efficacious and may be discontinued early because of gastrointestinal side effects. Between 10% and 40% of women with untreated for N. gonorrhoeae or C. trachomatis cervicitis may have clinical symptoms of acute pelvic inflammatory disease (PID), so treatment is important if there is any clinical suspicion. 4

PELVIC INFLAMMATORY DISEASE

Pelvic inflammatory disease (PID) refers to infection of the uterus, fallopian tubes, and adjacent pelvic structures that is not associated with surgery or pregnancy. Approximately 1 million U.S. women experience an episode of symptomatic PID each year. PID is believed to result from direct spread of organisms from the endocervix to the endometrial

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Table 5 Treatments for Chlamydia trachomatis Cervicitis Costsa

Recommended options Nonpregnant women Azithromycin 1 g PO ⫻ 1 dose Doxycycline 100 mg PO bid ⫻ 7 days Alternative options for nonpregnant women Erythromycin base 500 mg PO or Ethylsuccinate 800 mg PO qid ⫻ 7 days Ofloxacin 300 mg PO bid ⫻ 7 days Recommended options for pregnant women Erythromycin base 500 mg PO qid ⫻ 7 days Amoxicillin 500 mg PO tid ⫻ 7 days Alternative options for pregnant women Erythromycin base 250 mg PO qid ⫻ 14 day Erythromycin ethylsuccinate 800 mg PO qid ⫻ 7 days Erythromycin ethylsuccinate 400 mg PO qid ⫻ 14 days Azithromycin 1 g PO ⫻ 1 dose

$24.88 $2.37 $6.96 $68.21 $6.96 $4.25 $8.92 $16.25 $16.25 $24.88

a

2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company.

and fallopian tube mucosa. PID can cause severe morbidity and long-term sequelae, including chronic pelvic pain, infertility, and ectopic pregnancies. Complications requiring surgical intervention such as tubo-ovarian abscesses, pyosalpinx, and pelvic adhesions occur in 15%–20% of patients. After one episode of PID, a woman’s risk of ectopic pregnancy increases sevenfold. Approximately 12% of women are infertile after a single episode of PID, 25% after two episodes, and over 50% after three or more episodes. Women who are HIV-infected appear to have more severe episodes of PID and may be more likely to require surgical intervention.

Table 6 Treatments for Neisseria gonorrhoeae Cervicitis Recommended optionsa

Costsb

Cefiximec 400 mg PO ⫻ 1 dose Ceftriaxonec 125 mg IM ⫻ 1 dose (250-mg vial) Ciprofloxacind 500 mg PO ⫻ 1 dose Ofloxacind 400 mg PO ⫻ 1 dose plus Regimen for Chlamydia trachomatis (Table 5)

$10.88 $14.22 $3.62 $5.95

An alternative regimen is spectinomycin 2 g IM ⫻ 1 dose. This can be used for pregnant women intolerant of cephalosporins. b 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company. c Other single-dose cephalosporin regimens include ceftizoxime 500 mg, cefotaxime 500 mg, cefotetan 1 g IM, cefoxitin 2 g IM with probenecid 1 g. d Other single-dose quinolone regimens include enoxacin 400 mg, lomefloxacin 400 mg, norfloxacin 800 mg. a

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Table 7 Criteria for Diagnosis of Pelvic Inflammatory Disease Minimal clinical criteria Lower abdominal tenderness Bilateral adnexal tenderness Cervical motion tenderness Additional criteria Oral temperature >38.3⬚C Abnormal cervical or vaginal discharge Elevated erythrocyte sedimentation rate and/or C-reactive protein Culture or nonculture evidence of cervical infection with N. gonorrhoeae or C. trachomatis Definitive criteria Histopathological evidence on endometrial biopsy Tubo-ovarian abscess on sonography or other imaging technique Laparoscopic abnormalities consistent with pelvic inflammatory disease (PID) Source: Adapted from Centers for Disease Control and Prevention, 1997.

Multiple organisms have been implicated as etiological agents in PID, and most cases of PID are associated with more than one organism. The major causative microorganisms are C. trachomatis, N. gonorrhoeae, and a variety of anaerobic and aerobic bacteria. The microorganisms of BV are also commonly isolated from the upper genital tract of patients with PID, and BV is a frequent concurrent diagnosis. PID is generally a clinical diagnosis; see Table 7. PID may be asymptomatic; bilateral lower abdominal pain is the most common presenting complaint. The differential diagnosis includes endometriomas, ruptured ovarian cysts, adnexal torsions, ectopic pregnancy, appendicitis, and other intra-abdominal infections. Treatment of PID consists of bedrest, pelvic rest, and antibiotics. The two recommended outpatient regimens are listed in Table 8. For women with coexistent bacterial vaginosis, regimen B is preferred because of the inclusion of metronidazole. Not all women diagnosed with PID need hospitalization. However, patients treated as outpatients should be clinically reevaluated within 72 hours. Those not responding well

Table 8 Outpatient Treatment of Pelvic Inflammatory Disease Regimens

Costsa

A Cefoxitin 2 g IM plus probenecid 1 g PO in single dose or Ceftriaxone 250 mg IM or Other parenteral third-generation cephalosporin plus Doxycycline 100 mg bid PO ⫻ 14 days

$22.45 $14.22

$4.74

B Ofloxacin 400 mg PO bid ⫻ 14 days plus Metronidazole 500 mg PO bid ⫻ 14 days a

$133.74 $4.90

2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company.

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GENITAL ULCER DISEASE In the United States, the most common causes of genital ulcer disease are herpes simplex virus, syphilis, and chancroid (Table 9). Diagnostic tests for syphilis include serological testing, dark-field microscopy and direct immunofluorescent antibody staining. Testing for herpes simplex virus can be done by culture or antigen detection (Figure 1). Human immunodeficiency virus (HIV) testing should be considered in all women with genital ulcer disease. See the following tables for treatments: Table 10: herpes simplex virus Table 11: primary and secondary syphilis Table 12: chancroid

should be hospitalized. Other characteristics prompting hospitalization include an uncertain diagnosis, inability to exclude a surgical emergency, suspicion of a pelvic abscess, adolescence, pregnancy, failure to tolerate an outpatient regimen, and inability to arrange clinical follow-up within 72 hours. There should also be a low threshold for admitting HIV-infected women.

5

GENITAL ULCER DISEASE

In the United States and other developed countries, most genital ulcer disease is caused by herpes simplex virus (HSV), syphilis, or chancroid (also see Chapter 17). HSV is the most common of these. Differences among the three most common sexually transmitted infectious causes of genital ulcer disease are outlined in Table 9. There is considerable overlap in the clinical signs and symptoms of the various genital ulcer diseases. Therefore, diagnosis of genital ulceration based only on the morphological examination findings is difficult and subject to a high degree of inaccuracy. Figure 1 is a flow diagram suggesting a diagnostic approach. Donovanosis (granuloma inguinale), lymphogranuloma venereum (LGV), leishmaniasis, and amebiasis are rare causes of genital ulcers. All are unusual in the United States and should be primarily considered among patients from other countries. Donovanosis caused by Calymmatobacterium granulomatis is endemic in tropical and subtropical areas such as India, New Guinea, parts of South America, South Africa, Zambia, Vietnam, and

Table 9 Clinical Characteristics of Genital Ulcer Disease

Recurrence Pain Induration Adenopathy Incubation Description

Herpes simplex virus

Syphilis

Chancroid

Yes Yes No Yes 2–21 Days Vesicular, shallow ulcer

No No Yes Yes 9–90 Days Clean base

No Yes No Yes 3–7 Days Exudate, deep ulcer

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Figure 1 Flow diagram for workup of genital ulcer disease. For both the dark-field examination and direct immunofluorescent antibody staining, a slide is pressed against the open ulcer to pick up the serous ulcer exudate and then viewed under a special microscope by an experienced technician. Donoavanosis is highly unlikely unless travel history suggests exposure. HSV, herpes simplex virus; LVG, lymphogranuloma venereum.

Japan. Lymphogranuloma venereum, caused by LGV serovars of Chlamydia trachomatis, is most frequently seen in selected areas of India and Africa. Noninfectious causes of genital ulcer disease include Behc¸et’s disease, Crohn’s disease, lichen planus, ulcerated tumors (usually squamous cell carcinoma), and factitial ulceration. A rare manifestation described in women with advanced HIV disease is idiopathic aphthous vulvar or vaginal ulcer, which can be intractable, progress to fistula formation, and cause severe bleeding. There is a clear association between HIV infection and genital ulcer disease. The CDC recommends that HIV testing be performed in the management of patients who have either syphilis or chancroid and be considered for those diagnosed with HSV.

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311

Herpes Simplex Virus

Herpes simplex virus is an encapsulated double-stranded deoxyribonucleic acid (DNA) virus in the same family with Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, herpes 6 and 7 viruses, and herpes B virus. HSV-1 usually infects the oral mucosa, causing the common cold sore (see Chapter 20). Less common manifestations include encephalitis, keratitis, and herpetic whitlow. HSV-2 causes most genital ulcer disease, though there is overlap of infectious manifestation between types 1 and 2. About one in five Americans over the age of 12 has been infected with HSV-2 but less than 20% are aware of having been infected. On the basis of serological studies, genital HSV-2 has been diagnosed in at least 45 million persons in the United States. The prevalence of HSV has increased about 30% during the last two decades. Prodromal symptoms such as pain, burning, itching, or stinging may occur 1 to 4 days before lesions are apparent. The lesions of HSV are characteristically multiple, painful, small grouped vesicles on an erythematous base. The vesicles then erode over the next few days to form painful ulcerations. Immunocompromised patients such as the HIVinfected population, may have deep, large, coalescing ulcerations that do not resolve even with treatment. The first symptomatic outbreak of HSV is generally the most severe. There may be accompanying external genital edema and tender nonfluctuant inguinal adenopathy. Constitutional symptoms, including fever, malaise, and anorexia, may be present in up to 50%–80%. In untreated patients, ulcerations peak in severity at 10–12 days and then heal in 3–4 weeks. Subsequent episodes of genital HSV are usually not as symptomatic as the initial outbreak and heal more rapidly. Psychological or physical stress and the onset of menses may trigger recurrences. Individuals may experience an average of four recurrences annually. Up to 38% have 6 or more recurrences and 20% have 10 or more recurrences. Patients may shed HSV in genital secretions during asymptomatic times. HSV infection can be confirmed by either isolation of virus in tissue culture or demonstration of HSV antigens or DNA in scrapings of lesions. Most culture results are positive within 48–96 hours after inoculation. The sensitivity of viral isolation is best for vesicular lesions and primary episodes. Serological testing is generally not helpful since the majority of people in the United States and Europe are seropositive for HSV-1 (50%– 80%) and HSV-2 (20%–80%), depending on the population studied. Staining of cells by Papanicolaou or Wright-Giemsa stain (Tzanck test preparation) obtained from scrapping the base of the HSV ulcer may reveal charactersitic multinucleated giant cells and intranuclear inclusions. Treatment for HSV is very effective but not curative (see Table 10). Topical treatment is substantially less effective than the systemic therapies and its use is discouraged. Treatment may be extended beyond 10 days if healing is incomplete at that time. Nonparenteral outpatient therapies that can be considered after failure of initial regimens include acyclovir 400–800 mg five times daily, famciclovir 500 mg bid or tid, topical trifluridine, or topical cidofovir gel. Unfortunately, all acyclovir-resistant strains are resistant to valacyclovir and most are resistant to famciclovir. Suppressive therapy should be considered in those with six or more recurrences per year. It can reduce symptomatic outbreaks by 75%. Suppressive therapy has not been associated with emergence of clinically significant acyclovir resistance among immunocompetent patients. It may reduce but does not eliminate asymptomatic viral shedding.

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Table 10 Treatments for Herpes Simplex Virusa Treatment options Primary or first clinical episode Acyclovir 400 mg PO tid ⫻ 7–10 days or 200 mg PO 5 times/day ⫻ 7–10 days Famciclover 250 mg PO tid ⫻ 7–10 days Valacyclovir 1 g PO bid ⫻ 7–10 days Recurrent episodes Acyclovir 800 mg PO bid ⫻ 5 days Famciclover 125 mg PO tid ⫻ 5 days Valacyclovir 500 mg PO bid ⫻ 5 days Suppressive therapy Acyclovir 400 mg PO bid Famciclover 250 mg PO bid Valacyclovir 250 mg bid or 500 mg/day

Costsb $16.70 $20.79 $76.03 $84.00

for for for for

7 7 7 7

days days days days

a

The safety of oral therapies in pregnant women has not been established. GlaxoWellcome, Inc., in cooperation with the Center for Disease Control (CDC), maintains a registry to assess the use and efficacy of acyclovir and valacylovir during pregnancy. Women who use these drugs should be reported (telephone 800-7229292, extension 38465). The current registry findings do not indicate an increased risk for major birth defects after acyclovir treatment. There is limited information on valacyclovir and famciclovir. The fist clinical episode of herpes simplex virus (HSV) during pregnancy may be treated with oral acyclovir. b 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company.

5.2

Syphilis

Syphilis, caused by the spirochete Treponema pallidum, is characterized by three stages. Primary syphilis is manifested as a genital ulceration or chancre that starts as a small red macule that evolves into a painless ulcerated papule. The ulcer has a clean base with sharply demarcated raised and indurated borders. Nontender, rubbery regional adenopathy may develop. Without treatment the chancre resolves within 3–8 weeks. In about half the patients untreated primary syphilis progresses to secondary disease and in the other half latency occurs. Patients progressing to secondary syphilis may have systemic signs or symptoms that occur coincidentally with the primary chancre or weeks to months after chancre resolution. The characteristic finding is a cutaneous and/or mucosal rash, which occurs in 75%–100% of patients. The rash is a maculopapular eruption involving the trunk and characteristically the palms and soles. Patients may have other symptoms or findings, including a low-grade fever, sore throat, headache, lymphadenopathy, alopecia, arthritis, and hepatitis. A patient with latent syphilis by definition has serological evidence of syphilis but is asymptomatic. The U.S. Public Health Service defines early latency as 1 year from the onset of infection. Late latency is defined as more than 1 year from the acquisition of infection. Asymptomatic persons with positive serological findings but an unknown date of infection are also considered to have late latent syphilis. Tertiary syphilis refers to a chronic form of the infection involving the skin, bones, central nervous system, or viscera, particularly the heart and great vessels. Clinically manifest tertiary syphilis is rare: 20 years or more of latent infection may elapse before patients experience its symptoms.

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Diagnosis of primary syphilis can be made by physical exam and dark-field microscopy of the ulcer. Serological tests may not have positive results during this time. If available, the dark-field examination and direct immunofluorescent antibody staining of the ulcer are excellent inexpensive methods to diagnose primary syphilis. With an experienced technician, in 85%–92% of persons with primary syphilis T. pallidum is visualized under the microscope. Secondary syphilis can be diagnosed by characteristic findings on physical exam, dark-field microscopy of skin lesions, and serological testing. Serological tests can be divided into two major categories: (1) tests that detect nonspecific nontreponemal antibodies including the Venereal Disease Research Laboratories (VDRL) and rapid plasma reagin (RPR) card test and (2) tests that detect antibodies specific to T. pallidum, including the Treponema pallidum hemagglutination assay (TPHA), enzyme immunoassay (EIA), and flourescent antibody absorbed (FTA-abs) tests. The nontreponemal tests (RPR, VDRL) are used for screening. All positive nontreponemal test results are confirmed with a specific T. pallidum test. Immunodeficient persons, such as symptomatic HIV-infected patients, are more likely to have falsely negative RPR or VDRL test results. False-negative nontreponemal test findings may also result from the prozone phenomenon when the serological finding becomes positive only after dilution of the test sample. A positive RPR finding in the context of a negative FTA-abs finding is generally considered a false-positive result, indicating that the patient does not have syphilis. The reasons for false-positive results are numerous; they include infection with HIV, other spirochete infections, autoimmune diseases, pregnancy, chronic liver disease, infectious mononucleosis, chickenpox, measles, parasitic infections, and tuberculosis. The VDRL test becomes reactive approximately 2 weeks after the appearance of the chancre and is reactive in 70% of persons with primary syphilis. It yields a positive result in virtually all persons with secondary syphilis. Treatment options are summarized in Table 11. The preferred treatment is penicillin. All pregnant women should be screened for syphilis. High-risk patients should also be screened twice; once in the third trimester and once at delivery. Pregnant women allergic to penicillin should be desensitized. Some experts recommend a second dose of benzathine penicillin for pregnant women who have primary, secondary, or early latent syphilis. Women treated for syphilis during the second half of pregnancy are at risk for

Table 11 Treatments of Syphilis Primary, secondary, and early latent Preferred option for pregnant and nonpregnant women Benzathine penicillin 2.4 million U IM ⫻ 1 dose Penicillin-allergic options for nonpregnant women Doxycycline 100 mg PO bid ⫻ 14 days Tetracycline 500 mg PO qid ⫻ 14 days Erythromycin 500 mg PO qid ⫻ 14 days Late latent Preferred option (pregnant and nonpregnant women) Benzathine penicillin 2.4 million U IM/week ⫻ 3 weeks Penicillin-allergic options for nonpregnant women Doxycycline 100 mg PO bid ⫻ 4 weeks Tetracycline 500 mg PO qid ⫻ 4 weeks Erythromycin 500 mg PO qid ⫻ 4 weeks

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premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction, an acute febrile reaction often accompanied by headache, myalgia, and other symptoms that occur within the first 24 hours of treatment. 5.3

Chancroid

Chancroid or soft chancre is caused by Haemophilus ducreyi. Though uncommon in most areas, it has been shown to cause discrete microepidemics in specific cities. The incidence among women is generally very low. Chancroid begins as a small inflammatory papule that erodes over a few days to form an extremely painful deep ulcer with soft, ragged margins. The ulcer base is often friable and covered with a yellow-gray exudate. There may be multiple ulcers. After 1 week, in the majority of patients painful inguinal lymphadenopathy that is usually unilateral develops. Lymph node suppuration (bubo formation) can occur in up to 25% of cases. Although the ulcer is usually painful in men, it frequently is not in women. The majority of lesions are at the entrance to the vagina, the forchette, labia, vestibule, and clitoris. The diagnosis of chancroid is usually presumptive; it is based on negative test findings for syphilis and HSV. The organism can be cultured but is very fastidious and requires selectively enriched chocolate-based agar with vancomycin supplementation. Even with this medium, the sensitivity is ⱕ80%. A polymerase chain reaction (PCR) method has been developed but is not routinely available in most clinics. Preferred treatments are listed in Table 12. Several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported worldwide. Fluctuant lymph nodes over 5 cm in diameter should be drained. 6

HUMAN PAPILLOMA VIRUS

The human papilloma viruses (HPVs) are nonencapsulated double-stranded DNA viruses that cause cutaneous and mucosal warts (also see Chapter 17). Some have potential for carcinogenesis. Venereal HPV infections may present as anogenital warts or condylomata acuminata (usually caused by types 6 and 11) or cause abnormal Papanicolaou smear results. Over 50% of the population become infected with HPV during their lifetime. The annual risk for an incident infection in sexually active women is 14%. Although most genital tract HPV infections in women are subclinical, it is clear that specific high-risk types (i.e., types 16, 18, 31, 35) are associated with cervical dysplasia or neoplasia. Cytological and histopathological findings of squamous intraepithelial lesions (SILs) are manifestations of cervical infection by HPV. Several studies have found that HPV may be a transient infection. Among immunocompetent women, the median duration of HPV infection has been found to be 8

Table 12 Treatments for Chancroid Recommended options Azithromycin 1 g PO ⫻ 1 dose Ceftriaxone 250 mg IM ⫻ 1 dose Ciprofloxacin 500 mg PO bid ⫻ 3–5 days Erythromycin base 500 mg PO qid ⫻ 7 days a

Costsa $24.88 $14.22 $21.72, 3-day supply $6.96

2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company.

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HUMAN PAPILLOMAVIRUS Genital tract infections with human papillomavirus (HPV) may result in genital warts and cervical disease including cervical intraepithelial neoplasia (CIN) and cancer. Women should be routinely screened for HPV disease through cervical screening tests such as Papanicolaou smears or colposcopy. Women with HPV infection should be offered human immunodeficiency virus (HIV) testing. Treatment is outlined in Table 13.

months. By 12 months after the initial infection, 70% have cleared the infection. Risk factors for persistent infection are older age and infection with high-risk types. Women with persistent HPV infection are at higher risk for SIL or CIN. Reliable serological tests for HPV infection are not available, and HPV cannot be cultured. Diagnosis of genital warts may be made by the characteristic clinical appearance and confirmed by biopsy. There are no data to support the use of type-specific HPV nucleic acid tests in the routine diagnosis or management of either visible genital warts or abnormal Papanicolaou smear results. The Papanicolaou (Pap) smear is an effective and relatively low-cost screening test for HPV-related cervical disease. Both the American College of Obstetricians and Gynecologists and the American Cancer Society recommend annual Pap smears for all sexually active women. The guidelines for follow-up cervical screening depend on a woman’s HIV status. Uninfected women should be referred to colposcopy if they have high-grade SIL. Women with low-grade SIL or atypical cells of uncertain significance (ASCUS) may either be referred for colposcopy or followed closely with Papanicolaou smears every 4–6 months for 2 years until the results of three consecutive smears are negative. If the abnormalities persist on repeat smears, then the women should be referred to colposcopy. Women who have had a hysterectomy do not require an annual Papanicolaou smear unless the hysterectomy is related to cervical cancer or dysplasia. It is clear that HIV-infected women are at higher risk for HPV-related disease such as genital warts and SIL. The frequency and severity of SIL lesions are related to the degree of immunosuppression. Women with low CD4 cell counts are at highest risk for abnormal Pap smear findings, which may herald an undiagnosed HIV infection. Women with abnormal Pap smear results not explained by an intercurrent infectious cause (such as vulvovaginitis or cervicitis) should be offered HIV testing. Because of the increased risk for cervical disease, HIV-infected women are advised to have a Pap smear at the time they are diagnosed with HIV infection. If the findings are normal, the smear should be repeated in 6 months. Women who have never had abnormal findings and who have two normal smear results after the HIV diagnosis may undergo annual screening. If inflammation or atypia is present, the Pap smear should be repeated in three months. Routine baseline colposcopy screening is not recommended, but women with SIL, HPV disease, ASCUS, and persistent atypia should be referred to colposcopy. Not all warts progress. If left untreated, visible genital warts may resolve spontaneously or remain unchanged. It is therefore not necessary to try to treat all warts. Topical treatment options are outlined in Table 13. Unfortunately there are high treatment failure and recurrence rates. If the patient and provider believe treatment would be beneficial,

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Table 13 Topical Treatments for External Genital Wartsa Options Patient-applied Podofilox 0.5% solution or gel (may give up to 4 cycles) Imiquimod 5% cream (may give up to 16 weeks) Provider-administered Podophyllin resin 10%–25% Tricholoracetic acid (TCA) or bichloroacetic acid (BCA)c 80%–90%

Costsb $62.28, 4 ml $116.64 (250 mg, 12 packets)

a

The safety of podofilox, imiquimod, and podophyllin resin during pregnancy has not been determined. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics Company. c TCA or BCA and podophyllin may also be used to treat vaginal warts. b

there are several treatment choices, including topical applications, cryotherapy, surgical removal, intralesional interferon, or laser surgery. 7 7.1

OTHER GYNECOLOGICAL INFECTIONS Acute Urethral Syndrome

Other illnesses to consider when evaluating women with symptoms suggestive of cervicitis are acute cystitis and acute urethral syndrome. Dysuria is a predominant complaint for both these diagnoses, although women with urethritis generally have a more gradual onset of mild symptoms. Typically fewer than 105 organisms are recovered from each milliliter of urine among women with urethritis. However, the urine sediment should show PMNs if the woman has an infectious cause of urethritis. Women with urethritis often have a concurrent cervicitis. The urethra is actually the usual site of infection for N. gonorrhoeae and C. trachomatis among women who have had a hysterectomy. If a sexually transmitted infection is suspected as the cause for urethritis, then diagnostic testing for both N. gonorrhoeae and C. trachomatis should be performed from urethral or urinary specimens. Escherichia coli, Staphylococcus saprophyticus, and Trichomonas spp. are other possible etiological agents that have been shown to cause urethritis. The antibiotic choice for treatment should be guided by findings from the diagnostic workup. 7.2

Bartholinitis

Bartholin’s gland is a 1-cm structure near the base of the labia minora on each side of the vagina. The gland is generally nonpalpable and nontender. If there are inflammation and subsequent blocking of the duct, a sterile cyst may develop. Infection of the gland behind the blockage results in a Bartholin’s gland abscess. Women with this infection are often asymptomatic but may have palpable enlargement, tenderness, and edema of the gland. Up to 28% of women with concurrent N. gonorrhoeae cervicitis have the pathogen isolated from their gland. In series evaluating women with Bartholin’s abscesses, N. gonorrhoeae accounted for only 5%–12% of the infections. Other etiological agents include C. trachomatis, anaerobic bacteria, Escherichia coli, Proteus mirabilis, S. aureus, streptococci, Haemophilus influenzae, and Ureaplasma urealyticum. Antibiotic therapy should be directed to cover the infectious isolate and surgical drainage considered. For women

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with bartholinitis of uncertain cause, either a combination of ofloxacin plus clindamycin or doxycycline alone may be tried. 7.3

Intrauterine Device–Related Infections

Intrauterine devices (IUDs) have been an important method of contraception worldwide. Because of concerns about pelvic inflammatory disease, IUDs are used infrequently in the United States. The Dalkon Shield device (now withdrawn from the market) was associated with a higher risk for PID throughout the duration of its use. In contrast, the risk from other IUDs has been markedly less (presently there are two available in the United States: Paragaurd and Progestasert), and the increased risk has only been detectable within the first 4 months of insertion. This finding implies that contamination of the endometrial cavity at the time of insertion, and not the device itself, is predominantly responsible for IUD-related PID. For this reason prophylactic administration of doxycycline at time of insertion is recommended. Experts have indicated that an IUD is not an optimal contraception method among HIV-infected women because of the increased risk for PID and the more severe presentation noted in this population. The IUD should be immediately removed in all women suspected of having PID and appropriate cultures performed. In addition to antibiotics directed to treat PID, pelvic ultrasonography should be considered to determine whether a pelvic abscess is present. Other gynecological complications that have been linked to IUDs include infertility (associated primarily with the Dalkon Shield) and pelvic actinomycosis. IUDs may be associated with BV but the mechanism that increases the risk is not well understood. 7.4

Fitz-Hugh–Curtis Syndrome

Fitz-Hugh–Curtis syndrome is acute perihepatitis associated with N. gonorrhoeae or C. trachomatis. Although this infection generally occurs by direct extension from the fallopian tubes to the liver capsule and overlying peritoneum, it can spread by lymphatic or hematogeneous means. Symptoms include abdominal pain, hepatic tenderness, and right upper quadrant peritoneal signs. A definitive diagnosis may be made at laparoscopy when adhesions described as ‘‘violin strings’’ are seen between the liver capsule and peritoneum. The standard treatment recommended for PID is adequate to treat perihepatitis. BIBLIOGRAPHY Centers for Disease Control. Pelvic inflammatory disease: Guidelines for prevention and management. MMWR Morb Mortal Wkly Rep 40:1–25, 1991. Centers for Disease Control. 1998 Guidelines for treatment of sexually transmitted diseases. MMWR Morb Mortal Wkly Rep 47:1–118, 1997. Ho GYF, Bierman R, Beardsley L, Chang CH, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338:423–428, 1998. Holmes KK, Mardh PA, Sparling PF, Wiesner PJ, Cates W, Lemon SM, Stamm W. Sexually Transmitted Diseases, 2nd ed., McGraw-Hill, 1990. Korn A, Landers DV. Gynecological disease in women infected with human immunodeficiency virus type 1. J Acquir Immune Defic Syndr 9:361–370, 1995. Koutsky LA, Holmes KK, Critchlow CW, Stevens CE, Paavonen J, Beckmann AM, DeRouen TA, Galloway DA, Bernon D, Kiviat NB. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 327:1272–1278, 1992.

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Kurman RJ, Henson DE, Herbst A, Nollar KL, Schiffman MH. Interim guidelines for management of abnormal cervical cytology. JAMA 271:1866–1869, 1994. Mandell GL, Bennett JE, Doling R. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia, Churchhill Livingstone, 2000. Sobel JD. Vaginitis. New Engl J Med 337:1896–1903, 1997. Stamm WE, Wagner KF, Amsel R, Alexander ER, Turck M, Counts GW, Holmes KK. Causes of the acute urethral syndrome in women. N Engl J Med 303:409–415, 1980.

17 Male Urogenital Syndromes Craig S. Conover and Sheila M. Badri Cook County Hospital, Chicago, Illinois, U.S.A.

Mark Potter Loyola Stritch University, and Provident Hospital of Cook County, Chicago, Illinois, U.S.A.

1

INTRODUCTION

This chapter provides an overview of common male urogenital syndromes including urethritis, genital ulcers, genital warts, prostatitis, epididymitis, and orchitis. Clinical presentation, differential diagnosis, diagnostic testing, and management strategies including indications for referral are outlined. Many of the syndromes reviewed are caused by sexually transmitted diseases (STDs). The Centers for Disease Control and Prevention (CDC) STD guidelines provide evidence-based recommendations for STD evaluation, management, and prevention and should be available as a reference in clinics seeing even the occasional patient with a STD. CDC Guidelines are available on the Internet at http://www.cdc.gov/ nchstp/dstd/dstdp.html, or as hardcopies which may be ordered by calling 1-888-232-3228. 2

URETHRITIS

Penile discharge or dysuria is the usual manifestation of urethritis in males. The characteristic findings are mucoid or purulent urethral discharge with polymorphonuclear leukocytes (PMNs) on urethral smear Gram stain. Urethritis is called gonococcal urethritis (GU) when due to Neisseria gonorrhoeae and nongonococcal urethritis (NGU) if N. gonorrhoeae is not detected. The major causes of urethritis are outlined in Table 1. N. gonorrhoeae and Chlamydia trachomatis are the most important microbiological entities considered in men with urethritis. N. gonorrhoeae is well adapted for growth on mucous membranes and can infect any part of the genital tract as well as extragenital sites. C. trachomatis is the most common bacterial pathogen to cause STD and is a copathogen in up to a quarter of men infected with N. gonorrhoeae. Other pathogens implicated as causes of nonchlamydial NGU are outlined in Table 1. About 35% of men with symptomatic urethritis have no pathogen identified despite extensive microbiological testing. A small percentage of cases of urethritis have noninfectious causes; they are also reviewed in Table 1. Occasionally heavy crystalluria, semen, or urine is mistaken for urethral discharge. Causes of urethral discharge other than STD should be considered especially in older patients and those who are not sexually active. 319

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URETHRITIS Penile discharge, dysuria May be asymptomatic Usually due to N. gonorrhoeae or C. trachomatis and less commonly to other infectious agents or noninfections (Table 1) Difficulty of accurately differentiating gonococcal urethritis (GU) from nongonococcal urethritis (NGU) Diagnosis based on Presence of WBCs in urethral swab or urine Identification of pathogen by culture (GU) or nucleic acid amplification techniques (GU and NGU) Treatment (Table 2) Treatment for GU and NGU if gonorrhea suspected Treatment for NGU alone if gonorrhea not suspected Approach to urethritis patient summarized in Figure 1 Partners of patients with sexually transmitted disease–(STD)-associated urethritis treated even when asymptomatic

Table 1 Major Causes of Urethritis Infectious Gonococcal urethritis (GU) Neisseria gonorrhoeae Nongonococcal urethritis (NGU) Chlamydia trachomatis Trichomonas vaginalis Herpes simplex virusa Neisseria meningitidisb Ureaplasma urealyticumc Mycoplasma genitaliumc Candida speciesd Bacterial urethritis associated with urinary tract infection (UTI), prostatitis, urethral stricture, phimosis, trauma, or congenital abnormalities a

Noninfectious Self-induced discharge from repeated urethral ‘‘milking’’e Foreign object/trauma Chemical irritation (e.g., spermicides, ?alcohol) Reiter’s syndromef Stevens Johnson syndromeg Wegener’s granulomatosis

Occurs especially with primary infection; penile lesions are almost always present. Occasional cause of urethritis that is indistinguishable from GU on Gram stain; most commonly occurs in males who have been the recipients of fellatio. c Controversial—found in asymptomatic patients without urethral inflammation or subsequent urethritis. d Usual symptom is dysuria at tip of penis only; may be accompanied by candidal balanitis. e Discharge is minuscule and typically occurs in health-conscious patients; may be preceded by an ‘‘affair’’ or a documented episode of urethritis. f Arthritis, uveitis, skin and mucous membrane lesions most commonly seen in young men; associated with human leukocyte antigen 27 (HLA-27) histocompatibility antigen. g Can be triggered by herpes infection. b

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Clinical Evaluation

The majority of males with urethritis due to C. trachomatis and a minority of males with N. gonorrhoeae urethritis are reportedly asymptomatic. Such asymptomatic infections contribute substantially to ongoing transmission and are currently the focus of populationbased screening. Aside from a report of clear or purulent discharge, male patients may also report dysuria, vague penile pain, or an itchy sensation. Profuse purulent discharge with acute onset and moderate dysuria is highly suggestive of gonorrhea. Minimal to no detectable mucoid discharge with minimal dysuria is highly suggestive of NGU. Discharge may be detected only in the morning or detected as crusting at the meatus or staining on the underwear especially with NGU. Typical incubation periods for GU (2–7 days) and NGU (7–21 days) vary. Because of multiple potential exposures in most patients, this variation is usually not a useful differentiating feature. Differentiation between GU and NGU based on clinical grounds alone is about 75% accurate. On entry to the clinic, patients with possible urethritis should be instructed not to void prior to the examination if possible. Voiding eliminates discharge from the urethra and may result in difficulty in detecting discharge during subsequent examination. Examination is usually performed with the patient standing in front of the seated examiner and should include a search for genital skin lesions, penile induration due to scarring, foreign body, inguinal lymphadenopathy, and testicular, epididymal, and urethral abnormalities. Occasionally penile edema due to lymphangitis or thrombophlebitis is present. The foreskin should be retracted in uncircumcised patients to check for balanitis, ulcers, and tumors. The urethral opening (penile meatus) should be examined by gentle pinching at the 6 and 12 o’clock positions. Urethral discharge may not always be present at the time the physical exam is performed; in this situation, milking the distal urethra by squeezing the penis proximally to distally or repeating the examination after a period of no voiding for 2 hours may be helpful in order to elicit a discharge. Gonococcal and chlamydial urethritis may be associated with conjunctivitis due to self-inoculation. Extragenital gonococcal infections (e.g., pharyngitis, proctitis) are more common in homosexual men and are often asymptomatic. Untreated gonococcal infections can also disseminate, causing skin lesions, endocarditis, arthritis, and meningitis. C. trachomatis can cause proctitis. It rarely (<1% of cases) is associated with reactive arthritis or Reiter’s syndrome. Uncommonly urethritis is associated with chills, fever, nocturia, hematuria, frequency, urgency, perineal pain, scrotal masses, or genital pain other than dysuria or urethral pain. These findings should prompt consideration of alternative diagnoses including urinary tract infection (UTI), prostatitis, epididymitis, or orchitis. Symptoms of urethritis usually resolve spontaneously, even without treatment, within 6 months for GU and 3 months for NGU. However, untreated, asymptomatic individuals may remain infectious. 2.2

Laboratory Diagnosis

Many men are inappropriately treated with multiple courses of antibiotics for suspected urethritis even though there is no objective evidence of an inflammatory process. Clinicians should attempt to document the presence of urethral inflammation by one of the following methods: 1. 2.

Presence of mucopurulent or purulent discharge Gram stain of urethral discharge demonstrating ⱖ5 white blood cells (WBC) per high-powered microscopic field (100⫻ lens, oil immerson)

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3.

First-void urine demonstrating leukocyte esterase on dipstick or >10 WBC per high dry microscopic field (40⫻ lens)

Urethral discharge should be examined by Gram stain if feasible. The presence of gram-negative intracellular diplococci is sufficient to make the diagnosis of GU. If the Gram stain result is negative or equivocal (e.g., extracellular gram-negative diplococci), a culture or nucleic acid–based test for N. gonorrhoeae should be performed. Cultures for N. gonorrhoeae should be plated and processed immediately on selective media such as Thayer Martin agar. If discharge cannot be elicited on physical exam, a diagnostic specimen can be obtained by insertion of a small calcium alginate swab about 1–2 cm into the urethra. In addition, a first-void urine (initial 10 cc) can be obtained in patients with no discharge to evaluate for WBC (see earlier discussion) and for diagnostic testing using nucleic acid amplification techniques (see later discussion). The diagnosis of NGU is often based on Gram stain findings (increased WBC and no visible bacteria) without further diagnostic testing. Testing for Chlamydia sp. is advisable from a public health standpoint. Confirming the diagnosis is useful for the purposes of partner notification and treatment. Culture for C. trachomatis is impractical in most settings. The sensitivity of rapid antigen tests, deoxyribonucleic acid (DNA) hybridization probes, and enzyme immunoassays for C. trachomatis is limited although their specificity is in the range of 97%–99%. Nucleic acid amplification tests have decreased in cost substantially and are increasingly used to detect C. trachomatis and N. gonorrhoeae DNA in urine as well as other genital specimens. These methods have equal sensitivity to cultures for N. gonorrhoeae and are more sensitive than culture, antigen-based testing, or DNA probes for the detection of C. trachomatis. Trichomonas vaginalis can be identified on Gram stain or wet mount; however, both these methods are inferior to culture, which is not readily available. Tests for detection of Ureaplasma urealyticum are not widely available or useful clinically. An approach to the patient with suspected urethritis is summarized in Figure 1. Because patients with urethritis may be at risk for other STDs, serological testing for syphilis and human immunodeficiency syndrome (HIV) is advisable for men with confirmed N. gonorrhoeae or C. trachomatis urethritis. 2.3

Treatment Recommendations

Treatment recommendations are summarized in Table 2. Emphasis is placed on singledose regimens. Such regimens delivered under direct observation help ensure compliance and have greater effectiveness than multiple-dose regimens. Given the possibility of incubating infection and potential difficulties with follow-up after test results become available, patients with GU are assumed to have NGU for the purposes of treatment. If treatment is initiated presumptively because of delay in availability of diagnostic test results, patients should be given antibiotics as appropriate for GU if the discharge is purulent or profuse or if recommended by public health authorities on the basis of local incidence figures for gonorrhea. If Gram stain is available, initial treatment decisions are based on the criteria outlined in Figure 1. 2.4

Follow-Up

Patients should abstain from sexual intercourse for 7 days after a single-dose regimen or until a 7-day regimen has been completed and until the partner has completed a course of

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Figure 1 The evaluation of the patient with suspected urethritis should begin with a Gram stain of urethral discharge. If gram-negative intracellular diplococci are present, test and treat for GU and NGU. If NGU is more likely, test for NGU and GU and treat for NGU. (1) Urine or urethral swab for DNA probe or PCR. (2) Urethral swab for culture or urine for DNA probe or PCR. GU, gonococcal urethritis; NGU, nongonococcal urethritis; Rx, prescription; WBC, white blood cell; hpf, high-powered field; DNA, deoxyribonucleic acid; PCR, polymerase chain reaction. (Adapted from Fox and Cohen (1999) with permission.)

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Table 2 Treatment Regimens for Urethritis (with Emphasis on Single-Dose Regimens) Uncomplicated gonococcal infections of the urethra, rectum, or pharynx

Comments

Cefixime 400 mg PO ⫻ 1 dose or Ciprofloxacin 500 mg PO ⫻ 1 dose

Quinolones no longer recommended if patient or patient’s sex partner acquired infection in California, Hawaii, Pacific Islands, or Asia

or Ofloxacin 400 mg PO ⫻ 1 dose or Ceftriaxone 125 mg IM ⫻ 1 dose or Spectinomycin 2 g IM ⫻ 1 dose

Expensive, recent shortages; reserved for patients who cannot tolerate cephalosporins or quinolones

and Azithromycin 1 g PO ⫻ 1 dose

For treatment of presumed coinfection with NGU

Disseminated gonococcal infection Ceftriaxone 1 g IM or IV q24h

Hospitalization of all patients for parenteral therapy for 24–48 hours; after improvement begins, total of 7 days of therapy completed with cefixime 400 mg PO bid or ciprofloxacin 500 mg PO bid

or Ciprofloxacin 500 mg IV q12h or Spectinomycin 2 g IM q12h

As above

Nongonococcal urethritis Azithromycin 1 g PO ⫻ 1 dose or

冎

Doxycyline 100 mg PO bid ⫻ 7 days or Ofloxacin 300 mg bid ⫻ 7 days Recurrent/persistent urethritis Metronidazole 2 g PO ⫻ 1 dose plus

Erythromycin base 500 mg qid ⫻ 7 days

Completion of therapy less likely with multidose regimens but good results in efficacy studies

For treatment of Trichomonas vaginalis and Ureaplasma urealyticum

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therapy. Tests of cure are not necessary. Partners of patients with STD-associated urethritis exposed within 60 days of diagnosis should be evaluated and treated even if asymptomatic. If the patient’s last sexual intercourse was more than 60 days before the onset of symptoms or diagnosis, the patient’s most recent sex partner should be treated. A postgonococcal urethritis syndrome characterized by a recurrence of symptoms after treatment for GU has been described. This ‘‘recurrence’’ is in fact almost always due to untreated C. trachomatis infection. This should no longer be seen in clinical practice since all patients with GU should also be empirically treated for C. trachomatis. 2.5

Recurrent or Persistent Symptoms

With proper treatment, gonorrhea symptoms usually resolve rapidly. NGU symptoms sometimes persist for several days beyond completion of therapy. Patients with persistent or recurrent symptoms should be reevaluated as outlined in Figure 1. If no discharge is present and urethral inflammation is not documented, treatment is typically withheld on the follow-up visit pending results of retesting. If confirmed N. gonorrhoeae infection does not respond to standard therapy and the patient was not reexposed, the possibility of antibiotic resistance should be considered and further testing discussed with the local health department. Reexposure to an untreated partner or noncompliance with initial therapy should prompt retreatment. If the patient was compliant with the original regimen and reexposure did not occur, most experts currently consider it reasonable to manage recurrent or persistent urethritis by empirically treating for T. vaginalis and U. urealyticum with metronidazole 2 g in a single dose and erythromycin 500 mg qid for 7 days. Optimal management of patients with symptoms that persist after this regimen is not clear. Such patients are typically referred for urological evaluation, although this is beneficial in only a minority of cases. 3

GENITAL ULCER ⴞ LYMPHADENOPATHY SYNDROME

Genital ulcers are open lesions that form on genital mucous membranes or skin (also see Chapter 16). They are often accompanied by inguinal and/or femoral lymphadenopathy. Disruption of the genital epithelial skin barrier is typically caused by sexually acquired organisms. In the United States, the most common cause is herpes simplex virus (HSV). Syphilis and chancroid also are significant pathogens and have wide geographic variation in incidence. It is well established that a clinical diagnosis of genital ulcers based on history and physical exam has limited accuracy. Laboratory testing is therefore important in the evaluation of most patients with genital ulcer disease. Because of delays associated with laboratory testing it is often prudent to treat patients with genital ulcers presumptively on the basis of prevalence of pathogens in a given geographic region. Effective treatment is particularly important because genital ulcers have been identified as a cofactor in the transmission of HIV. Table 3 includes a comprehensive list of reported causes of genital ulcers. HSV causes latent infection in dorsal root ganglia with subsequent risk of reactivation. HSV-2 is the major cause of genital herpes. It is estimated that 20% of the adult population has a positive result for HSV-2 antibody. HSV-1 classically causes orolabial lesions but may be responsible for up to 40% of initial episodes of genital herpes. Epidemiological data indicate that the majority of HSV infections are subclinical. Currently available antiviral drugs partially control signs and symptoms of herpes episodes but are not curative.

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GENITAL ULCERS Causes (Tables 3 and 4) Herpes simplex virus (HSV) HSV-2 > HSV-1 Spontaneous resolution Recurrence common Primary infection worse than recurrence; possible association with systemic symptoms (Table 5) Painful clustered vesicles progressing to ulcers Diagnosis by tissue culture or HSV antigen Need to rule out other sexually transmitted diseases (STDs) (Table 6) Testing for human immunodeficiency virus (HIV) Treatment (Table 7) Primary syphilis Painless ulcer (chancre) Spontaneous resolution; may be followed by secondary syphilis (rash) Treatment with benzathine penicillin G 2.4 million U IM ⫻ 1 dose Also see Chapter 16, Table 11

Treponema pallidum, the infectious agent of syphilis, causes a mild primary infection (ulcer) that is accompanied by clinically inapparent bacteremia and dissemination throughout the body. Secondary syphilis develops when the concentration of spirochetes in infected tissues reaches a threshold, triggering an inflammatory response. The manifestations of primary and secondary syphilis resolve even if untreated, but infection persists in numerous organs, including the central nervous system, with the potential to lead to neurosyphilis and manifestations of tertiary syphilis. Chancroid is caused by Haemophilus ducreyi. It is uncommon in the United States (<400 cases reported annually) although new diagnostic techniques suggest a higher prevalence than previously suspected in some areas. Endemic areas currently include New York City and portions of the Southeast. Epidemic chancroid is often associated with substance abuse and trading of sex for drugs. Donovanosis or granuloma inguinale, caused by Calymmatobacterium granulomatis, and lymphogranuloma venereum (LGV), caused by serovars of C. trachomatis, are rare causes of genital ulcer disease in the United States. The major clinical features of genital ulcer disease are outlined in Table 4. 3.1

Clinical Evaluation

History should include type and number of sexual exposures, setting in which the exposures occurred, substance abuse, recent travel, as well as diagnoses or symptoms in sexual partners. The physical exam in patients with genital ulcers should focus on lymph nodes, skin, and mucous membranes and inspection of the ulcerative lesion. Most genital ulcers in men are found on the prepuce, near the frenulum, in the coronal sulcus, or on the shaft of the penis. Ulcers may also be detected on the lips, throat, buttocks, and perianal area, depending on the location of oral and/or genital contact. Although genital ulceration due to specific agents may be associated with specific clinical features, multiple causes may coexist and clinical features often cannot be used

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Table 3 Causes of Genital Ulcers in the United States Most common infectious causes Herpes simplex virus (HSV) type 2 or 1 Syphilis Chancroid Other infectious causes Acute human immunodeficiency virus (HIV) infection Scabies (with secondary bacterial infection) Lice (with secondary bacterial infection) Lymphogranuloma venereum Donovaniasis (granuloma inguinale) Infectious mononucleosis Trichomonas Noninfectious causes Abrasions and traumaa Fixed drug eruptionb Cancer Reiter’s syndrome (e.g., circinate balanitis) Aphthous ulcers Behc¸et’s syndromec Psoriasis Contact dermatitis Stevens Johnson syndromed a

Common self-diagnosis; obtain clear-cut history of injury and rule out herpes/syphilis. b Typically begins 7–10 days after beginning of drug; initial erythema often followed by sloughing of skin. c Deep painful necrotic ulcers usually with concurrent history of recurrent oral ulcers. d Can be triggered by herpes infection.

reliably to diagnose a specific pathogen. Even with extensive evaluation, a quarter of all patients with genital ulcerations do not have a laboratory-confirmed diagnosis. Local application of self-prescribed remedies, oral antibiotic therapy, and coinfections may all modify the appearance of ulcerations from ‘‘classic’’ descriptions. Several presentations have sufficient specificity to prompt consideration of specific diagnoses. Herpes simplex virus infection is characterized by a prodrome of tingling, paresthesias, or shooting pains in the buttocks, legs, or hips 12–48 hours before the appearance of the vesicle or papule. Grouped vesicles on an inflamed erythematous base are the hallmark of genital herpes. These vesicles rupture, leaving shallow painful ulcerations. Lesions typically evolve over 2–3 days from a papule to a vesicle and then finally to a crusted over pustule. Primary infection is typically much more severe and of longer duration than initial nonprimary or recurrent infection (see Table 5). Primary herpes simplex infection is associated with pharyngitis, meningitis, and occasionally other neurolgical syndromes, including transverse myelitis and autonomic nervous system dysfunction (e.g., urinary retention and constipation). Cutaneous dissemination is rare with herpes simplex except in newborns and immunocompromised hosts. Atypical presentations of herpes simplex virus infection are not uncommon and may include single ulcers, shallow ulcers, multiple coalescent ulcers, linear fissures, and serpig-

a

Recurrent meningitis (Mollaret’s syndrome)

Firm, small, tender; often bilateral with initial episode

None Often tender

Superficial Serous, erythematous, nonvascular

Tertiary syphilis, neurosyphilis

LGV, lymphogranuloma venereum.

Skin overlying swollen lymph nodes Chronic manifestations

Lympadenopathy

Induration Pain

Depth Base

Multiple; often grouped 1–2 mm Erythematous

Not erythematous

Variable (single ⬃50%) 5–15 mm Sharply demarcated, elevated, round, or oval Variable Smooth, nonpurulent, relatively nonvascular Firm None or minimal tenderness None or small and firm/rubbery, bilateral, discrete, not painful (tender in 1/3)

Number of lesions

Papule > vesicle

2– days

Herpes

Not erythematous

Papule

Primary lesions

Diameter of lesions Edges

9–90 days

Usual incubation period

Syphilis

Table 4 Clinical Features of Genital Ulcers

Tender; may suppurate; loculated; usually unilateral; occasionally may involve inguinal and femoral nodes Erythematous

Soft Very tender

Excavated Purulent, ready bleeding

Variable Undermined, ragged, irregular

Often multiple

Pustule

1–14 days

Chancroid

Pelvic/perirectal abscesses, rectal fistulae and strictures, lymphatic occlusion

Multiple, tender and matted, may suppurate, usually unilateral; may involve inguinal and femoral nodes Erythematous

Occasionally firm Variable

Variable Variable, nonvascular

Papule, vesicle, or pustule Usually one (ulcer usually not seen) 2–10 mm Elevated, round or oval

3 days–6 weeks

LGVa

Lymphatic occlusion; inguinal masses due to spread of inflammation

None (pseudobuboes due to subcutaneous extension of granulomatous process) N/A

Firm Uncommon

Elevated Red, velvety, ready bleeding

Variable (usually not presenting feature) Variable Elevated, irregular

1–4 weeks (occasionally longer) Papule

Donovanosis

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Table 5 Characteristics of Symptomatic Genital Herpes Infection Type of infection Lesions

Urethritis (e.g., dysuria) Neurological complications Regional lymphadenopathy Systemic manifestationsc Typical duration

Primarya Many, bilateral, widely spaced Common Common Usual Usual 2–3 weeks

Initial nonprimaryb

Recurrent

Few

Fewer, unilateral

Occasional Uncommon Occasional Occasional 1–2 weeks

Uncommon Rare Rare Rare 5–10 days

a

First recognized infection with no serological evidence of previous infection. First recognized infection with positive serological evidence of previous infection. c Fever, aseptic meningitis, myalgia, and extragenital lesions on buttock, groin, and thigh. Source : Fox, 1999. Used by permission of Oxford University Press, Inc. b

inous ulcers. Therefore, regardless of the appearance of the lesion, there should be a low threshold for diagnostic testing to confirm the presence of herpes simplex. Most ulcers clinically diagnosed as due to syphilis or chancroid are typically due to herpes. Patients with genital HSV-1 infection typically have 0–1 recurrences per year; the first year after symptomatic HSV-2 infection, men have an average of 5 recurrences per year and 20% have 10 or more outbreaks. The rate of recurrence declines in subsequent years. Reactivation of HSV-2 has been associated with recurrent aseptic meningitis (Mollaret’s syndrome). Syphilis is classically associated with a painless ulcer (chancre) that is indurated and has a clean base. Lymph nodes are typically small and rubbery or absent. The chancre and lymphadenopathy usually resolve in a few weeks even without treatment. Secondary syphilis usually does not develop for 2–4 months after primary infection but may overlap occasionally with primary infection and therefore is described briefly in this chapter. The classic rash, which is ‘‘papulosquamous’’ and nonpruritic, involves the trunk, palm, and soles. However, syphilis is the ‘‘great imitator’’ and the rash can be confused with that of psoriasis, scabies, pityriasis rosea, and nonspecific dermatitis. Patchy hair loss on the scalp, painless mucous membrane lesions in the mouth, and genital condyloma lata (sometimes confused with warts) may also be present. Aseptic meningitis and other neurological manifestations can also occur with secondary syphilis. Secondary syphilis also typically resolves without treatment over time. The skin rash may recur within the first year after infection. Latent (asymptomatic) syphilis follows and is detectable on the basis of reactive serological testing. Latent syphilis may progress to neurosyphilis and occasionally classic late manifestations of tertiary syphilis such as syphilitic aortitis and gumma formation. CDC guidelines provide additional information regarding diagnosis and treatment of latent syphilis, tertiary syphilis, and neurosyphilis (http://www.cdc.gov/nchstp/dstd/dstdp.html). Chancroid is classically described as painful. The ulcer edge may be ragged and the base rough and purulent. Associated inguinal adenopathy is not common. 3.2

Laboratory Diagnosis

Clinically differentiating genital ulcer disease is difficult. Laboratory testing is therefore important and should include a serological test for syphilis as well as diagnostic testing for herpes simplex (see Table 6).

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Table 6 Laboratory Evaluation of Sexually Active Patients with Genital Ulcer Diseasea Lesions typical of genital herpes Culture or direct fluorescent antibody for HSV (optional; warrants strong consideration) Screening tests for other STDs (syphilis, HIV, chlamydia, and gonorrhea) Other genital ulcers Culture or direct fluorescent antibody test or PCR for HSV Dark-field microscopy for T. pallidum, if available Syphilis serological testing (RPR, VDRL) Selected cases Culture for H. ducreyi Culture for pyogenic bacteria Biopsy Type-specific HSV serological testing a

HSV, herpes simplex virus; STD, sexually transmitted disease; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratories. Source : Fox, 1999. Used by permission of Oxford University Press, Inc.

3.2.1

Syphilis

Dark-field microscopy requires very specialized training and is not available in most clinical laboratories including urban medical centers. Referral to a local health department if dark-field microscopy is available should be considered for possible primary syphilis. Nontreponemal serological tests such as the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) do not distinguish present from past infection. These tests have positive results in about 80% of cases of primary syphilis. Results are reported as reactive to a dilutional titer. The degree of titer elevation is not necessarily reliable for staging syphilis, but appropriate titer decline does define a successfully treated case. Virtually all patients with primary syphilis have a positive serological test finding by the time the ulcer heals. All patients with secondary syphilis have positive serological results. Reactive nontreponemal tests require confirmation with a specific treponomal test such as the fluorescent treponemal antibody-absorbed (FTA-abs) or microhemagglutination–T. pallidum (MHA-TP) test to rule out biological false-positive results, which may occur in the setting of injection drug use (IDU), acute viral infections, and autoimmune disease. A lumbar puncture (LP) is indicated for primary and secondary syphilis only if there is evidence of neurological involvement such as meningitis, ophthalmic or auditory symptoms, or cranial nerve palsies. Patients with ocular symptoms should have a slit lamp exam to rule out uveitis. It is often advisable to refer patients with suspected neurosyphilis to a specialist for evaluation and follow-up. If LP is performed, 3–5 cc of cerebrospinal fluid (CSF) should be frozen in the event additional diagnostic studies are needed. 3.2.2

Herpes Simplex Virus

Because herpes simplex is by far the most common cause of genital ulceration, failure to perform diagnostic testing for atypical ulcerations often leads to misdiagnosis. Testing is particularly useful when diagnostic uncertainty is present or for firm establishment of the diagnosis before beginning long-term suppressive therapy. The presence of HSV can be confirmed by tissue culture, HSV antigen detection by enzyme immunoassay (EIA), or direct or indirect fluorescent antibody (IF). Type-specific testing may be helpful as the prognosis for recurrence varies between HSV-1 and HSV-2 (see previous discussion). The

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Tzanck test smear is a simple cytological test used to detect multinucleate giant cells characteristic of herpes infection. It is performed by scraping the base of the ulcer with a swab or scalpel and transferring the specimen onto a slide for staining (e.g., Gram or Wright’s stain). Sensitivity compared to that of culture ranges from 50% in the ulcer stage to 67% in the vesicle stage, with a specificity of about 95%. Herpes cultures obtained more than 48 hours after ulcer onset usually yield negative results. Polymerase chain reaction (PCR) for genital herpes simplex is extremely sensitive and may become commercially available in the near future. If chancroid is suspected, the patient’s ulcer should be cultured for H. ducreyi or a specimen sent for PCR. Unfortunately, most clinical laboratories do not have the appropriate culture media for this organism and H. ducreyi PCR is not currently available commercially. Multiplex PCR detects HSV, T. pallidum, and H. ducreyi and may soon be commercially available for clinical use. HIV testing is recommended for any patient newly diagnosed with a STD and should always be performed in patients with primary and secondary syphilis or chancroid. If HIV results are negative, testing should be repeated in 3–6 months if possible. 3.3

Treatment

Treatment of genital ulcer disease is often initiated empirically. It is prudent to treat for the more likely diagnosis (HSV or syphilis) and see the patient again in 7 days. Many experts recommend presumptive treatment for syphilis particularly in the setting of community outbreaks. Repeat serological testing for syphilis may be useful at follow-up as a change in titer from negative to positive virtually assures the diagnosis of syphilis. The regimen of choice for primary syphilis is benzathine penicillin G 2.4 million U intramuscularly (IM) in a single dose. For those with penicillin allergies, doxycycline 100 mg orally bid for 2 weeks or tetracycline 500 mg orally qid for 2 weeks can be used. If the patient is penicillin-allergic and tetracycline-intolerant, erythromycin 500 mg orally qid for 2 weeks or ceftriaxone 1 g IM daily for 8–10 days can be substituted. Patients should be reevaluated clinically and serologically at 6 and 12 months. A fourfold change in titer is required to demonstrate a significant difference. Follow-up syphilis serological tests should be performed in the same lab because simultaneously obtained titers may vary two- to fourfold between labs. A fourfold increase in titer or recurrence of signs or symptoms suggests treatment failure or reinfection; a LP should be performed and HIV serological characteristics checked. If neurosyphilis is excluded, the patient should be retreated with benzathine penicillin G 2.4 million U IM weekly for 3 weeks. The Jarisch-Herxheimer reaction (JHR) is an acute febrile reaction that occurs after treatment of syphilis with penicillin. It may occur in up to 70%–90% of patients with secondary syphilis and less often in those of other stages. Treatment is supportive. An expert should be consulted regarding use of prednisone to abort JHR in patients with cardiovascular or symptomatic neurosyphilis. Treatment to reduce the duration and severity of symptoms is recommended for all primary genital herpes infections if started within 1 week of symptom onset (see Table 7). Treatment may also be indicated for severe recurrences. Chancroid may be treated with single-dose azithromycin 1 g orally or ceftriaxone 250 mg IM. Alternatives include oral ciprofloxacin 500 mg orally bid for 3–5 days or erythromycin 500 mg orally qid for 7 days. Patients with suspected syphilis and chancroid should generally be managed in cooperation with the local health department.

5 Days

Months to years

7–10 Days or until clinical resolution

Recurrentc,d

Suppressivee,f

Severe diseaseg,h (meningitis, neurological dysfunction)

mg mg mg mg mg mg

5⫻/day tid 5⫻/day tid bid bid

5–10 mg/kg IV q8h until clinical resolution Then completion of 7–10 day course with oral therapy

200 400 200 400 800 400

Acyclovira

250 bid 500 mg qd 1 g qd

500 mg bid

1 g bid–tid

Valacyclovir

250 mg bid

125 mg bid

250 mg tid

Famciclovir

b

Topical treatment with acyclovir is far less effective than systemic therapy, and use is strongly discouraged. First episode: Treatment should be initiated early (within a week of onset) for all patients with a first episode (presumed or confirmed) of genital herpes. Treatment decreases duration of pain, viral shedding, and systemic symptoms but has no effect on rate or frequency of relapse. c Recurrent episodes: Treatment should be started with the prodome or within 1 day of lesion onset. Patients should be provided with a prescription so that treatment can be promptly initiated at onset of prodrome or genital lesions as this is more effective than physician-initiated treatment. Valacyclovir 500 mg once daily may be less effective than other valacyclovir doses in patients with >10 recurrences/year. d The mechanism of reactivation is not well understood. The role of stress and fatigue as risk factors for recurrence has not been proved. e Suppressive therapy: Consider with ⱖ6 episodes a year and for severely psychologically affected patients. Safety and efficacy are documented for continuous prophylaxis with acyclovir for up to 10 years without cumulative toxicity or risk of resistance. There is also a significant reduction in viral shedding with prophylactic therapy. f Intermittent or suppressive treatment is commonly needed in those with HIV infection. g Obtain expert consultation in patients with severe disease. h Resistance is rarely seen in immunocompetent patients; refer patients with genital lesions that progress on high-dose therapy for further evaluation.

a

7–10 Days

First episodeb

Duration

Table 7 Treatment Options for Genital Herpes Simplex Virus Infections

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Counseling and Partner Notification

3.4.1

Syphilis and Chancroid

Patients should be counseled that prevention of genital ulcer disease due to STD is achieved by abstinence or use of condoms. Reporting of cases of chancroid and syphilis, as required by state regulations, may help ensure that partner notification and treatment occur. 3.4.2

Herpes

Depression, fear of rejection, and anxiety may accompany the diagnosis of genital herpes. These symptoms may be best addressed after resolution of symptoms related to the acute illness. Patients should be reassured that the diagnosis of herpes simplex is compatible with ongoing intimate relationships. Key points to emphasize during counseling are listed in Table 8. Counseling patients about use of condoms when having sexual intercourse is probably prudent, although use of the latex condom in males has not been demonstrated to provide complete protection in discordant couples. If available, type-specific serological testing of the patient’s partner may prove helpful as it may demonstrate that the partner has HSV infection of the same serotype. If so, the use of condoms to prevent infection of the partner is presumably unnecessary.

4

GENITAL WARTS

Human papillomavirus (HPV) cause numerous clinical syndromes including cutaneous and anogenital warts (condyloma acuminata). More than 20 HPV types infect the genital tract and are increasingly recognized to play a role in genital tract cancers including penile squamous intraepithelial neoplasia and anal carcinoma in men who have sex with men. Subtypes 6 and 11 cause most clinical episodes of anogenital warts. Subtypes 16, 18, 31, 33, and 35 are strongly associated with malignant transformation.

Table 8 Key Points to Be Emphasized in Counseling Patients with Genital Herpes Patients who have genital herpes should be told about the natural history of the disease with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and sexual transmission. Patients should be advised to abstain from sexual activity when lesions or prodromal symptoms are present and encouraged to inform their sex partners that they have genital herpes. The use of condoms during all sexual exposure with new or uninfected sex partners should be encouraged. In stable relationships, the annual rate of transmission is estimated to be 5% if the source patient is female and 19% if the source patient is male. Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding occurs more frequently in patients who have genital HSV-2 infection than HSV-1 infection and in patients who have had genital herpes for <12 months. The risk for neonatal infection should be explained to all patients including men. Patients with a first episode of genital herpes should be advised that episodic antiviral therapy during recurrent episodes may shorten the duration of lesions and suppressive antiviral therapy can help reduce the number of recurrent outbreaks.

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GENITAL WARTS Human papillomavirus (HPV) Papular or verrucous Preputial cavity, penile shaft, and perianal area most common May cause penile squamous intraepithelial neoplasia or anal carcinoma Provider-applied treatment Bichloroacetic acid (BCA) or trichloroacetic acid (TCA) Podophyllin resin (10%–25%) Surgical removal or cryotherapy Patient-applied treatment Podofilox 0.5% solution/gel Imiquimod 5% cream Recurrence in 75%

4.1

Clinical Evaluation

Numerous studies indicate that the majority of genital HPV infections are subclinical. Patients with visible warts are usually concerned about cosmetic appearance. However, about 25% of patients with warts complain of itching, burning, bleeding, pain, or tenderness. Diagnosis is usually based on clinical appearance. Warts are categorized into four morphological types. By far the most commonly observed genital warts are papular, fleshto gray-colored, and either sessile or attached with a broad base to the skin. Warts with other morphological characteristics are more difficult to recognize and may require referral for diagnosis. Warts occur singly or in clusters and may vary in size from several millimeters to several centimeters in diameter when coalescent. Warts are typically located in the preputial cavity in uncircumcised men and on the shaft of the penis in circumcised men. It is important to examine the entire genital area as warts may also be located in the urethra, on the scrotum, and in the perianal area. Perianal warts occasionally occur in men who do not report a history of anal sex, although intra-anal warts are highly associated with receptive anal intercourse. Occasionally warts may appear on the lips or in the mouth as a result of orogenital contact. The differential diagnosis of genital warts includes skin tags, pearly penile papules, sebaceous glands, seborrheic keratosis, nevi, condyloma lata (caused by T. pallidum), carcinoma, and molluscum contagiosum. Biopsy is occasionally indicated when the diagnosis is uncertain, warts fail to respond to standard therapy, or there is concern about malignancy (e.g., ulcerated warts or pigmented anal warts). 4.2

Treatment

Left untreated, warts may remain unchanged, increase in size and number, or regress. There is a 10%–20% spontaneous remission rate in untreated lesions over 3–6 months. The goals of therapy are to eliminate cosmetically significant warts and to relieve any associated symptoms including emotional distress. During the 6-month period following therapy, most treatment modalities have clearance rates (i.e., no recurrence) of 30%–70%. The best results are usually achieved in treating small warts of less than 1 year’s duration. No treatment modality is clearly superior to others or known to prevent transmission or

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to eradicate HPV. Unless warts are removed surgically, multiple treatments are usually necessary for satisfactory results. Providers should become familiar with at least one treatment in each of these categories. The choice of therapy for an individual patient is dependent on size, location, and number of warts; patient preference; and clinician training. Referral to a specialist is indicated for patients with warts on the rectal mucosa, patients with extensive disease, and lesions refractory to a full course of therapy. Meatal warts should be removed by using cryotherapy or podophyllin. Anal warts should be removed by cryotherapy, trichloroacetic acid (TCA) 80%–90%, or surgery. Toxic and expensive agents are generally not used initially, and use of multiple treatment modalities on a single wart is not warranted. All therapies have the potential to cause mild local irritation. Ablative treatments can result in scarring and/or hyper/hypopigmentation. Available treatments can be categorized as either provider- or patient-administered. 4.2.1

Provider-Administered Treatments

Provider-initiated therapies used in the primary care setting include topical treatments with cryotherapy, podophyllin resin, bichloroacetic acid (BCA), or TCA. Surgical and injectable treatments are usually only available by referral to a subspecialist. Office treatment of warts using cryotherapy requires proper training to ensure that over- or undertreatment does not occur. It is most effective for small warts. One to six applications per session (once every 7–14 days) for up to 4–6 weeks are typically required. Treatment can result in pain, necrosis, and blistering, and if multiple warts are being treated with cryotherapy, local anesthesia may be necessary. Podophyllin resin (10%–25%) in benzoin or ethanol is an antimitotic agent that is applied by a cotton tipped swab, with a limit per session of 0.5 ml or 10 cm2 per session to prevent potential systemic side effects. Air drying should be complete before the treated area has contact with clothing. Podophyllin is washed off 1–4 hours after treatment to limit irritation and can be reapplied once a week for up to 6 weeks. TCA or BCA 80%–90% is applied weekly for up to 6 weeks and destroys warts by chemically induced protein coagulation. TCA and BCA are low-viscosity agents and should therefore be applied in small amounts to minimize damage to normal tissue. Air drying after treatment with BCA or TCA should occur before the patient changes position. Baking soda may be applied to surrounding skin to neutralize any acid that has spread beyond the intended area of treatment. 4.2.2

Patient-Administered Treatments

For patient-applied therapies, the provider should demonstrate the proper application technique in the office and establish that the patient is able to follow instructions for application as well as identify and reach the warts to be treated. Patient-applied therapies include podofilox 0.5% solution or gel and imiquimod cream. Podofilox is purified from podophyllin resin. It does not need to be removed by washing. Although systemic side effects are minimal, use of less than 0.5 ml per treatment session is recommended. Podofilox is applied daily for 3 days by using a cotton swab for the solution and a gloved finger for the gel then withheld for 4 days. This 7-day cycle is repeated as necessary up to four times. Imiquimod 5% cream is applied every other night by hand at bedtime for up to 4 months. This compound stimulates local interferon production and is often associated with a mild inflammatory reaction. Therapeutic results are usually seen by 8–10 weeks. Patients should wash with soap and water 6–10 hours after application. This treatment is not approved for perianal, rectal, or urethral warts.

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Follow-up for genital and perianal warts is not required if the desired result is achieved with therapy. Recurrences are frequent (75%) and typically occur within 3 months of treatment. Sex partners may benefit from examination for genital warts and other STDs. Female partners should be sure to have yearly Papanicolaou smears as recommended for all sexually active women as HPV is clearly implicated as a cause of cervical cancer. Patients should be told that condoms are protective against the transmission of other STDs, but their benefit is unproved in HPV transmission. In addition, elimination of genital warts does not eliminate transmission risk to sexual partners.

5

PROSTATITIS

The lifetime incidence of symptoms suggestive of prostatitis has been estimated to be 50%, and symptoms originating in the lower genital tract or perineum are the cause of 1% of visits to primary care providers. Prostatitis is invoked as the cause of almost any genitourinary symptom, including pain in the low back, pelvis, or genitals; dysuria; urinary frequency or urgency; recurrent urinary tract infection; and ejaculatory pain. Clear evidence of an infection in the prostate can be found in only 5%–20% of patients with a diagnosis of prostatitis, even in research settings. Trials of empirical therapy are often undertaken on the basis of history alone with relatively low cure rates. Evidence-based approaches to diagnosis and treatment of chronic prostate disorders are lacking; as such, prostatitis has been dubbed a ‘‘wastebasket of clinical ignorance.’’ 5.1

Clinical Evaluation

The 1995 National Institutes of Health (NIH) classification of prostatitis (Table 9) reflects current understanding of prostatitis subgroups and is now widely accepted as a standard classification that is helpful for both clinical and research purposes. Most patients with symptoms suggesting prostatitis have either chronic nonbacterial prostatitis or chronic pelvic pain syndrome.

PROSTATITIS National Institute of Health (NIH) classification (Table 9) Characteristics of prostatitis syndromes (Table 12) Bacteriological characteristics (Table 11) Acute bacterial Acute onset of fever, dysuria, pelvic pain, prostate tenderness Uncommon: 1%–5% of prostatitis cases Chronic Bacterial 5%–10% of prostatitis cases Subacute onset of symptoms (Table 10) Recurrent urinary tract infection (UTI) Nonbacterial Most common cause of prostatitis symptoms (85%–90%) Diagnosis by pre-/postmassage test (Table 13) Antibiotic therapy (Table 14)

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Table 9 1995 National Institute of Health Classification of Prostatitis Category I. Acute bacterial prostatitis II. Chronic bacterial prostatitis III. Chronic pelvic pain syndrome/ nonbacterial prostatitis

IIIA. Inflammatory chronic pelvic pain syndrome IIIB. Non-inflammatory chronic pelvic pain syndrome IV. Asymptomatic inflammatory prostatitis

Definition Acute infection of the prostate Recurrent urinary tract infection (UTI) Chronic infection of the prostate Discomfort or pain in the pelvic region for at least 3 months with variable voiding and sexual symptoms but no demonstrable infection White blood cells (WBCs) in semen and expressed prostatic secretions No WBCs in semen and expressed prostatic secretions Evidence of prostatic inflammation on biopsy, in semen, or in expressed secretions but no symptoms

A diagnosis of prostatitis should be considered for all men who exhibit the symptoms listed in Table 10, which are listed by frequency of occurrence. In addition to defining time course and location of symptoms, the history should include questions regarding any prior genitourinary infections, STD, and urinary tract instrumentation. Physical examination should include the abdomen, genitalia, perineum, and the prostate. Urethral discharge and prostate size, tenderness, and nodularity should be noted. 5.1.1

Acute Prostatitis

Patients with acute bacterial prostatitis (ABP) experience fever, dysuria, and pelvic pain, often with associated urinary urgency and frequency. This condition may progress to urinary retention. On digital examination the prostate is very tender and is often warm and tense. Prostate massage is contraindicated in acute prostatitis as it is extremely painful and may cause bacteremia. The causative bacteria can almost always be recovered by urine culture. The most common etiological agents are listed in Table 11. Most experts consider gram-positive organisms other than those listed and diphtheroids to be contaminants from the anterior urethra. Ascending infection via the urethra or reflux of infected urine into the prostate is the presumed route of infection in most cases of acute prostatitis. In addition, in patients with UTI who undergo transurethral resection of the prostate (TURP) acute prostatitis may develop. Staphylococus aureus infections suggest the possibility of hematogeneous seeding from another site. Metastatic infection and prostatic abscess are uncommon complications of acute prostatitis. 5.1.2

Chronic Prostatitis

Whereas patients with acute prostatitis often appear acutely ill and have symptoms clearly attributable to the prostate, patients with chronic prostatitis have a more varied and subtle array of presentations (see Table 12). Chronic bacterial prostatitis (CBP) constitutes only 5%–10% of prostatitis cases. It is a disease of older men. By definition, symptoms must be present for at least 3 months.

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Table 10 Presenting Complaints in Patients with Prostatitis Irritative urinary symptoms Frequency Slow urination Urgency Dribbling Dysuria Incomplete emptying Pain syndromes Perineal pain Genital pain Ejaculatory pain Lower abdominal pain Other symptoms Hemospermia Hematuria Erectile dysfunction

Table 11 Common Etiological Agents in Bacterial Prostatitis Escherichia coli Proteus spp. Providencia spp. Klebsiella spp. Pseudomonas aeruginosa Enterobacter spp. Enterococcus spp.

Table 12 Characteristics of Prostatitis Syndromesa

Condition

Typical presentation

Age range, years

Examination findings

Bacteriuria

Acute bacterial

Acute illness

40–70

Tender, warm

⫹

Chronic bacterial

Recurrent urinary tract infection (UTI)

50–80

Variable Usually normal

⫹

Chronic nonbacterial (inflammatory)

Genitourinary and voiding discomfort

30–50

Variable

⫺

Chronic nonbacterial, noninflammatory

Genitourinary and voiding discomfort

30–40

Usually normal

⫺

Therapy and response Prompt response to antibiotics Slow response to antibiotics Consideration of ␣blockers Lack of randomized controlled trials to support use of antibiotics No antibiotics Symptomatic therapy

All cases, % 1%–5% 5%–10%

40%–65%

20%–40%

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Typically patients have recurrent UTI in the absence of bladder catheterization. Between episodes of UTI, men may be asymptomatic or may have the irritative or pain symptoms listed in Table 10. Physical examination findings are usually normal, although prostatic edema, hypertrophy, and tenderness may be present. Patients with CBP often have persistently positive culture findings of prostatic fluid or urine. Bacteriological characteristics are summarized in Table 11. Nonbacterial prostatitis/chronic pelvic pain syndromes (NBP/CPPS) occur most often in younger men. Pain complaints predominate slightly over voiding complaints. There is no history of UTI and urine and prostatic culture results are negative. Physical examination may show tight or tender pelvic floor muscles, but this finding is not predictive of other laboratory findings or responses to treatment. The cause of NBP/CPPS is not known. The possible role of infection with organisms such as C. trachomatis, Mycoplasma hominis, and U. urealyticum has led to the common practice of treating individuals with culture-negative inflammatory prostatitis with prolonged courses of antibiotics. Other proposed causes include tension myalgia of the pelvic floor muscles, spasms of the bladder neck, irritation from reflux of urine into the prostate, psychological disturbances, and autoimmune or primary inflammatory disorders. Strong evidence supporting these hypotheses is lacking although patients with NBP/CPPS have been found to have higher than normal rates of urinary flow abnormalities, depression, stress, and sexual dysfunction. Additional diagnostic considerations in apparent chronic NBP include interstitial cystitis and cancer of the prostate or bladder. If symptoms are progressive or persistent hematuria is found, prompt urological referral is warranted. Patients with chronic bacteriuria indicated on specimens provided prior to prostatic massage (discussed later) require ultrasound evaluation for bladder or kidney stones and diverticuli. Patients with obstructive voiding symptoms require evaluation for stricture. Asymptomatic inflammatory prostatitis, defined as inflammatory infiltrates in prostatic tissue obtained at biopsy or TURP, is of uncertain clinical significance. ‘‘Prostatitis’’ is the most common pathological diagnosis made on biopsy specimens performed during TURP. 5.2

Diagnosis

The urine culture result is almost always positive during ABP and is a reliable guide to therapy. Some authors advocate an intravenous pyelogram (IVP) or renal computed axial tomography (CT) scan in the setting of acute bacterial prostatitis to rule out renal calculi. Laboratory evaluation of chronic prostatitis is hampered by difficulty in obtaining representative material for culture. Expressed prostatic secretions may be contaminated by infectious agents from the skin, the urethra, or the bladder. Needle sampling of the prostate is insensitive because of the often focal nature of prostate infection and is rarely indicated. The classic evaluation for chronic prostatitis includes the ‘‘four glass test’’ described by Meares and Stamey in 1968, which attempts to localize infection to the urethra, prostate, or bladder. Although this is considered the standard diagnostic approach to prostatitis, it has not been validated, may be uncomfortable for patients, and is expensive, time-consuming, and seldom used in general practice. A simplified pre- and postmassage test (PPMT) that compares pre- and postmassage urine specimens representing bladder and prostate localization has been described. Although this test is also not well validated, it provides what appears to be a rational basis for making therapeutic decisions and is feasible in most outpatient settings. In this test, urine is collected before and after prostatic massage. Prostatic massage is performed by inserting a well lubricated finger through the anus and

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applying firm sweeping pressure from the periphery of the gland toward the midline. Interpretation is based on the results of urine culture and presence or absence of WBCs, as outlined in Table 13. The PPMT should be performed at initial presentation or after antibiotics have been discontinued for 4 weeks. If cystitis or urethritis is present (both may occur in association with prostatitis or as separate entitities), PPMT results are potentially misleading (a urethral smear for inflammatory cells may be needed to clarify whether or not urethritis is present in questionable situations). Patients with NBP subtype IIIA have inflammatory changes seen in their prostatic fluid with ⱖ10–15 WBC per highpowered field and/or fat laden macrophages. Patients with noninflammatory subtype III B have normal appearing prostatic fluid as well as negative culture findings. 5.3

Management

5.3.1 Acute Prostatitis Management of acute bacterial prostatitis should begin in the hospital for very ill patients. Antibiotics that do not usually penetrate the prostate are quite effective in ABP. Some regimens with demonstrated efficacy are listed in Table 14. Other measures include hydration, analgesics, and stool softeners. Urinary retention is common and should be managed in consultation with a urologist. Placement of a suprapubic cystotomy tube is often necessary as urethral catheterization may be painful and impede prostatic drainage. Prostatic abscess should be considered if fever lasts more than 3–4 days on appropriate treatment. Diagnosis is made by performing a CT scan or transrectal ultrasound and treatment may require surgical drainage. 5.3.2 Chronic Prostatitis Reported cure rates for trimethoprim (TMP) with or without sulfamethoxazole (SMX), doxycycline, and quinolones range from 0% to 90%. Varying diagnostic criteria, duration

Table 13 Interpretation of the Pre- and Postmassage Test Results Diagnosis

NIH category

Cystitis without prostatitis

N/A

Chronic bacterial prostatitis (with associated cystitisb) Chronic bacterial prostatitis (without associated cystitis) Chronic nonbacterial prostatitis (inflammatory) Chronic nonbacterial prostatitis (noninflammatory)

II II IIIA IIIB

WBCb Culture WBC Culture WBC Culture WBC Culture WBC Culture

Premassagea

Postmassagea

⫹ ⫹ ⫹ ⫹d ⫺ ⫺ ⫺ ⫺ ⫺ ⫺

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫺

⫹, present; ⫺, not present or negative. White blood cell (WBC), ⱖ10 per high-powered field. c Episodes of cystitis or bladder bacteriuria often associated with chronic bacterial prostatitis. d Results of the pre- and postmassage test (PPMT) are not considered diagnostically useful when premassage colony counts are >10,000 organisms/ml. Repeat PPMT evaluation after a 3-day course of nitrofurantoin (which typically clears cystitis but does not penetrate the prostate well) may help establish an underlying prostatic focus of infection. a

b

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Table 14 Treatment of Bacterial Prostatitis Infection

Duration

Drugs and dose

Acute bacterial

4 weeks Initial therapy intravenously until stable then orally

Chronic bacterial

4–12 Weeks

Ampicillin 2 g IV q6h plus gentamicin Ciprofloxacin 400 mg IV q8h then 500 mg PO bid Ofloxacin 400 mg IV q12h then 300 mg PO q12h TMP-SMX ds bida Ciprofloxacin 500 mg PO bid Levofloxacin 500 mg/day PO Doxycycline 100 mg PO bid

a

TMP-SMX, trimethoprim-sulfamethoxazole.

of treatment, and follow-up in these studies make comparisons of different regimens difficult. Optimal therapy and duration of treatment for CBP have not been clearly established. Most authors recommend 4 to 12 weeks of continuous treatment. In most situations, therapy need not be urgently initiated and should be based on results of culture and sensitivity (see Table 14). One randomized controlled trial demonstrated improved outcome and reduced recurrence rate for patients with CBP treated with ␣1-adrenergic receptor antagonists (e.g., 1–10 mg terazosin daily) in addition to antibiotics. Clinical response to the ␣-antagonist may take 4–6 weeks. Relapse after treatment for CBP occurs in 10%–70% of cases in the form of either recurrent UTI or prostatitis symptoms. If the initial course of curative therapy was 12 weeks repeated full-dose regimens have not been shown to result in increased rates of cure. Patients with refractory or relapsing CBP require urological evaluation to rule out abscess, seminal vesicle abnormality, or infected calculi. Evidence to support the common practice of chronic ‘‘suppression’’ using low-dose antibiotic therapy is lacking. Surgical, dietary, and life-style modifications do not have established benefit in the treatment of CBP. Minimal evidence is available to guide the management of NBP/CPPS. On the basis of available data, empirical treatment of this syndrome with antibiotics is not indicated, although trials of antibiotic therapy, especially to cover atypical bacteria such as Ureaplasma and Mycoplasma spp., are common in many settings. One randomized controlled trial (RCT) suggests a possible benefit of ␣1-adrenergic receptor antagonists in this setting. The benefits of other treatments for chronic nonbacterial prostatitis such as benzodiazepines, nonsteroidal antiinflammatory agents, allopurinol, prostatectomy, sitz baths, dietary modifications, frequent ejaculation, prostatic massage, dietary supplements (e.g., saw palmetto, zinc), microwave therapy, bladder neck incision, and psychotherapy have not been established. Progressive symptoms or new physical or laboratory findings should prompt reevaluation of the diagnosis and referral to a urologist. Otherwise, reassurance and periodic follow-up are reasonable. Granulomatous prostatitis may be idiopathic; it may occur in the setting of infection with Mycobacterium tuberculosis, Cryptococcus neoformans, Coccidioides immitis, or Histoplasma capsulatum or after an episode of acute bacterial prostatitis. Symptoms are variable, ranging from asymptomatic to those typical of acute bacterial prostatitis. Exami-

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nation usually reveals a firm or nodular prostate suggestive of prostatic carcinoma. Granulomatous prostatitis is a pathological diagnosis established by biopsy with special stains required to detect fungi or acid-fast bacilli. Referral to a specialist is recommended for management of this condition. 6

EPIDIDYMITIS

Epididymitis is a common condition, accounting for more lost days of military service than any other disease. Epididymitis causes unilateral pain, swelling, and tenderness of the epididymis. Onset is usually over hours to days. Early in the course of disease, pain and swelling may be localized to the epididymis, though involvement of the testes is frequent, ultimately resulting in epididymo-orchitis. Fever and dysuria are common. Sexually active men aged ⱕ35 years typically have a STD such as C. trachomatis or N. gonorrhoeae as the cause of epididymitis. Asymptomatic urethritis due to STD may also be present. Gram-negative rods (GNRs) are the most common cause of epidydimitis in men who are older than 35, have anatomical abnormalities, or have had recent urinary tract procedures or instrumentation. Men who have sex with men, of any age, who are insertive partners during anal intercourse are likely to have infection with GNRs as well as N. gonorrhoeae and C. trachomatis. Complications of epididymitis are uncommon but can include scrotal abscess, testicular infarction, chronic epididymal pain, and infertility. Rarely, epididymitis is caused by Behc¸et’s disease, amiodarone, or granulomatous disease of multiple causes (e.g., sarcoid, idiopathic, infectious). History should include questions regarding sexual exposures, past UTI, and urological malformation or instrumentation. Physical examination often reveals tenderness and erythema of the posterior scrotum. In more advanced cases epididimo-orchitis, spermatic cord tenderness, or hydocele (due to inflammatory fluid between the layers of the tunica vaginalis) is present and may result in an enlarged painful hemiscrotum with difficult to identify landmarks. Urethral discharge may be elicited by ‘‘stripping’’ the urethra even in men without urethral symptoms. EPIDYDIMITIS AND ORCHITIS Epidydimitis Unilateral pain and swelling, fever, dysuria Age <35 years: N. gonorrhoeae or C. trachomatis Age >35 years: history of gonococcal urethritis (GU) abnormalities or instrumentation; aerobic gram-negative rods (GNRs) Need to rule out testicular torsion (Table 15) Diagnosis Urethral smear Urinalysis and culture Antibiotic treatment (Table 16) Orchitis Testicular pain and fever Viral cause most common Coxsackie B virus or mumps Bacterial cause uncommon Usually caused by spread from epididymal infection

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The most urgent and challenging diagnostic issue in young men with pain or swelling of the scrotal contents is ruling out of testicular torsion. Younger men with a sudden onset of pain in the testis and others in whom the diagnosis of torsion is under consideration require urgent surgical consultation as testicular viability may be at risk. Distinguishing features are outlined in Table 15. Surgical correction of the torsion has a good chance of salvaging a viable testicle within the first 12 hours of torsion, some chance for salvage between 12 and 24 hours of torsion, and almost no chance for salvage after 24 hours. Most cases of testicular torsion result from congenital lack of fixation of the testicle within the scrotum and therefore occur during late adolescence as the testes enlarge. Among sexually active teenagers with testicular pain, both torsion and STD-associated epididymitis should be considered likely diagnoses. 6.1

Laboratory Evaluation

A Gram stain of urethral discharge (if present) should be collected. Presence of more than 5 WBCs per high-powered field in urethral discharge is abnormal and suggests chlamydia or gonorrhea as the cause. Specific testing for chlamydia and gonorrhea should be performed with urethral swab or first-void urine. Urine microscopic examination and culture should also be performed. When urinary tract infection is present, accompanying epidydimitis is highly likely to be caused by the same organism. The CDC recommends syphilis serological testing and HIV testing and counseling for all men with epididymitis. Color flow Doppler and radionuclide scanning may be used to rule out testicular torsion, because it demonstrates reduced or absent blood flow to the testicle in torsion and increased blood flow in epididymitis. However, delay of surgical evaluation and management should not occur while waiting for such testing. 6.2

Management

Empirical therapy should be instituted while waiting for culture results (see Table 16). Treatment should be adjusted on the basis of culture and sensitivity results.

Table 15 Clinical Features of Epidydimitis and Testicular Torsion Epididymitis Age group

Adults

Onset

Days to weeks

Associated symptoms

Often fever Dysuria

Physical findings

Sometimes discharge Predominant epididymal tenderness

Laboratory Imaging

Pyuria common Enhanced blood flow

Testicular torsion Adolescents Most cases 12–18 years Usually sudden Prior episodes with spontaneous resolution in many patients Vomiting in most cases Fever Dysuria rare Testis often elevated with abnormal lie Cremasteric reflex absent Pyuria in approximately 15% Blood flow usually reduced or absent in Doppler or nuclear studies

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Table 16 Treatment of Epididymitis If epididymitis most likely due to Chlamydia and/or gonorrhea

Gram-negative rods

Drugs Ceftriaxone 250 mg IM ⫻ 1 dose plus Doxycycline 100 mg PO bid for 10 days or Ofloxacin 300 mg PO bid for 10 days Ciprofloxacin 500 mg PO bid or 400 mg IV for 10–14 days or Ofloxacin 200 mg PO or IV for 10–14 days

Costs $45.00 $10.00 $98.00 $83.00 (PO) $600.00 (IV) $78.00 (PO) $260.00 (IV)

Hospitalization and intravenous treatment should be considered when inflammation is advanced, the patient appears systemically ill, or noncompliance with outpatient antibiotic therapy is expected. In addition to antibiotics, bedrest, scrotal elevation on a towel, and analgesics are recommended. Once appropriate treatment has begun, clinical improvement should be rapid. A follow-up examination should be performed to assure the return of scrotal contents to normal. If significant resolution of symptoms has not occurred within 3 days of antibiotic treatment or testicular enlargement persists for more than 1 week, alternative diagnoses, including testicular cancer, abscess, infarction, tuberculosis, or fungal infection, should be considered. Abnormalities of the genitourinary tract should be ruled out when epididymitis is caused by GNRs without precipitating factors such as recent urinary tract instrumentation. Sexual contacts within the past 60 days of partners with a sexually transmitted cause of epididymitis should be evaluated and treated. Sexual intercourse with partners should be avoided until the patient and partner have completed therapy and no longer have symptoms. 7

ORCHITIS

Viruses are the major pathogens causing orchitis, usually in the setting of viremia related to mumps or less commonly coxsackie B virus infection. Approximately 25% of postpubertal males with mumps have evidence of orchitis. The onset occurs 4–6 days after parotiditis and may be subclinical in up to 40% of cases. Orchitis in this setting is usually unilateral but may progress to involve the epididymis or both testes. Symptoms, including pain, nausea, vomiting, and fever, may be mild or quite severe. Resolution occurs within days to several weeks. Treatment is symptomatic. Some atrophy occurs in approximately half of cases but sterility appears now to be uncommon. Bacterial orchitis is very unusual and almost always occurs as a result of extension from epididymal infection. Patients with bacterial orchitis appear very ill and often have high fever, nausea, and vomiting. Skin overlying the tender and swollen testicle is typically erythematous and boggy and there may be an associated acute hydrocele. Empirical intravenous antibiotic therapy should cover the most common causative pathogens including

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Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, staphylococci, and streptococci. Initial empirical therapy could include ceftazidime 2 g q8h or ciprofloxacin 400 mg q8h and vancomycin 15 mg/kg q12h, with subsequent adjustment on the basis of culture results. Complications include testicular infarction and abscess formation. Urological consultation is advised for patients suspected of having bacterial orchitis. BIBLIOGRAPHY Ballard RC. Genital ulcer adenopathy syndrome. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases, New York: McGraw-Hill, 1999, pp 887–892. Barbalias GA, Nikiforidis G, Liasikos N. Alpha blockers for the treatment of chronic prostatitis in combination with antibiotics. J Urol 159(3):883–887. CDC. 2002 Guidelines for treatment of sexually transmitted diseases. MMWR 51 (No. RR-6), 2002. Fox KK, Cohen MS. Gonococcal and chlamydial urethritis. In: Armstrong D, Cohen J, eds. Infectious Diseases, Mosby International, 1999. Fox KK, Isbey SF, Cohen MS, Carson CC. Urethritis, epidydimitis, orchitis, prostatitis. In: Root R, et al., eds. Clinical Infectious Diseases: A Practical Approach. Oxford University Press, 1999, pp 669–678. Handsfield HH. Genital herpes, syphilis, and genital ulcer disease. In: Root R, et al., eds. Clinical Infectious Diseases: A Practical Approach. Oxford University Press, 1999, pp 657–668. Krieger JN. Prostatitis syndromes. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999, pp 859–871. Krieger JN. Prostatitis, epididymitis, and orchitis. In: Mandell G, Bennett J, and Dolin R, eds. Principles and Practice of Infectious Diseases. Churchill Livingstone, 2000, pp 1243–1250. Krieger JN, Graney DO. Clinical anatomy, histology, and physical exam of the male genital tract. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999, 699–709. Lipsky BA. Prostatitis and UTI in men: What’s new; What’s true. Am J Med 106(3):327–334. Martin DM, Bowie WR. Urethritis in males. In: Holmes KK, Mardh P, Sparling PF, et al., eds. Sexually Transmitted Diseases. New York: McGraw-Hill, 1999, pp 833–845. Nickel, JC. Prostatitis: Evolving management strategies. Urol Clin North Am 26(4):737–751, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

18 Endocarditis JoAnn Tufariello Albert Einstein College of Medicine, Bronx, New York, U.S.A.

Franklin D. Lowy Columbia University, New York, New York, U.S.A.

1

INTRODUCTION

Infective endocarditis (IE) is a condition in which microorganisms invade the endothelial lining of the heart. Although typically referring to infection of the heart valves, the term also encompasses infection of septal defects and of the mural endocardium. Because the clinical manifestations of IE can be quite varied, the condition may be encountered by internists, family medicine practitioners, and members of the various medical subspecialties. Despite the varied presentation, prompt recognition of IE with institution of appropriate antimicrobial therapy and in some cases adjunctive surgical intervention is critical to a favorable outcome. Although morbidity and mortality rates remain considerable, advances in both antibiotic therapy and surgical approaches have now rendered curable what had been a uniformly fatal disorder in the preantibiotic era. Since the first comprehensive description of IE provided by William Osler in an address to the Royal College of Physicians in London in 1885, this disease has attracted considerable attention from clinicians and scientific investigators. 2

EPIDEMIOLOGICAL CHARACTERISTICS

The incidence of IE is on the order of ⬃1 patient per 1000 hospital admissions in the United States, or an estimated 10,000 to 20,000 new cases per year. Although this incidence has remained largely unchanged over the past 30 to 40 years, the mean age of patients with IE has increased throughout the antibiotic era, from below 30 years in 1926 to above 50 years at present. Although almost any structural heart disease can predispose to the development of endocarditis, certain cardiac conditions are associated with IE more frequently than others. Acquired valvular dysfunction due to rheumatic heart disease (RHD) was a common predisposing condition in the past, involving the mitral valve in 85% of cases, either alone or in combination, and the aortic valve in about half of cases. However, rheumatic valvular disease is now much less common in Western countries, found in fewer than 15% of patients in many recent series. In developing nations, RHD remains a common disorder 347

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and a frequent predisposing factor in the development of IE. Congenital cardiac conditions including patent ductus arteriosus, ventricular septal defect, primum atrial septal defect, bicuspid aortic valve, coarctation of the aorta, tetralogy of Fallot, and pulmonic stenosis together account for approximately 6%–24% of cases. The congenitally bicuspid aortic valve is a common condition, found in 1%–2% of the general population, and is becoming an increasingly important predisposing factor for native valve endocarditis. IE involving bicuspid aortic valves tends to be severe, requiring surgery in 80%–90% of cases, and carries a significant mortality rate even with prompt surgical intervention. The mitral valve prolapse (MVP) syndrome is also associated with endocarditis. This relatively common condition is found in 0.5%–20% of otherwise healthy individuals, particularly young women. The risk of IE appears to be increased in the group of patients who manifest the holosystolic murmur, rather than those with the isolated midsystolic click, presumably because it is the regurgitant flow and not the valve prolapse itself that creates the turbulence that predisposes to IE. Patients exhibiting myxomatous degeneration of the mitral valve, with mitral valve leaflet thickening and redundancy on echocardiogram, are also at increased risk for IE. Idiopathic hypertrophic subaortic stenosis (IHSS) is another cardiac condition that can lead to IE, which occurs in 5% of patients with IHSS. This has been attributed to turbulent flow at the aortic valve, which is distal to the hypertrophied portion of the interventricular septum, as well as to coexisting mitral regurgitation due to displacement of the anterior leaflet by the abnormally shaped ventricle. The role of ‘‘degenerative’’ cardiac conditions such as calcified lesions due to arteriosclerotic cardiovascular disease or a calcified mitral annulus in predisposition to IE remains unclear. In a number of series, the majority of patients with acute IE had no known underlying cardiac disease. As these degenerative conditions are common in the elderly population, it is possible though unproved that they play a role in the development of IE. The presence of implanted foreign material within the heart or arterial system is also a risk factor for the development of IE. As will be discussed further, prosthetic valve endocarditis (PVE) is a distinct form of IE, occurring in about 3%–6% of patients within 5 years after valve replacement. Intracardiac pacemaker wires and hemodialysis shunts and fistulas also predispose to endocarditis. IE also occurs with increased frequency in hospitalized patients who have undergone invasive vascular access procedures that can lead to bacteremia, including placement of intravenous catheters, hyperalimentation lines, and central venous pressure monitors. Injection drug users (IDUs) are also at increased risk for IE. In IDUs, the endocarditis is often right-sided, involving the tricuspid valve. Infection in these subjects often occurs on previously undamaged valves. A number of theories have been proposed to explain the predominance of right-sided endocarditis in this population, including damage to the endothelium of right-sided valves by injected particulate material; physiological effects of injected substances, including vasospasm, ischemia, tissue injury, and thrombus formation; and direct injection of large bacterial loads, which cause a high-grade bacteremia. An additional trend has been the increasing incidence of nosocomial native and prosthetic valve endocarditis. These infections, frequently related to the use of intravascular devices, are often difficult to detect as a result of supervening medical problems and the intermittent administration of antibiotics. 3

PATHOPHYSIOLOGICAL CHARACTERISTICS

The development of IE is the result of complex interplay among a damaged valvular surface, local hemodynamic factors, transient bacteremia with certain microorganisms, and

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host defenses. Nonbacterial thrombotic endocardial lesions are regions of fibrin deposition and platelet aggregation that result from trauma to the valve surface. In experimental models, many types of stresses can produce these lesions, including high-velocity jet streams of blood, high cardiac output states, and infection. Nonbacterial thrombotic endocarditis (NBTE) has been found to occur in patients with malignancy, especially lung, gastric, and pancreatic cancers, as well as uremia, collagen vascular disease, congenital heart disease, and in those who have undergone placement of Swan-Ganz catheters. On the basis of these associated conditions, either endothelial trauma or a hypercoagulable state is thought to underlie the condition. Hemodynamic factors are also important to the development of IE. Infected vegetations are usually located on the atrial surface of the atrioventricular valves or the ventricular surface of the semilunar valves when associated with insufficiency. That is, when flow occurs through the valve orifice from a region of high to low pressure, the favored location for deposition of bacteria is just beyond the low-pressure side of the orifice. Lesions associated with high degrees of turbulence such as jet streams through small ventricular septal defects (VSDs) also favor bacterial colonization. In contrast, lesions associated with low-pressure flow abnormalities such as ostium secundum, atrial septal defects, or pure mitral stenosis are rarely associated with IE. The NBTE lesions become colonized with bacteria when skin or mucosal integrity is breached, leading to transient bacteremia. Many manipulations that involve the oropharyngeal, gastrointestinal, and genitourinary tracts result in bacteremia (see Table 1). The bacteremia is relatively low-grade and transient; sterilization of blood cultures occurs within about 30 minutes. The bacteremias are due to the indigenous microbial flora at the site involved—often viridans streptococci after oropharyngeal procedures and gramnegative bacilli and enterococci after gastrointestinal and genitourinary manipulations. The specific adherence characteristics of the organisms play an important role in the colonization of nonbacterial thrombotic lesions, which leads to endocarditis. Many strains of viridans streptococci produce a complex extracellular polysaccharide, called dextran, which is thought to promote the adherence of the organisms to NBTE lesions. The ability to produce dextran has been correlated with ability to adhere to damaged valvular tissue in vitro and to induce IE in vivo in a rabbit model. Viridans streptococci also express a surface protein, FimA, which is located at the tips of the fimbriae and is involved in attachment to NBTE lesions. 4

CLINICAL PRESENTATION

The clinical manifestations of IE can be highly varied and involve multiple organ systems (see Table 2). In the past, bacterial endocarditis was classified as acute (ABE) or subacute (SBE) on the basis of the tempo of progression of the disease, although this distinction has now been in large part superseded by classification based on the specific microbiological cause. In general, ABE follows a rapidly progressive course characterized by high fevers, systemic toxicity, and death within days to several weeks if untreated. The causative organisms, usually highly virulent, include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes (group A streptococcus), and Neisseria gonorrhoeae. In contrast, SBE follows a more indolent course over weeks to several months with lowgrade fever, sweats, fatigue, and weight loss and is typically caused by viridans streptococci. This constellation of symptoms can lead to erroneous diagnoses of tuberculosis, malignancy, or collagen vascular disease. In some cases an antecedent event likely to produce bacteremia (for example, a dental procedure) can be identified. The varied signs and symptoms seen in IE are the result of (1) local destruction of the valve and intracardiac

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Table 1 Incidence of Bacteremia: Various Procedures Procedure/manipulation Dental Dental extraction Periodontal surgery Chewing of candy or paraffin Tooth brushing Oral irrigation device Upper airway Bronchoscopy (rigid) Tonsillectomy Nasotracheal suctioning/intubation Gastrointestinal (GI) Upper GI endoscopy Sigmoidoscopy/colonoscopy Barium enema Percutaneous needle biopsy of liver Urological Urethral dilatation Urethral catheterization Cystoscopy Transurethral prostatic resection Obstetrical/gynecological Normal vaginal delivery Punch biopsy of cervix Removal/insertion of intrauterine device (IUD)

Positive blood culture results, % 18–85 32–88 17–51 0–26 27–50 15 28–38 16 8–12 0–9.5 11 3–13 18–33 8 0–17 12–46 0–11 0 0

Source: Adapted from Everett and Hirschmann 1977.

extension of the infection, (2) septic embolization to distant organs or vessels, (3) bacteremia that causes metastatic seeding of distant sites, and (4) prolonged antigenic stimulation that leads to formation of circulating antigen-antibody complexes. 4.1

Fever

Fever is present in the vast majority of patients with IE; therefore, absence of documented fever in a patient not on antipyretic agents calls the diagnosis into question. However, fever may be absent in the setting of prior antibiotic use, severe congestive heart failure, or renal failure and in elderly or debilitated patients. Fever usually remits with antibiotic treatment within 1–2 weeks in approximately 90% of patients. Fever beyond 2 weeks of appropriate antibiotic therapy may be due to embolization (either major vessel or microvascular phenomena) or intracardiac abscess formation. Prolonged fever may presage the need for cardiac surgery and higher mortality rate. In addition to the endocarditis or its complications, persistent fever may be due to intravenous catheter–related phlebitis, drug fever, or superimposed nosocomial infection. 4.2

Cardiac Manifestations

An audible heart murmur is found in 85% of patients. IE in the absence of a murmur can occur with isolated tricuspid involvement (as in IDUs), with infection of the mural en-

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MANIFESTATIONS AND DIAGNOSIS Clinical manifestations (Table 2) Acute (days) or subacute (months) onset of fever, sweats, weight loss, and myalgias Cardiac Murmur in 85% of subacute cases Congestive heart failure (CHF), heart block Peripheral stigmata such as splinter hemorrhage, Osler’s nodes, Janeway lesions, Roth spots uncommon Renal involvement with glomerulonephritis, abscess, or emboli causing hematuria Neurological involvement due to emboli or ruptured mycotic aneurysm that accompanies stroke Emboli to spleen, mesenteric arteries, extremities, and lung (in injection drug user [IDU] with tricuspid valve infection) Laboratory Blood culture results positive in 85%–95% Normochromic, normocytic anemia Elevated erythrocyte sedimentation rate (ESR) Microscopic hematuria and proteinuria Elevated immunoglobulin, low complement levels Positive rheumatoid factor finding Diagnosis Two or three sets of blood cultures from different venipunctures prior to antibiotics (i.e., persistent bacteremia) Duke criteria: Tables 3 and 4 Use of echocardiography: Figure 1

docardium rather than valvular tissue, and very early in the course of ABE that occurs on previously normal valves. The appearance of new murmurs or of obvious changes in preexisting murmurs, although considered characteristic of IE, is actually uncommon. When present, new murmurs often signify an acute staphylococcal disease with valve destruction leading to aortic or mitral insufficiency and often presage the development of congestive heart failure (CHF), which is now the foremost cause of death in IE. The infection can spread locally from valve leaflets to surrounding structures, producing ring abscesses and mycotic aneurysms. This is especially of concern with staphylococcal endocarditis. Myocardial abscesses can involve the conduction system and produce heart blocks. Septic pericarditis is uncommon and occurs predominantly in the setting of myocardial abscess formation with fistulas to the pericardial sac in S. aureus infection. Myocarditis can occur and lead to arrythmias and to CHF. Coronary artery emboli usually arise from the aortic valve and can produce myocardial infarction. Rarely, very large vegetations can result in valvular stenosis. 4.3

Cutaneous, Peripheral, and Intraocular Findings

A number of cutaneous and peripheral manifestations have been described in IE. As many of these findings are immunologically mediated and increase with duration of untreated illness, they are more common in SBE than in ABE. These peripheral signs were more prevalent in the preantibiotic era. Petechiae occur with prolonged infection and can be

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Table 2 Clinical Manifestations of Infective Endocarditis Symptoms

Patients affected, %

Fever Chills Weakness Dyspnea Sweats Anorexia Weight loss Malaise

80 40 40 40 25 25 25 25

Cough Skin lesions Stroke Nausea/vomiting

25 20 20 20

Headache Myalgia/arthralgia Edema Chest pain Abdominal pain Delirium/coma Hemoptysis Back pain

20 15 15 15 15 10–15 10 10

Signs Fever Heart murmur Changing murmur New murmur Embolic phenomena Skin manifestations Osler nodes Splinter Hemorrhages Petechiae Janeway lesions Splenomegaly Septic complications (pneumonia, meningitis, etc.) Mycotic aneurysms Clubbing Retinal lesions Signs of renal failure

Patients affected, % 90 85 5–10 3–5 >50 18–50 10–23 15 20–40 <10 20–57 20 20 12–52 2–10 10–25

Source: Adapted from Bayer AS and Scheld WM 2000.

found on the buccal mucosa, conjunctivae, and extremities. They are the result of either local vasculitis or microemboli. Splinter hemorrhages are dark red to brown linear streaks found beneath the fingernails and toenails. Although seen in IE, they are nonspecific and also occur with trauma or a variety of other causes. Clubbing is seen in 10%–20% of patients. Osler’s nodes are small, tender subcutaneous nodules found in the pulp of the digits or on the thenar eminence. These lesions can be transitory, resolving in hours to days, and are believed to be caused by an immunologically mediated vasculitis. Osler’s nodes are seen more commonly with SBE. Janeway lesions are hemorrhagic, painless macular lesions located on the palms or soles; are thought to be the result of septic microemboli; and are more common with acute staphylococcal endocarditis. Roth spots are oval retinal hemorrhages with pale centers, which are usually located near the optic disc. These lesions are uncommon in IE, occurring in about 5% of patients; similar lesions can be seen in systemic lupus erythematosus (SLE) or leukemia. 4.4

Renal Complications

Renal artery emboli can result in infarctions that cause flank pain, gross or microscopic hematuria, and, less commonly, renal failure and hypertension. Rarely, a renal abscess can be caused by septic embolization. In approximately 10%–15% of patients with IE an immune complex glomerulonephritis similar to that caused by collagen vascular diseases such as SLE develops with subepithelial deposition of immunoglobulin in the glomerular

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basement membrane. There are often an accompanying hypocomplementemia and a positive serum assay finding for rheumatoid factor. The glomerulonephritis may result in microscopic hematuria, proteinuria, uremia, and renal failure. 4.5

Neurological Manifestations

Emboli to the major cerebral arteries, which occur in 10%–30% of patients, can appear as a strokelike syndrome of hemiplegia, ataxia, aphasia, hemisensory deficits, or depressed sensorium. Neurological symptoms can also be due to mycotic aneurysms of the cerebral circulation, which occur most commonly in peripheral branches of the middle cerebral artery. These are usually clinically silent until the time of rupture, when life-threatening subarachnoid hemorrhage can occur. Brain abscess and rarely meningitis are additional central nervous system (CNS) complications of IE. Patients may exhibit seizures, mononeuritis, cranial nerve palsies, and severe headache. Given the prevalence of neurological disturbances in IE and the possibility that these may be the presenting signs or symptoms in 50% of patients, IE should be suspected when any febrile person has sudden neurolgical deterioration. 4.6

Musculoskeletal Manifestations

Musculoskeletal manifestations are also a common part of the clinical presentation of IE. One-quarter to nearly one-half of patients experience low back pain, diffuse myalgias, or mono- or oligoarticular arthralgias. An intense back pain that hampers mobility may be the presenting symptom of IE in 5%–10% of patients. Septic arthritis and osteomyelitis may be seen with ABE, especially with S. aureus infection. 4.7

Embolic Events

Embolic events are common, occurring in up to 50% of patients. The consequences of renal, cerebral, and coronary artery emboli were discussed earlier. Emboli to the retinal artery can cause sudden blindness, and emboli to mesenteric arteries can cause abdominal pain due to vascular occlusion and ischemia. Splenic artery emboli with infarction can cause left upper quadrant pain that radiates to the left shoulder, left pleural effusion, and a splenic or pleural rub. With right-sided endocarditis in IDUs, pulmonary septic emboli can occur with findings of pulmonary infiltrates or pleural effusions on chest radiography. Septic emboli to the vasa vasorum or direct bacterial invasion of the vessel wall can lead to mycotic aneurysms. These are more common with viridans streptococci than with other pathogens, and although any vessel may be involved, mycotic aneurysms occur more commonly in the abdominal aorta and the cerebral, coronary, pulmonary, and superior mesenteric arteries. 5

LABORATORY STUDIES

Blood culture is the most significant test in the diagnostic evaluation of IE. Cultures should be obtained whenever the diagnosis of IE is suspected. They reveal a pathogen in 85%– 95% of cases in which at least two sets of cultures have been obtained. Blood cultures so frequently yield positive results because the bacteremia of endocarditis, although lowgrade, is usually continuous. When ABE is suspected and there is urgent need to begin antibiotic therapy, three blood culture sets (each taken from a separate venipuncture site) should be collected over 1–2 hours. For suspected SBE, three blood culture sets obtained

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over a 24-hour period are usually adequate. Additional specimens may be necessary if the patient received antibiotic therapy in the preceding 2 weeks. In this situation, if therapy is not urgent, it is preferable to obtain blood cultures for at least several days after antibiotic therapy has stopped. Culture-negative endocarditis occurs in only about 5% of cases when the patient has not received prior antibiotic therapy. When blood culture results remain negative after several days and endocarditis is still suspected, a number of special techniques may be helpful. Some nutritionally variant streptococci (NVS, now classified as Abiotrophia spp.) can be isolated by adding pyridoxal hydrochloride or L-cysteine to the culture medium. Special medium (buffered charcoal yeast extract agar) permits the growth of Legionella sp., a potential pathogen in culture-negative prosthetic valve endocarditis. Lysis-centrifugation blood cultures have enhanced recovery rate and decreased detection time for certain ˜ microorganisms, especially fungi. Culture of blood in a Castaneda bottle containing both agar and liquid medium is also useful in enhancing the yield of fungal blood cultures. These supplementary techniques are important since blood culture findings are negative in about half of cases of fungal endocarditis. Holding cultures for 4 weeks may increase the yield for especially slow-growing organisms such as Brucella spp. and members of the HACEK group (see Sec. 7.1.4). Serological studies are useful for the diagnosis of endocarditis due to Coxiella burnetii (Q fever), Chlamydia psittaci (psittacosis), Legionella sp., and Bartonella sp. Subculture of the aerobic broth medium is also a useful method for identifying endocarditis due to Bartonella sp., a recently described cause of IE in alcoholic and homeless patients. A variety of specialized molecular techniques to detect deoxyribonucleic acid (DNA) or ribosomal ribonucleic acid (RNA) in tissue or blood as well as polymerase chain reaction (PCR) analysis of blood may eventually gain utility in identifying a number of difficult-to-culture pathogens such as Tropherema whipelli, the agent of Whipple’s disease. Microscopic examination of vegetation tissue or of resected emboli, including special stains (for example, for fungal elements) and fluorescent-labeled antibody detection methods, have also proved useful in identifying causative agents of IE. Nonspecific laboratory abnormalities are common in IE. There is often a normochromic normocytic anemia. Thrombocytopenia is also observed, especially in neonatal IE or in IE of long duration that has been complicated by splenomegaly. The white blood cell count is often elevated in acute IE but is frequently normal in SBE. The erythrocyte sedimentation rate (ESR) is elevated in nearly all patients with SBE. This finding is so universal that if the ESR is normal in a patient in whom the test would be expected to be accurate (a patient without renal failure, CHF, or disseminated intravascular coagulation), the diagnosis of IE is called into question. Also commonly found are hypergammaglobulinemia, hypocomplementemia, and a positive assay result for rheumatoid factor. Urinalysis reveals proteinuria in 50% or more of cases and often microscopic hematuria as well. Less commonly, gross hematuria, pyuria, and bacteriuria are observed. Red blood cell casts may be found if an immune complex glomerulonephritis has developed. 6

DIAGNOSTIC CRITERIA

Diagnostic criteria for endocarditis were proposed in 1981 by von Reyn and colleagues. These criteria, although useful, have been considered overly strict since a diagnosis of ‘‘definite IE’’ required pathological confirmation. Other limitations were lack of inclusion of echocardiographic findings in the diagnostic schema and lack of recognition of IDU as a significant predisposing factor. These limitations led investigators at Duke University Medical Center to propose revised diagnostic criteria for IE, which were published in

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1994. The Duke criteria divide patients into three categories: (1) definite IE, (2) possible IE, and (3) rejected (see Table 3). The major and minor criteria defining a definite case of IE are detailed in Table 4. It should be noted that bacteremia with certain pathogens that are typical causes of IE but uncommonly isolated from blood outside the context of endocarditis, such as viridans streptococci or members of the HACEK group, constitutes a major criterion whenever the organisms are isolated from two separate blood cultures; in contrast, bacteremia due to S. aureus or enterococcus is a major criterion only if the bacteremia is communityacquired and has no primary focus. More recently, in 2000 Li and associates proposed that S. aureus bacteremia should constitute a major criterion whether community-acquired or nosocomial. This change was proposed because of the high incidence of IE diagnosed in patients with S. aureus bacteremia even when the bacteremia was nosocomially acquired and a removable focus such as an intravascular catheter was present. The Duke criteria also incorporate echocardiographic findings of vegetations (as oscillating intracardiac masses on valves or supporting structures) or paravalvular complications of IE (abscess or new dehiscence of a prosthetic valve). The recent use of intravenous drugs is included as a minor criterion in the Duke diagnostic criteria. The Duke criteria have been found to be highly specific for the diagnosis of IE, with a specificity as high as 99% in a study by Hoen and colleagues (1996). The sensitivity and specificity of the Duke criteria are reviewed in detail by Bayer and colleagues (1998). One shortcoming of the Duke criteria is the heavy reliance on the results of transthoracic echocardiography (TTE), since when the criteria were formulated transesophageal echocardiography (TEE) had not yet undergone systematic evaluation in the assessment of endocarditis. TTE is a powerful, rapid, and noninvasive technique with excellent specificity for detecting vegetations. However, its sensitivity is significantly lower than that of TEE, especially for left-sided vegetations <10 mm in diameter. With regard to right-sided

Table 3 Duke Criteria for Diagnosis of Infective Endocarditis Definite infective endocarditis Pathological criteria Microorganisms: demonstrated by culture or histology in a vegetation, in a vegetation that has embolized, or in an intracardiac abscess or Pathological lesions: vegetation or intracardiac abscess present, confirmed by histological result showing active endocarditis Clinical criteria, using specific definitions listed in Table 4 Two major criteria, or One major and three minor criteria, or Five minor criteria Possible infective endocarditis Findings consistent with infective endocarditis that fall short of Definite, but not Rejected Rejected Firm alternate diagnosis for manifestations of endocarditis, or Resolution of manifestation of endocarditis with antibiotic therapy for 4 days or less or No pathological evidence of infective endocarditis at surgery or autopsy after antibiotic therapy for 4 days or less Source: Adapted from Durack DT et al. 1994.

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Table 4 Definitions of Terms Used in the Duke Criteria for the Diagnosis of Infective Endocarditis Major criteria 1. Positive blood culture for infective endocarditis a. Typical microorganisms for infective endocarditis from two separate blood cultures (1) Viridans streptococci,a Streptococcus bovis, HACEKb group, or (2) Community-acquired Staphylococcus aureus or enterococci in the absence of a primary focus, or b. Persistently positive blood cultures defined as recovery of a microorganism consistent with infective endocarditis from (1) Blood cultures drawn more than 12 hours apart, or (2) All of three or a majority of four or more separate blood cultures with first and last drawn at least 1 hour apart 2. Evidence of endocardial involvement a. Positive echocardiogram for infective endocarditis (1) Oscillating intracardiac mass, on valve or supporting structures, or in the path of regurgitant jets, or on implanted material, in the absence of an alternative anatomical explanation or (2) Abscess or (3) New partial dehiscence of prosthetic valve or b. New valvular regurgitation Minor criteria 1. Predisposition: predisposing heart condition or intravenous drug use 2. Fever: ⱖ38.0⬚C (100.4⬚F) 3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions 4. Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth spots, rheumatoid factor 5. Microbiological evidence: positive blood culture result but not meeting major criterion as noted previouslyc or serological evidence of active infection with organism consistent with infective endocarditis 6. Echocardiogram: consistent with infective endocarditis but not meeting major criterion as noted previously a

Including nutritionally variant strains. HACEK, Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. c Excluding single positive culture results for coagulase-negative staphylococci and organisms that do not cause endocarditis. Source: Adapted from Durack DT et al. 1994. b

IE, large vegetations on the tricuspid valve (which lies closer to the chest wall than the left-sided valves) are fairly readily detected by TTE, although TEE is still better able to localize the specific site and features of the lesions. TTE may be inadequate for detecting vegetations in a significant proportion (⬃20%) of patients because of obesity, emphysema, mechanical ventilation, chest wall deformities, or recent surgery. In many cases, TEE provides greater than 90% sensitivity for native valve IE as compared to 60%–65% for TTE. Transesophageal echocardiography also has enhanced sensitivity when compared with TTE for diagnosing complications of IE such as perivalvular abscess formation. TEE has also proved superior to TTE in diagnosis of PVE, especially in evaluating the function and anatomical features of mitral valve prostheses. TTE can provide a more complete view of the ventricular surfaces of mitral, tricuspid, and aortic prostheses and is also useful

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when the mechanical portions of prosthetic aortic valves cause acoustic shadowing that interferes with imaging. Therefore, TEE and TTE should be used together in evaluating suspected PVE, as they provide complementary information. It needs to be recognized that TEE is a more invasive and uncomfortable test than TTE. Patients need sedation for the procedure and some even general anesthesia. Bayer and colleagues (1998), writing for the American Heart Association, provide a management scheme for the diagnostic use of echocardiography in IE (see Figure 1). It is noteworthy that it is not advisable to utilize TTE as a screening test for any febrile patient when there is extremely low suspicion of endocarditis on clinical grounds or for a patient bacteremic with an organism very rarely associated with endocarditis such as Escherichia coli, especially if another source of the bacteremia is identified.

Figure 1 Diagnostic approach to the use of echocardiography in IE. * High-risk echocardiographic features include large and/or mobile vegetations, valvular insufficiency, suggestion of perivalvular extension, or secondary ventricular dysfunction. † For example, a patient with fever and a previously known heart murmur, and no other stigmata of IE. ‡ High-risk patients include those with prosthetic valves, previous endocarditis, many congenital heart diseases, new-onset murmur, heart failure, or other stigmata of endocarditis. Rx, antibiotic treatment for endocarditis. IE, infective endocarditis; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography. (Adapted from Bayer AS et al. 1998.)

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Although TEE is very sensitive for detecting vegetations, an initially negative TEE finding does not completely exclude IE. Causes of false-negative TEE study results include very small vegetations (especially for TEE done very early in the course) or recent embolization of vegetations. When the clinical suspicion remains high and another source of symptoms is not identified, a repeat TEE is warranted within 7–10 days to reassess for evidence of IE. Although both TTE and TEE are relatively specific for IE, false-positive findings of vegetations can be caused by the presence of old, healed IE lesions; thrombi; myxomatous valves; sclerotic leaflets; and a variety of other conditions. In some cases it may be impossible to distinguish the noninfected lesions of marantic endocarditis from IE and thorough assessment of the clinical setting is critical.

7 7.1

NATIVE VALVE ENDOCARDITIS Pathogens

The overwhelming majority of infections, approximately 80%–90%, are due to the grampositive pathogens streptococci and staphylococci. Viridans streptococci have caused the majority of cases of native valve endocarditis (NVE) and still represent the most common isolates at tertiary care referral centers. However, the percentage of cases due to staphylococci is growing, especially at local community hospitals.

BACTERIOLOGICAL CHARACTERISTICS AND TREATMENT Native valve endocarditis Viridans streptococci Enterococci S. aureus, coagulase-negative staphylococci uncommon Uncommon causes: HACEK, fungi, anaerobes, Corynebacterium spp., Coxiella burnetti, C. psittici Treatment Streptococci: Table 5 Enterococci: Table 6 Staphylococci: Table 7 HACEK: Table 8 Prosthetic valve endocarditis Early (within 2 months of surgery) Coagulase-negative staphylococci and S. aureus Diphtheroids Enterococci Gram-negative bacilli Fungi Late (>12 months since surgery) Viridans streptococci Enterococci S. aureus and coagulase-negative staphylococci HACEK Therapy of staphyloccal infection: Table 9 Indications for surgery: Table 10

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Streptococci

The term viridans streptococci refers to a heterogenous group of ␣-hemolytic streptococci (other than S. pneumoniae) that are usually nontypable by the Lancefield system; those most often causing endocarditis are S. sanguis, S. mutans, and S. mitior. Streptococcus bovis, a component of normal gastrointestinal (GI) tract flora, is a member of Lancefield group D. When NVE is caused by S. bovis, carcinoma of the colon and other GI tract abnormality should be ruled out. Other streptococci that cause IE are the ‘‘S. intermedius group,’’ which includes S. intermedius and S. anginosus. Although uncommon causes of IE, these organisms are noteworthy for their tendency to cause suppurative complications such as empyema or abscesses of kidney, liver, brain, or other organs. Another infrequent cause of IE is S. pneumoniae (about 1%–3% of cases), which often affects the aortic valve. Unlike other streptococci, it can exhibit a fulminant course with perivalvular abscess formation and pericarditis. Most of these patients have coexisting pneumococcal meningitis as well as endocarditis. The ‘‘nutritionally variant streptococci,’’ now called Abiotrophia spp., are responsible for about 5% of cases of streptococcal endocarditis and typically display an indolent subacute course in the setting of underlying cardiac valvular abnormalities. Group B streptococcus (Streptococcus agalactiae) causes IE in the context of serious underlying conditions such as diabetes mellitus, alcohol abuse, liver failure, and malignancy. Vegetations are large and friable with a tendency toward major systemic embolization. The mortality rates are high. Group A ␤-hemolytic streptococcus (Streptococcus pyogenes) remains a very uncommon cause of IE. 7.1.2

Enterococci

Enterococci are no longer members of the genus Streptococcus but have been assigned to their own genus, Enterococcus. They are increasing in importance as causes of IE. These organisms, components of normal GI and urethral flora, are members of Lancefield’s serogroup D. They are divided into at least 12 species, although Enterococcus faecalis and Enterococcus faecium are the major clinical isolates. The enterococci tend to cause a SBE that often occurs after genitourinary procedures in older men or obstetrical procedures in women. Enterococci are becoming increasingly resistant to standard antimicrobial therapy, often displaying resistance to even very high concentrations of aminoglycosides, which are used for synergy with cell-wall-active agents. Cell-wall-active agents such as ampicillin have limited efficacy when used alone. Enterococci resistant to vancomycin (VRE) have emerged as significant hospital pathogens and have in some cases been implicated as causes of IE. The intrinsic and increasing resistance of the enterococci to multiple antibiotics can make cure exceedingly difficult. Enterococcal bacteremia has been rising in incidence as a result of a number of factors including increasing use of broad-spectrum antibiotics such as cephalosporins, to which the enterococci are resistant, as well as increasing use of invasive procedures such as placement of indwelling lines and urinary catheters. Making the diagnosis of enterococcal endocarditis in the setting of enterococcal bacteremia can be difficult. In general, the bacteremia is most likely to indicate endocarditis if it is community-acquired, is monomicrobial rather than polymicrobial, lacks an obvious focus of infection, and occurs in the setting of preexisting valvular disease.

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Staphylococci

Staphylococci cause an estimated 20%–35% of cases of NVE, most of these due to S. aureus. This organism is able to cause disease on cardiac valves with no known abnormality and, when affecting the left side of the heart, causes fulminant disease with valve destruction and metastatic infection to brain, kidney, spleen, and other organs. Mortality rates approach 40%. Myocardial and valve ring abscesses and suppurative pericarditis occur more commonly than with other causes of endocarditis. Nosocomial IE due to S. aureus appears to be increasing in incidence, is often acquired in the setting of invasive vascular access devices, and is likely to be caused by methicillin-resistant S. aureus (MRSA) strains. S. aureus is also the most common cause of IE in IDU, although here the disease tends to be less severe with lower mortality rates and better response to treatment, perhaps because the tricuspid valve rather than the left side of the heart is most often affected. S. epidermidis and other coagulase-negative staphylococci cause a small proportion (⬃1%–3%) of cases of native valve endocarditis. Since coagulase-negative staphylococci are also the most common bacteria that contaminate blood cultures, the treating physician must attempt to determine whether culture results reflect true infection or contamination (see Chapter 9). The diagnosis of IE is more likely when the patient has underlying cardiac disease (particularly mitral valve prolapse), the organisms are isolated from multiple blood cultures, and isolates from separate cultures are shown to be the same strain (e.g., by antibiotic susceptibility profiles, plasmid profile analysis, and pulsed field gel analysis of chromosomal DNA). The presentation of NVE due to coagulase-negative staphylococci is typically subacute. An exception is IE due to a recently recognized pathogen, Staphylococcus lugdunensis, which causes an acute endocarditis with valve destruction and abscess formation. 7.1.4

Other Less Common Pathogens

Approximately 5% of cases of NVE are due to unusual gram-negative bacteria of the HACEK group: Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. These are small pleomorphic gram-negative coccobacilli that are normal flora of the oropharynx and upper respiratory tract. They tend to be slow growing and fastidious. As a group, these organisms tend to cause a SBE in the setting of preexisting valvular disease and to produce large vegetations with frequent arterial embolization. CHF is also a common complication. Endocarditis due to Neisseria gonorrhoeae has declined markedly in incidence since the introduction of penicillin. Gram-negative aerobic bacilli are uncommon causes of IE. There are a host of other uncommon causes of IE, including Corynebacterium spp., Listeria monocytogenes, and Bacteroides fragilis. Epidemiological clues that may help define rare causes of IE include identification of Brucella spp. in endemic areas such as Saudi Arabia and Spain, Bartonella sp. organisms in homeless alcoholic males, Coxiella burnetii (Q fever endocarditis) with exposure to infected aerosols from animal products, and Chlamydia psittaci with exposure to psittacine birds. Fungal endocarditis occurs in IDUs, patients with indwelling lines who have received prolonged antibiotic therapy, and those who have undergone cardiac surgery. 7.2

Treatment

IE is difficult to cure even with antimicrobial agents to which the infecting organisms are exquisitely sensitive in vitro. This may be due in part to the extraordinarily high bacterial

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densities achieved within vegetations, estimated at 109 –1010 organisms per gram of tissue. At these densities, bacteria may have altered metabolic activity and reduced rates of cell division that render them less sensitive to cell-wall-active agents such as penicillin. Antibiotics may also have reduced penetration into vegetations. Host defenses may also be impaired in the microenvironment of the vegetation as the fibrin network that surrounds the bacterial colonies may limit entry of phagocytic cells. Given the difficulty in achieving sterilization of vegetations due to the considerations mentioned, it is necessary to administer agents that have bactericidal activity, to maintain adequate blood levels of these agents, and to administer these agents over prolonged periods of time, typically at least several weeks. Parenteral administration is almost always necessary. Specific recommendations regarding antibiotic treatment of IE due to streptococci, enterococci, staphylococci, and HACEK microorganisms have been issued by Wilson and colleagues (1995) and the American Heart Association Committee on Endocarditis (see Bibliography). Tables abstracted from this publication are provided (Tables 5–9). 7.2.1

Streptococci

Many viridans streptococci and S. bovis are highly susceptible to penicillin G, with minimal inhibitory concentrations (MICs) ⱕ 0.1 ␮g/ml. As indicated in Table 5, patients with IE due to these organisms can be successfully treated with a 4-week regimen of penicillin G or ceftriaxone. These single-agent regimens may be preferable for patients with renal impairment or those at risk for aminoglycoside-induced ototoxicity. Short-course therapy consisting of a 2-week regimen of penicillin G plus an aminoglycoside results in similarly high cure rates (⬃98%) and is appropriate for uncomplicated endocarditis (absence of intracardiac abscess, thromboembolic disease, etc.) in younger patients at low risk for aminoglycoside toxicity. Gentamicin is the aminoglycoside most often utilized, offering the option of intravenous (IV) or intramuscular (IM) administration, and serum levels of gentamicin can be routinely determined. For viridans streptococci with relative resistance to penicillin G (MIC >0.1 and <0.5 ␮g/ml), a combined regimen of penicillin for 4 weeks with gentamicin for the initial 2 weeks is recommended (see Table 5). This regimen is also recommended by some for IE due to highly penicillin susceptible strains when the course has been complicated or symptoms have been present longer than 3 months. It should be noted that ceftriaxone-based regimens, using 2 weeks of once-daily ceftriaxone plus an aminoglycoside, have been successfully used for IE due to penicillin-susceptible viridans streptococci. This regimen offers the advantage of outpatient therapy for patients in stable condition. Some viridans streptococci display penicillin tolerance, with penicillin minimal bactericidal concentration (MBC) considerably higher (32-fold or more) than the MIC. There is no consensus on the implications of penicillin tolerance for treating streptococcal IE, and the preferred regimen is unclear, although ␤-lactam–aminoglycoside combinations have been recommended by some experts. Determination of MICs for the nutritionally variant streptococci can be difficult. These organisms frequently display low-level penicillin resistance. The relapse rate of IE with these organisms is high. For these reasons, IE due to the nutritionally variant streptococci is generally treated as for enterococcal endocarditis (discussed later; also see Table 6). IE due to S. pneumoniae and groups A, B, C, and G streptococci is less common, and treatment in consultation with an infectious disease specialist is recommended. 7.2.2

Enterococci

IE due to enterococcus can be exceedingly difficult to treat. This is especially true of E. faecium, which tends to have greater resistance to ␤-lactams than E. faecalis. The en-

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Table 5 Suggested Regimens for Therapy of Native Valve Endocarditis Due to Viridans Streptococci and Streptococcus bovis, Based on Penicillin G Minimal Inhibitory Concentrationa Penicillin G MIC, ␮g/ml ⱕ0.1

Antibiotic

Dosage and route

Aqueous crystalline 12–18 million U/24 hr IV eipenicillin G ther continuously or in 6 sodium equally divided doses or Ceftriaxone sodium 2G once daily IV or IMb

ⱕ0.1

Duration, wk 4

Comments Preferred in most patients older than 65 yr and in those with impairment of the eighth nerve or renal function

4

Aqueous crystalline 12–18 million U/24 hr IV eipenicillin G ther continuously or in 6 sodium equally divided doses

2

With gentamicin sulfatec

1 mg/kg IM or IV every 8 hr

2

Vancomycin hydrochlorided

30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels monitored

4

Vancomycin therapy recommended for patients allergic to ␤-lactams; peak serum concentrations of vancomycin should be obtained 1 hr after completion of the infusion and should be in the range of 30–45 ␮g/ml for twice-daily dosing

>0.1 and Aqueous crystalline 12–18 million U/24 hr IV ei<0.5 penicillin G ther continuously or in 6 sodium equally divided doses

4

Cefazolin or other first-generation cephalosporin may be substituted for penicillin in patients whose penicillin hypersensitivity is not of the immediate type

With gentamicin sulfatec

1 mg/kg IM or IV every 8 hr

2

>0.1 and Vancomycin hy<0.5 drochlorided

30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels monitored

4

ⱕ0.1

a

When obtained 1 hr after a 20- to 30-min IV infusion or IM injection, serum concentration of gentamicin of approximately 3 ␮g/ml is desirable; trough concentration should be <1 ␮g/ml

See comments on vancomycin therapy above

Dosages recommended are for patients with normal renal function. For nutritionally variant streptococci see Table 6. IV, intravenous; IM, intramuscular. b Patients should be informed that IM injection of ceftriaxone is painful. c Dosing of gentamicin on a milligram/kilogram (mg/kg) basis will produce higher serum concentrations in obese patients than in lean patients. Therefore, in obese patients, dosing should be based on ideal body weight. Relative contraindications to the use of gentamicin are age >65 yr, renal impairment, or impairment of the eighth nerve. Other potentially nephrotoxic agents should be used cautiously in patients receiving gentamicin. d Vancomycin dosage should be reduced in patients with impaired renal function. In obese patients, dosing should be based on ideal body weight. Each dose of vancomycin should be infused over at least 1 hr to reduce the risk of histamine-release ‘‘red man’’ syndrome. Source: Wilson WR et al. 1995.

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Table 6 Suggested Regimens for Therapy of Endocarditis Due to Enterococcia Antibiotic

Dosage and route

Duration, wk

Aqueous crystalline penicillin G sodium

18–30 million U/24 hr IV either continuously or in six equally divided doses

4–6

With gentamicin sulfateb Ampicillin sodium

1 mg/kg IM or IV every 8 hr 12 g/24 hr IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 hr 30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored

4–6 4–6

1 mg/kg IM or IV every 8 hr

4–6

With gentamicin sulfateb Vancomycin hydrochloridec

With gentamicin sulfateb

4–6 4–6

Comments 4-wk therapy recommended for patients with symptoms <3 mo in duration; 6-wk therapy for patients with symptoms >3 mo in duration As above As above

As above Vancomycin therapy is recommended for patients allergic to ␤-lactams; cephalosporins are not acceptable alternatives for patients allergic to penicillin

a

All enterococci causing endocarditis must be tested for antimicrobial susceptibility in order to select optimal therapy. This table is for (1) gentamicin- or vancomycin-susceptible enterococci, (2) viridans streptococci with a penicillin minimal inhibitory concentration >0.5 ␮g/ml, (3) nutritionally variant viridans streptococci, or (4) prosthetic valve endocarditis caused by viridans streptococci or Streptococcus bovis. Antibiotic dosages are for patients with normal renal function. IV, intravenous; IM, intramuscular. b For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. c For specific dosing adjustment and issues concerning vancomycin (obesity of patients, length of infusion), see Table 5 footnotes. Source: Wilson WR et al. 1995.

terococci are relatively resistant to penicillin (median MIC 2 ␮g/ml), ampicillin, and vancomycin. These agents are bacteriostatic against enterococci and must be administered in combination with aminoglycosides to achieve bactericidal activity (see Table 6). Combination therapy is typically given for at least 4–6 weeks. Enterococci are resistant to cephalosporins. Enterococcal strains exhibit highly variable resistance to aminoglycosides; MIC greater than or equal to 2000 ␮g/ml of streptomycin or 500–2000 ␮g/ml of gentamicin is used as the cutoff value to distinguish between low- and high-level resistance. Enterococci that have high-level resistance to one of the aminoglycosides are not killed synergistically with combination therapy. Good therapeutic alternatives do not exist and expert consultation is suggested. Enterococcal penicillin resistance can be due to ␤-lactamase production or to altered penicillin binding proteins (PBPs). ␤-Lactamase production can be countered by adding sulbactam to ampicillin (Unasyn); PBP mutations require the use of vancomycin. Unfortunately, vancomycin-resistant enterococci have emerged as significant pathogens in recent years. Consultation with experts is recommended for these very difficult cases.

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Staphylococci

Most S. aureus strains causing IE, whether acquired in the community or in the hospital, produce ␤-lactamase and are resistant to penicillin G. The recommended regimens include a semisynthetic penicillinase-resistant penicillin such as nafcillin or oxacillin or a firstgeneration cephalosporin given for 4–6 weeks (see Table 7). Addition of gentamicin causes synergistic killing in vitro and in animal models and a more rapid clearing of bacteremia has been observed in clinical trials. Cure rates, though, are not improved with combination

Table 7 Therapy for Endocarditis Due to Staphylococcus in the Absence of Prosthetic Materiala Antibiotic

Dosage and route

Duration

Comments

Methicillin-susceptible staphylococci Regimens for non-␤lactam-allergic patients Nafcillin sodium or oxacillin sodium With optional addition of gentamicin sulfateb Regimens for ␤-lactamallergic patients Cefazolin (or other first-generation cephalosporins in equivalent doses) With optional addition of gentamicin Vancomycin hydrochloridec

2 g IV every 4 hr

4–6 wk

1 mg/kg IM or IV every 8 hr

3–5 days

2 g IV every 8 hr

4–6 wk

1 mg/kg IM or IV every 8 hr 30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored

3–5 days 4–6 wk

Benefit of additional aminoglycosides has not been established As above

Cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin As above Recommended for patients allergic to penicillin

Methicillin-resistant staphylococci Vancomycin hydrochloridec

30 mg/kg per 24 hr IV in two equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored

4–6 wk

For treatment of endocarditis due to penicillin-susceptible staphylococci (minimal inhibitory concentration ⱕ0.1 ␮g/ ml), aqueous crystalline penicillin G sodium (Table 5, first regimen) can be used for 4–6 wk instead of nafcillin or oxacillin. Shorter antibiotic courses have been effective in some IDUs with right-sided endocarditis due to Staphylococcus aureus. IV, intravenous; IM, intramuscular. b For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. c For specific dosing adjustment and issues concerning vancomycin (obesity of patients, length of infusion), see Table 5 footnotes. Source: Wilson WR et al. 1995. a

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therapy. Therefore, some authorities recommend addition of gentamicin for the first 3 to 5 days of therapy, especially for severe cases of left-sided S. aureus IE, with the objective of reducing metastatic seeding and abscess formation while minimizing the toxicities associated with more prolonged courses of aminoglycoside (see Korzeniowski and Sande 1982, and reviewed in Bayer and Scheld 2000 and in Wilson et al. 1995). Shorter courses of therapy, consisting of an antistaphylococcal semisynthetic penicillin plus an aminoglycoside given for 2 weeks, have yielded high cure rates (90% or greater) in IDUs with uncomplicated right-sided S. aureus IE (for example, Chambers et al. 1988). These abbreviated regimens are not recommended for IDUs with any evidence of left-sided involvement or metastatic infection. In patients with allergies to penicillin and cephalosporins and in cases when the S. aureus isolate is methicillin-resistant, the recommended therapy is vancomycin. However, both in vitro studies and clinical data have shown that vancomycin is an inferior antistaphylococcal agent when compared with the semisynthetic penicillins (discussed in Bayer and Scheld 2000). For penicillin-allergic patients who do not respond to vancomycin therapy for a methicillin-susceptible S. aureus, one can consider ␤-lactam desensitization. For patients infected with methicillin-resistant strains who are responding suboptimally to vancomycin therapy, one may consider adding rifampin, or gentamicin, or both agents (if the isolate is sensitive), or a number of alternative regimens relying on quinolones, trimethoprim-sulfamethoxazole, or minocycline. Infectious disease consultation is advisable in these difficult cases. 7.2.4

HACEK

In the past, the HACEK microorganisms exhibited a consistent susceptibility to ampicillin. However, more recently ␤-lactamase-producing strains have emerged, rendering third-generation cephalosporins the treatment of choice for IE that is due to these organisms. Native valve infections are treated for 4 weeks; prosthetic valve infections require 6 weeks of therapy (see Table 8).

Table 8 Therapy for Endocarditis Due to HACEK Microorganisms (Haemophilus parainfluenzae, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae)a Antibiotic

Dosage and route

Duration, wk

Ceftriaxone sodiumb

2 g once daily IV or IM

4

Ampicillin sodiumc

12 g/24 hr IV either continuously or in six equally divided doses 1 mg/kg IM or IV every 8 hr

4

With gentamicin sulfated a

Comments Cefotaxime sodium or other third-generation cephalosporins may be substituted

4

Dosages recommended are for patients with normal renal function. IV, intravenous; IM, intramuscular. Patients should be informed that IM injection of ceftriaxone is painful. c Ampicillin should not be used if laboratory tests show ␤-lactamase production. d For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. Source: Wilson WR et al. 1995. b

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PROSTHETIC VALVE ENDOCARDITIS Pathogens

Within the first 5 years after surgery, PVE occurs in about 3%–6% of patients who have had valve replacement. The incidence is highest during the initial 6–12 months after surgery and declines thereafter to a low but constant rate of about 0.4% per year. PVE can be divided into cases occurring early (within 2 months after surgery) and late (more than 12 months after valve replacement) with an additional intermediate group (2–12 months post surgery). The early cases are often due to coagulase-negative staphylococci (30%–35%) and S. aureus (⬃17%), although Enterbacteriaceae, Pseudomonas aeruginosa, enterococci, diphtheroids, and fungi each account for a small proportion of cases. The early cases are thought to be the result of intraoperative contamination at the time of valve implantation or of seeding of the valve during an early postoperative bacteremia from intravenous catheters and skin or wound infections. The vast majority of the coagulasenegative staphylococci isolated in these early infections are methicillin-resistant. In the intermediate period, the spectrum of organisms is similar, although streptococci are more often involved and gram-negative bacilli and diphtheroids less so. These cases represent a mixture of nosocomial infections with delayed presentation as well as some community-acquired cases. Late PVE is often due to viridans streptococci, enterococci, and HACEK organisms as well as coagulase-negative staphylococci and S. aureus. In these late cases, the coagulase-negative staphylcococci are often methicillin-sensitive and a variety of non–S. epidermidis species are isolated. Fungi account for about 4%–6% of cases of PVE; Candida albicans is responsible for most cases. The clinical presentation of PVE is similar to that of native valve endocarditis especially when it develops several months or more after surgery. However, the diagnosis of PVE in the early postoperative period can be challenging given the variety of surgical and postoperative complications that may give rise to fever and to bacteremia. Patients with early PVE may have fever in the absence of prosthetic valve dysfunction or peripheral manifestations. Diagnosis rests on maintaining high suspicion, obtaining multiple sets of blood cultures, and imaging the valve by echocardiography. When blood cultures sporadically yield organisms such as coagulase-negative staphylococci and diphtheroids, which could represent either PVE pathogens or contaminants, molecular techniques may be pursued to determine whether the isolates are indeed clonal in origin, a source that would make endocarditis more likely. Evaluation of a prosthetic valve for infection requires imaging by both TTE and TEE in order to afford adequate imaging of all valvular surfaces. TEE is especially useful for diagnosis of periprosthetic leaks, abscesses, and fistulas. 8.2

Treatment

The treatment of PVE rests on the same considerations outlined for native valve endocarditis. In general, a bactericidal combination of antimicrobial agents is administered for a minimum of 6 weeks; see Table 9 for regimens for treatment of staphylococcal PVE. Regimens for other organisms are outlined in Karchmer (2000). In contrast to the treatment of NVE, in therapy of staphylococcal PVE, rifampin plays a critical role. This recommendation is based on results from animal models and clinical experience (reviewed in Karchmer, 2000). Resistance to this drug can develop very rapidly, especially if it is given as monotherapy. It is preferable to administer two effective antistaphylococcal agents along with rifampin; if the isolate is resistant to gentamicin or an alternative aminoglycoside, then consideration should be given to substitution of a fluoroquinolone to which the strain is susceptible.

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Table 9 Therapy for Staphylococcal Endocarditis in the Presence of a Prosthetic Valve or Other Prosthetic Materiala Antibiotic

Dosage and route

Duration, wk

Comments

Regimen for methicillin-resistant staphylococci Vancomycin hydrochlorideb

ⱖ6

With rifampinc

30 mg/kg per 24 hr IV in two or four equally divided doses, not to exceed 2 g/24 hr unless serum levels are monitored 300 mg orally every 8 hr

And with gentamicin sulfated,e

1.0 mg/kg IM or IV every 8 hr

Nafcillin sodium or oxacillin sodium

2 g IV every 4 hr

ⱖ6

With rifampinc And with gentamicin sulfated,e

300 mg orally every 8 hr 1.0 mg/kg IM or IV every 8 hr

ⱖ6 2

ⱖ6

Rifampin increases the amount of warfarin sodium required for antithrombotic therapy

2

Regimen for methicillin-susceptible staphylococci First-generation cephalosporins or vancomycin should be used in patients allergic to ␤-lactam Cephalosporins should be avoided in patients with immediate-type hypersensitivity to penicillin or with methicillin-resistant staphylococci

a

Dosages recommended are for patients with normal renal function. IV, intravenous; IM, intramuscular. For specific dosing adjustment and issues concerning vancomycin (obesity of patients, length of infusion), see Table 5 footnotes. c Rifampin plays a unique role in the eradication of staphylococcal infection involving prosthetic material; combination therapy is essential to prevent emergence of rifampin resistance. d For specific dose adjustment and issues concerning gentamicin (obesity of patients, relative contraindications), see Table 5 footnotes. e Use during initial 2 wk. Source: Wilson WR et al. 1995. b

Despite antimicrobial therapy, patients with PVE often experience complications that require surgical intervention. Such complications include periprosthetic dehiscence, CHF due to valvular dysfunction, paravalvular extension of infection, persistent bacteremia despite antibiotic treatment, and very large, highly mobile vegetations. 9

SURGERY IN INFECTIVE ENDOCARDITIS

Surgery is necessary in approximately 25% of cases of infective endocarditis. The indications for surgery have remained relatively constant, although several newer indications have been suggested. The traditionally accepted indications are summarized in Table 10. The hemodynamic status of the patient remains the primary determinant of the need for surgery. Heart failure is the most common indication for surgery and is the most common cause of death in this population. Patients with severe failure unresponsive to medical management, even in the presence of continued active infection, should have surgery

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Table 10 Indications for Surgery 1. 2. 3. 4. 5.

Congestive heart failure (CHF) unresponsive to medical therapy or severe valvular disease resulting from infection Multiple systemic emboli Infection caused by an antimicrobial-resistant organism such as fungi, Enterobacteriaceae, and Pseudomonas aeruginosa Prolonged bacteremia or relapse after appropriate therapy Most patients with prosthetic valve endocarditis

without delay. The indication for surgery due to recurrent emboli is less clear. The frequency of embolic disease decreases rapidly after institution of appropriate therapy. Patients with embolic disease who have persistent, large left-sided vegetations appear to be at increased risk of additional systemic emboli. Mitral valve lesions are associated with the highest risk of embolization. The studies on vegetation size and the risk of emboli as documented by echocardiography are inconclusive: some studies suggest that size increases risk, and others do not support this conclusion. Infections caused by certain bacterial species including Enterobacteriaceae, Pseudomonas sp., and staphylococci are often poorly responsive to therapy. Recent retrospective studies suggest that patients with left-sided S. aureus endocarditis have an improved outcome if they have a combination of medical and surgical therapy. In patients with early (<2 months) onset of PVE, surgery is frequently necessary because the infection often involves the perivalvular ring. The clinical presentation in these cases may be subtle and include persistent fever, valve dehiscence, new-onset conduction abnormalities, or pericarditis.

10

ANTIBIOTIC PROPHYLAXIS

It has become accepted practice to administer antibiotic prophylaxis to patients at increased risk for endocarditis prior to performing certain procedures with a high likelihood of inducing bacteremia. However, it should be noted that the current guidelines for prophylaxis of IE, which have been published by a number of national boards, are based not on proven efficacy for preventing IE in humans, but on studies of bacteremia related to dental and other procedures, findings from experimental animal models of endocarditis, bacterial susceptibility data, and clinical experience.

PROPHYLAXIS Efficacy not proved but strongly recommended Approach to prophylaxis: Figure 2 Infective endocarditis (IE) caused by transient bacteremia after procedures: Table 1 Indications for prophylaxis: Table 11 Regimens for dental and respiratory tract procedures: Table 12 Regimens for gastrointestinal and genitourinary tract procedures: Table 13

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Table 11 Indications for Endocarditis Prophylaxis 1.

2.

3.

Endocarditis prophylaxis is recommended for the following cardiac conditions: High-risk category Prosthetic cardiac valves including bioprosthetic and homograft valves Previous bacterial endocarditis Complex cyanotic congenital heart disease (e.g., single ventricle states, transposition of the great arteries, tetralogy of Fallot) Surgically constructed systemic pulmonary shunts or conduits Moderate-risk category Most other congenital cardiac malformations (other than above) Acquired valvular dysfunction (e.g., rheumatic heart disease) Hypertrophic cardiomyopathy Mitral valve prolapse with valvular regurgitation and/or thickened leaflets Endocarditis prophylaxis is recommended for the following dental procedures if the conditions under #1 are present (for other procedures, endocarditis prophylaxis is not indicated): Dental extractions Periodontal procedures including surgery, scaling and root planing, probing, and recall maintenance Dental implant placement and reimplantation of avulsed teeth Endodontic (root canal) instrumentation or surgery only beyond the apex Subgingival placement of antibiotic fibers or strips Initial placement of orthodontic bands but not brackets Intraligamentary local anesthetic injections Prophylactic cleaning of teeth or implants where bleeding is anticipated Other procedures where endocarditis prophylaxis is recommended if the conditions under #1 are present (for other gastrointestinal, genitourinary, and respiratory procedures, prophylaxis is not indicated): Respiratory tract Tonsillectomy and/or adenoidectomy Surgical operations that involve respiratory mucosa Bronchoscopy with a rigid bronchoscope Gastrointestinal tract Sclerotherapy for esophageal varices Esophageal stricture dilation Endoscopic retrograde cholangiography with biliary obstruction Biliary tract surgery Surgical operations that involve intestinal mucosa Genitourinary tract Prostatic surgery Cystoscopy Urethral dilation

Source: Adapted from Dajani et al. 1997.

Despite the difficulty in demonstrating the efficacy of antibiotic prophylaxis for IE in human studies, most authorities concur that selected at-risk patients would benefit from antibiotic prophylaxis during procedures with a high propensity to cause bacteremia. Some procedures such as dental extraction, gingival surgery, esophageal sclerotherapy, or incision and drainage at an infected site pose a higher risk of bacteremia than other procedures. In deciding whether to provide prophylaxis to an individual patient, one must take into account not only the procedure involved but also the patient’s underlying cardiac

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Table 12 Recommended Prophylactic Regimens for Dental, Oral, Respiratory Tract, or Esophageal Procedure Situation Standard general prophylaxis Inability to take oral medications Allergy to penicillin

Allergy to penicillin and inability to take oral medications

Agent

Regimena

Amoxicillin Ampicillin

2 g PO 1 hr before procedure 2 g IV/IM within 30 min before procedure

Clindamycin or Cephalexin or Azithromycin Clindamycin or Cefazolin

600 mg PO 1 hr before procedure 2 g PO 1 hr before procedure 500 mg PO 1 hr before procedure 600 mg IV within 30 min before procedure 1 g IV/IM within 30 min before procedure

a IM, intramuscular; PO, per os. Source: Adapted from Dajani et al. 1997.

condition. The presence of a prosthetic valve and a history of previous infective endocarditis are associated with especially high risks of endocarditis. The most recent American Heart Association (AHA) recommendations (Dajani et al. 1997) provide guidelines for those who should receive prophylaxis (see Table 11). This publication also provides recommended prophylactic regimens for the various procedures (see Tables 12 and 13). An approach to the patient at risk is summarized in Figure 2. To ensure optimal serum levels, oral agents are given 1 hour before the procedure and intravenous agents are given within 30 minutes of the procedure.

Table 13 Recommended Regimens for Genitourinary and Gastrointestinal (Excluding Esophageal) Procedures Situation

Agents

High-risk patients

Ampicillin plus gentamicin

High-risk patients allergic to ampicillin/amoxicillin

Vancomycin plus gentamicin

Moderate-risk patients

Amoxicillin or ampicillin

Moderate-risk patients allergic to ampicillin/ amoxicillin

Vancomycin

a IM, intramuscular; PO, per os; IV, intravenous. Source: Adapted from Dajani et al. 1997.

Regimena Ampicillin 2 g IV/IM plus gentamicin IV/IM 1.5 mg/kg (not to exceed 120 mg) within 30 min of starting procedure; 6 hr later, ampicillin 1 g IM/IV or amoxicillin 1 g PO Vancomycin 1 g IV plus gentamicin IV/IM 1.5 mg/kg (not to exceed 120 mg); complete infusions within 30 min of starting procedure Amoxicillin 2 g PO 1 hr before procedure or ampicillin 2 g IV/IM within 30 min of starting procedure Vancomycin 1 g; complete infusion within 30 min of starting procedure

Endocarditis

371

Figure 2 Approach to endocarditis prophylaxis. * Prophylaxis is optional for high-risk patients undergoing flexible bronchoscopy, transesophageal echocardiography, endoscopy with or without gastrointestinal biopsy, vaginal hysterectomy, and vaginal delivery. (Adapted from Grace and Ahern 2001.)

BIBLIOGRAPHY Bansal RC. Infective endocarditis. Med Clin North Am 79(5):1205–1240, 1995. Bayer AS, Bolger AF, Taubert KA, Wilson W, Steckelberg J, Karchmer AW, Levison M, Chambers HF, Dajani AS, Gewitz MH, Newburger JW, Gerber MA, Shuklman ST, Pallasch TJ, Gage TW, Ferrieri P. Diagnosis and management of infective endocarditis and its complications. Circulation 98:2936–2948, 1998.

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Bayer AS, Scheld WM. Endocarditis and Intravascular Infections. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000, pp 857–902. Berbari EF, Cockerill FR III, Steckelberg JM. Infective endocarditis due to unusual or fastidious microorganisms. Mayo Clin Proc 72:532–542, 1997. Chambers HF, Miller RT, Newman MD. Right-sided Staphylococcus aureus endocarditis in intravenous drug abusers: two-week combination therapy. Ann Int Med 109:619–624, 1988. Dajani AS, Taubert KA, Wilson W, Bolger AF, Bayer A, Ferrieri P, Gewitz MH, Shulman ST, Nouri S, Newburger JW, Hutto C, Pallasch TJ, Gage TW, Levison ME, Peter G, Zuccaro G Jr. Prevention of bacterial endocarditis. JAMA 277:1794–1801, 1997. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: Utilization of specific echocardiographic findings: Duke endocarditis service. Am J Med 96:200–209, 1994. Durack DT. Prophylaxis of infective endocarditis. In: Mandell GL, Bennett JE, Dolin R, ed. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000, pp 917–925. Everett ED, Hirschmann JV. Transient bacteremia and endocarditis prophylaxis: A review. Medicine (Baltimore) 56:61–77, 1977. Frontera JA, Gradon JD. Right-sided endocarditis in injection drug users: Review of proposed mechanisms of pathogenesis. Clin Infect Dis 30:374–379, 2000. Grace C, Ahern J. The Green Book. Fletcher Allen Health Care, 2001. Hall G, Heimdahl A, Nord CE. Bacteremia after oral surgery and antibiotic prophylaxis for endocarditis. Clin Infect Dis 29:1–10, 1999. Hoen B, Be´guinot I, Rabaud C, Jaussaud R, Selton-Suty C, May T, Canton P. The Duke criteria for diagnosing infective endocarditis are specific: Analysis of 100 patients with acute fever or fever of unknown origin. Clin Infect Dis 23:298–302, 1996. Karchmer AW. Infections of prosthetic valves and intravascular devices. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000, pp 903–917. Kemp WE Jr, Citrin B, Byrd BF III. Echocardiography in infective endocarditis. South Med J 92: 744–754, 1999. Korzeniowski O, Sande MA. The National Collaborative Endocarditis Study Group. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts. A prospective study. Ann Int Med 97:496–503, 1982. Lamas CC, Eykyn SJ. Bicuspid aortic valve—a silent danger: Analysis of 50 cases of infective endocarditis. Clin Infect Dis 30:336–341, 2000. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, Bashore T, Corey RG. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 30:633–638, 2000. Osler W. The Gulstonian lectures on malignant endocarditis. Br Med J 1:467–470, 522–526, 577– 579, 1885. Salem DN, Levine HJ, Pauker SG, Eckman MH, Daudelin DH. Antithrombotic therapy in valvular heart disease. Chest 114:590S–601S, 1998. Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS, Stolley PD, Levison ME, Korzeniowski OM, Kaye D. Dental and cardiac risk factors for infective endocarditis: A population-based, case-control study. Ann Intern Med 129:761–769, 1998. Von Reyn CF, Levy BS, Arbeit RD, Friedland G, Crumpacker CS. Infective endocarditis: An analysis based on strict case definitions. Ann Intern Med 94:505–518, 1981. Wilson WR, Karchmer AW, Dajani AS, Taubert KA, Bayer A, Kaye D, Bisno AL, Ferrieri P, Shulman ST, Durack DT. Antibiotic treatment of adults with infective endocarditis due to streptococci, enterococci, staphylococci, and HACEK microorganisms. JAMA 274:1706– 1713, 1995.

19 Bacterial Infections of the Skin and Soft Tissues Jeffrey Parsonnet Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

1

INTRODUCTION

The approach to a patient suspected of having an infection of skin or associated soft tissues requires consideration of five key historical and clinical elements: 1. 2.

3. 4. 5.

What anatomical structures are involved in the infection? What organisms, in general, are most likely to cause infection of the involved skin structure(s), and what is the pathogenesis of infection caused by these organisms? What factors may have contributed to the acquisition of pathogenic bacteria and/ or the introduction of such bacteria into host tissues? What factors may be contributing to the host’s susceptibility to infection or to the severity of infection? What is the severity of infection? Is hospitalization necessary for proper treatment of the infection? Is the patient likely to require surgery for cure of infection?

The physician must conscientiously and deliberately consider all of these elements in order to assess the patient with skin or soft tissue infection properly and institute appropriate care. 1.1

Anatomical Structures

The skin is comprised of three layers: epidermis, dermis, and subcutaneous tissue. The principal cell of the epidermis is the keratinocyte, which produces keratin and plays a role in the immune function of the skin by secreting a wide array of cytokines and inflammatory mediators. Intact epidermis constitutes effective protection against infection by providing (1) a physical barrier to bacteria, (2) an inhibitory ‘‘acid mantle’’ resulting from hydrolysis of lipids, (3) colonization resistance by normal resident microflora, and (4) the antibacterial effects of sebaceous secretions and immunoglobulin secretion. The net result of these hostdetermined mechanisms is that infections of intact skin and supporting structures are unusual unless one or more of these mechanisms have become inoperative. Infections involving only the epidermis, such as impetigo, are well defined anatomically, are not usually associated with systemic manifestations of illness, and heal without scarring. 373

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Underlying the epidermis is the dermis, the principal components of which are collagen and elastic fibers produced by fibroblasts. An infection involving the dermis that has a characteristic raised border caused by containment of fibrous elements of the dermis is known as erisipelas. The dermal vasculature consists of both small and large blood vessels and dermal lymphatics that facilitate systemic spread of exogenous and endogenous mediators of inflammation, causing systemic toxicity. Beneath the dermis lies the panniculus, composed of lobules of fat cells separated by fibrous septa of collagen and large blood vessels. Infections spread more readily through this tissue than through the overlying layers, resulting in the characteristic features of cellulitis. Eccrine and apocrine glands and ducts and pilosebaceous units constitute the skin adnexa. Infections of these structures, such as folliculitis, are common. It is important to recognize infections involving soft tissues underlying these skin structures, such as fasciitis and myositis, because of their severity and the need for surgical de´bridement in proper management. 1.2

Organisms and Host Factors

The vast majority of skin and soft tissue infections are caused by one of two organisms: Staphylococcus aureus and Streptococcus pyogenes (group A streptococcus [GAS]). These organisms are transient colonizers of skin rather than ‘‘normal flora’’ in the usual sense, but cause most infections even in the setting of events or conditions that suggest the possibility of infection by other organisms. Empirical therapy for skin and soft tissue infections must almost always take into account the primacy of these organisms as pathogens. Failure to ‘‘cover’’ these organisms adequately is a more common error than failure to treat for a broader spectrum of pathogens. A history of travel, animal or occupational exposure, or penetrating trauma may suggest an infection caused by pathogens other than S. aureus and GAS. A variety of host factors may contribute to the susceptibility to skin infection or the severity of infection. Abnormal leukocyte function or neutropenia predisposes to infection with what would otherwise be unlikely pathogens, such as aerobic gram-negative rods (GNRs) and coagulase-negative staphylococci. Patients with diabetes mellitus have increased susceptibility to skin infections, especially of the lower extremities. The basis for this phenomenon is probably multifactorial, including the presence of poorly vascularized tissues and subtle defects in neutrophil function. Diabetic patients are prone to infections not only with the usual skin pathogens but also with group B streptococci (S. agalactiae), GNRs, and mixed aerobic/anaerobic flora (see Chapter 29). Individuals who have chronic alcoholism and alcoholic cirrhosis are more prone to infection with both ‘‘usual’’ and unusual pathogens, such as Pasteurella multocida, other bacteria of animal origin, and environmental organisms such as Aeromonas species. One of the major host factors predisposing to infection is a damaged lymphatic system, such as that of women who have had mastectomy with axillary node dissection or patients who have had saphenous vein harvest for use in coronary bypass surgery. Such patients are especially prone to severe and recurrent infection with ␤-hemolytic streptococci. Chronic venous insufficiency, including that caused by previous episodes of infection such as cellulitis, also increases susceptibility to recurrent infection. 1.3

Severity of Illness

A final general area of special consideration is the severity of infection, especially as it relates to the need for hospitalization and for surgical exploration or de´bridement. Infec-

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375

tions that result in tissue necrosis generally require surgery, for determination of the extent of necrosis and for de´bridement. The development of dusky or frankly gangrenous skin, as is occasionally seen in ␤-hemolytic streptococcal infection, is an obvious clue to a necrotizing infection. It is important, however, to be alert for other more subtle clues, such as severe pain (out of proportion to cutaneous findings), swelling of a limb (again, out of proportion to erythema), sepsis syndrome or shock, gas in the tissues (suggesting anaerobic infection) as detected by physical examination or radiographic studies, or an elevated creatine kinase (CPK) level, suggesting myonecrosis. All such patients should be admitted to the hospital for evaluation and initiation of therapy. The author also favors hospital admission for patients with infections of the hand, as these infections often involve anaerobic bacteria or may result in significant loss of function if aggressive therapy (including de´bridement) is delayed. Patients with significant compromise of immune function, either local (infection of poorly vascularized tissue) or systemic (elderly patients, patients with cancer or cirrhosis, or those taking immunosuppressive medications), should also be admitted, as a general rule. The perceived need for high antibiotic levels at the outset of therapy for more severe skin infections does not necessarily mandate hospitalization. Several parenteral antibiotics can be given relatively easily on an outpatient basis (ceftriaxone, ertapenem, cefazolin plus probenecid, and even vancomycin), and some agents taken orally have such excellent bioavailability that high drug levels are achieved by this route of administration.

2 2.1

MAJOR PATHOGENS Staphylococcus aureus

The most common pathogens of skin and subcutaneous tissues are S. aureus and S. pyogenes (group A streptococcus). S. aureus is the major pathogen involved in wound infections. Infections are usually caused by a strain of staphylococcus that is part of the colonizing flora of the host, rather than a newly acquired strain. S. aureus is a component of normal host flora (judging by nasal colonization rates) in about 20% of healthy adults. It has been shown that most infections are caused by strains that colonized the host before infection. Staphylococcal colonization rates are higher among certain groups, including people with chronic skin conditions, such as eczema; people with recurrent minor trauma, such as that induced by injection of insulin or illicit drugs; residents in a nursing home or patients recently admitted to a hospital; employees in a hospital; and patients who have chronic intravenous catheters. Populations such as these, in whom the colonization rate may be in excess of 33%, have higher incidences of invasive staphylococcal infection. S. aureus is unique in the variety of infections it can cause, including abscesses, necrotizing and rapidly spreading infections, and toxin-mediated syndromes. S. aureus typically causes abscesses emanating from hair follicles. Tissue necrosis is caused by staphylococcal exoproducts, cell surface constituents, cellular debris, and local cytokines, resulting in local tissue destruction and cell death. Toxigenic strains of S. aureus mediate toxic shock and staphylococcal scalded skin. Finally, S. aureus can cause cellulitis but does so less frequently than ␤-hemolytic streptococci. 2.2

Streptococci

A variety of ␤-hemolytic streptococci can cause skin and soft tissue infections, the most common being S. pyogenes. This organism is carried by a small percentage of healthy

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individuals in the nasopharynx, on skin, and in the gastrointestinal tract. It is the major pathogen responsible for impetigo, a complication of which is poststreptococcal glomerulonephritis, which is associated with nephritogenic M types. GAS is the most common cause of cellulitis, in which organisms spread rapidly through superficial layers of skin with resultant acute pain and edema; lymphangitis and lymphadenitis are also common. The organism is also associated with scarlet fever, which is caused by pyrogenic exotoxins produced by some strains. Streptococcal toxic shock syndrome (TSS) is the most severe manifestation of the effects of streptococcal exotoxins. Cellulitis and deeper infections can also be caused by other ␤-hemolytic streptococci, principally of group B (S. agalactiae) and group G. These organisms are part of the normal bowel and vaginal flora of many individuals and can cause infections that are indistinguishable from those caused by group A streptococci. These organisms do not cause nonsuppurative sequelae such as glomerulonephritis. Group B streptococcal infections are especially likely to cause infection in patients with mildly to moderately impaired immune systems, including those with diabetes, peripheral vascular disease, alcoholism, or malignancy, and in elderly patients.

2.3

Other Pathogens

A variety of other organisms can cause skin infections under specific circumstances, such as loss of the normal cutaneous barrier or exposure to organisms that are not part of normal resident skin flora. Clostridium species, most notably C. perfringens, may be involved in infections that result from contamination of wounds or tissues by bowel flora or that follow trauma and wound inoculation with environmental organisms. After inoculation into tissues, C. tetani causes disease by production of a potent neurotoxin, whereas C. perfringens and C. septicum (most notably) cause severe, crepitant wound infections, myonecrosis, and septic shock. Vibrio vulnificus can cause a severe sepsis syndrome after exposure to raw oysters or salt water in the southern United States. After ingestion or exposure, V. vulnificus can invade the bloodstream with subsequent cutaneous manifestations. The skin lesions are initially erythematous but evolve into hemorrhagic bullae. Mortality rates approach 50%. Persons at most risk include those with cirrhosis, hemachromatoses, hemolytic anemia, and immune suppression. Other important skin and soft tissue pathogens, again under specific circumstances, include Bacillus anthracis, Pasteurella multocida, and Pseudomonas aeruginosa.

3

PRIMARY INFECTIONS OF SKIN (PYODERMA)

Most primary infections of skin involve the epidermal and superficial dermal layers or the subcutaneous tissue immediately underlying them. Infections involving the epidermis and dermis tend to be well demarcated, more readily apparent to the examiner, and unaccompanied by signs of tissue necrosis. Such infections may be accompanied by fever and other systemic signs of infection but are unlikely to result in the need for surgical de´bridement or in postinfectious sequelae. Clues to involvement of deeper layers of skin and soft tissue include poorly demarcated borders of infection or involvement of noncontinuous areas; severe pain, out of proportion to physical findings; swelling of a limb, extending beyond areas of readily apparent cutaneous involvement; crepitus (palpable gas in subcutaneous

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377

IMPETIGO AND ERYSIPELAS Impetigo S. pyogenes Most often children, involving the face Vesicles evolving to pustules covered with honey-yellow crust No systemic toxicity Concern for postinfectious glomerulonephritis Therapy: penicillin or cephalexin (see Table 1) Bullous impetigo S. aureus Flaccid bullae that rupture, revealing raw skin with adherent crust No systemic toxicity Therapy with dicloxacillin or cephalexin (see Table 1) Erysipelas Most often caused by group A streptococcus spp. (GAS); occasionally by other streptococci and S. aureus Sharply demarcated raised erythema; peau d’orange Systemic toxicity Therapy with penicillin (see Table 1)

tissues); and severe systemic toxicity, including signs of systemic inflammatory response or sepsis syndrome. 3.1

Impetigo

Infection limited to the epidermal layer of skin is called impetigo. S. pyogenes causes most cases of impetigo; the remainder are caused by S. aureus (which can also cause superinfection of lesions produced primarily by streptococci). Impetigo is primarily a disease of children, reflecting the higher rate of streptococcal colonization in this population. The lesions of impetigo begin as small intraepidermal vesicles, which then pustulate and rupture. The hallmark of impetigo is the honey-yellow crust that develops over ruptured pustules. Lesions may be widely scattered but occur most frequently on the face. The pustules may coalesce, making the clinical diagnosis less apparent, but ulceration does not occur and systemic manifestations of illness are minimal. The only notable complication of impetigo is postinfectious glomerulonephritis. S. pyogenes remains susceptible to penicillin, making this the drug of choice for treatment of patients with impetigo (see Table 1). Penicillinase-resistant ␤-lactam antibiotics, such as dicloxacillin and cephalexin, may be used when S. aureus is suspected to be the causative organism. Cephalexin is useful in treatment of penicillin-allergic patients. Bullous impetigo is an uncommon superficial infection caused by S. aureus. As is impetigo, it is largely a disease of children. The characteristic feature is the appearance of flaccid bullae that evolve quickly from small vesicular or pustular lesions. The bullae rupture, exposing moist erythematous skin, over which an adherent crust may develop. The disease is mediated by staphylococcal exfoliative toxins. It is not accompanied by

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Table 1 Antibiotics Used to Treat Primary Skin Infections Generic

Trade

Dosagea

Costsb

Commentc

Oral agents Penicillin VK

Dicloxacillin sodium Cephalexin

Beepen-VK Betapen-VK Pen-Vee K Dynapen Dycill Keflex Cefanex

500 mg qid

$5.60d

Drug of choice for S. pyogenes

500 mg qid

$26.00d

500 mg qid

$8.10d

Clindamycin

Cleocin

300 mg qid

$154.00

Ampicillinclavulanic acid Linezolid

Augmentin

875 mg bid

$95.00

Covers S. pyogenes and S. aureus Covers S. pyogenes and S. aureus Use for penicillin allergy (nonanaphylaxis) Penicillin and cephalosporinallergic patient May cause C. difficile colitis Animal bite–related infections

Zyvox

400–600 mg bid

$800.00

Treatment for MRSA

Intravenous agentse Cefazolin Cefriaxone Nafcillin

Kefzol Ancef Rocephin Generic

Penicillin G

Generic

Clindamycin phosphate

Cleocin

Vancomycin hydrochloride Ampicillinsulbactam Linezolid

Generic

a

1 g q8h

$26.70/dayf

1 g/day 2 g q4h

$26.50/dayf $27.00/dayf

1 million U q4h 900 mg q8h

$50.60/dayf

Unasyn

15 mg/kg q12h 1.5–3.0 g q6h

Zyvox

600 mg q12h

$28.00/dayf

$⬃55.00/dayf $27.20–$53.00/ dayf $120.00/dayf,g

Assuming normal renal function. Average wholesale price for 10 days of therapy. 2000 Drug Topics Red Book. c MRSA, methicillin-resistant S. aureus. d Generic costs. e May be used initially in the outpatient setting. f Does not include infusion costs. g Cost to hospital; charge to the patient may be higher. b

Once-daily dosing High dose to cover streptococci May cause hyperkalemia and phlebitis (rare) Penicillin- and cephalosporinallergic patients Risk for C. difficile colitis Treatment for MRSA Animal bite–related infections Treatment for MRSA

Bacterial Infections of the Skin and Soft Tissues

379

fever or other constitutional symptoms. The treatment of choice is a penicillinase-resistant penicillin (dicloxacillin) or cephalosporin (cephalexin). 3.2

Erysipelas

Erysipelas defines an infection involving tissues deep to the epidermis: the dermis and dermal lymphatics. Infection is essentially contained within the dermis, resulting in margins that are sharply demarcated from surrounding area. The hallmarks of erysipelas are a raised, clearly defined border, intense erythema, and often, dimpling of the skin, yielding the so-called peau d’orange appearance. Erysipelas most often involves the face, areas of chronic edema, and old cutaneous or lymphatic injury sites, especially in the lower extremities. Patients are often ‘‘toxic-appearing.’’ S. pyogenes is the cause in the vast majority of cases, making penicillin the empirical drug of choice for treatment of erysipelas. Non– group A streptococci and S. aureus are said to be occasional causes. 3.3

Cellulitis

Cellulitis is an acute infection that spreads through subcutaneous tissues deep to the dermis. Patients most often have an area of tender erythema. Occasionally, however, pain may dominate the clinical picture in the absence of impressive physical findings or patients may primarily have systemic manifestations of illness such as fever, chills, and vomiting. In contrast to those of erysipelas, the borders of cellulitis may be indistinct because of subcutaneous spread of infection and there may be discontinuous areas of involvement resulting in ‘‘blotchy’’ erythema. Systemic toxicity may be mild or severe, ranging from

CELLULITIS Acute spreading, painful erythema with indistinct borders May have a patchy, discontinuous appearance Often associated with systemic toxicity Potential development of foci of necrosis and bullae S. pyogenes most common Increased risk with tinea pedis, chronic venous or lymphatic obstruction, and previous cellulitis Associated with lymphangitis S. aureus often after penetrating trauma Clues to unusual organisms Dog/cat bite P. multocida Fish handling E. rhusiopathiae Fresh water A. hydrophilia Salt water, raw oysters V. vulnificus Treatment Indications for inpatient care (see Table 2) Dicloxacillin, cephalexin (see Table 1) Recurrent Associated with chronic lymphatic/venous obstruction Most often S. pyogenes Chronic suppression with penicillin VK potentially helpful

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fever, chills, and malaise to a more fully evolved picture of sepsis. Depending on a variety of host factors and on the etiological agent, in cellulitic areas induration, foci of necrosis, or flaccid bullae containing necrotic inflammatory debris may develop, especially in infections caused by S. pyogenes. S. pyogenes is the most common etiological agent of cellulitis; S. aureus causes a significant minority of cases. Cellulitis that develops without recent trauma or other proximate predisposing factors is most likely to be caused by streptococci. Although it is often the case that no predisposing factor is evident, the risk of streptococcal cellulitis is increased by chronic venous or lymphatic insufficiency and by chronic skin breakdown, as may occur with tinea pedis and after previous episodes of cellulitis. Staphylococcal cellulitis is usually a consequence of penetrating trauma. Lymphangitic ‘‘streaking,’’ when it occurs, implies a streptococcal cause, as does significant tissue necrosis. Gram stain of purulent exudate or fluid from bullae, when present, is often useful in establishing a presumptive bacteriological diagnosis. Injection and aspiration of fluid from the ‘‘leading edge’’ of erythema have not proved to be helpful often enough to warrant routine use. Blood cultures may be positive, however, especially in the case of streptococcal infection, and should always be performed before initiation of therapy. A careful review of epidemiological risks that suggest an unusual organism is important. P. multocida is part of the normal oral flora of dogs and cats and is a common cause of cellulitis that follows an animal bite or scratch. The clinical profile of cellulitis caused by Pasteurella spp. is similar to those caused by S. pyogenes; tender erythema, swelling, and systemic toxicity are common features of infection. Although a history of dog or cat contact suggests consideration of this organism, it must be remembered that host flora (staphylococci and streptococci) also cause infection in this setting. Furthermore, Pasteurella spp. can be the cause of cellulitis even when there is no knowledge of direct animal exposure, especially among immunocompromised hosts. Because Pasteurella sp. is resistant to some antibiotics that are commonly used for empirical treatment of cellulitis, this organism merits some consideration in every case of cellulitis (see Chapter 37). A good history may also reveal risk factors for other uncommon, but nonetheless important, causes of cellulitis. Such pathogens include (1) Erysipelothrix rhusiopathiae, the cause of erysipeloid (fish-handler’s disease); (2) Aeromonas hydrophilia, which can cause cellulitis after exposure to fresh water (usually by swimming), especially among compromised hosts; and (3) V. vulnificus, after exposure to temperate salt water or ingestion of raw oysters. 3.3.1

Treatment of Cellulitis

Treatment for cellulitis may be initiated on either an inpatient or outpatient basis, depending largely on host factors. Inpatient therapy is advisable at the outset for patients summarized in Table 2. Even patients who are deemed good candidates for outpatient therapy may be given an initial or several initial doses of a parenteral antibiotic to ensure immediate initiation of therapy and a high drug level from the outset (see Table 1). Because of the difficulty in differentiating between streptococcal and staphylococcal infection on clinical grounds alone, it is often necessary to target both organisms while culture results are pending. Appropriate parenteral agents include a penicillinase-resistant penicillin (nafcillin or oxacillin) or a first-generation cephalosporin (cefazolin). Nafcillin (or oxacillin) should be used at high dose (at least 8 g/day) as these drugs are less potent than penicillin against ␤-hemolytic streptococci. When there is a reasonable degree of confidence that an infection is caused by ␤-hemolytic streptococci (Gram stain of purulent material showing or revealing gram-positive cocci in chains or lymphangitic streaking), then penicillin remains the drug of choice. Penicillin-allergic patients usually tolerate

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Table 2 Criteria for Inpatient Therapy of Cellulitis Significantly impaired immune system Alcoholism Older age Neutropenia Malignancy Compromised local host defenses Severe peripheral vascular disease, especially caused by diabetes mellitus Lymphatic obstruction Significant systemic toxicity, such as signs of sepsis syndrome Infections of hand or face, including periorbital cellulitis Presence of tissue necrosis, gas, or rapidly spreading erythema Suspicion of infection involving deeper structures, such as fascia or muscle Suspicion that infection may be caused by an unusual or antibiotic-resistant organism Close outpatient follow-up difficult or not assured Possibility of imperfect adherence with outpatient antibiotic regimen

cefazolin without difficulty if the adverse reaction to penicillin was not a manifestation of immediate hypersensitivity. An excellent parenteral agent for patients with a history of serious adverse reactions to penicillins and cephalosporins is clindamycin. Vancomycin should be used only in the case of probable infection with methicillin-resistant S. aureus (MRSA). Finally, the possibility of infection with Pasteurella sp. makes empirical therapy with ampicillin/sulbactam desirable as this combination effectively treats this organism plus S. aureus and streptococci. For initial outpatient therapy, dicloxacillin, cephalexin, and penicillin are the usual drugs of choice (the latter when ␤-hemolytic streptococci are thought to be etiological agents). Erythromycin and newer macrolides should not be used as empirical therapy for cellulitis because of excessive resistance among both ␤-hemolytic streptococci and S. aureus. The author also strongly discourages use of quinolones as empirical or targeted therapy for cellulitis because (1) staphylococcal resistance can develop in a patient during therapy, (2) some of these agents (ciprofloxacin) are relatively ineffective against streptococci, and (3) their breadth of spectrum is excessive. Amoxicillin/clavulanate is an excellent choice when infection with Pasteurella sp. is a reasonable possibility. Clindamycin is appropriate for treatment of patients with severe allergy to ␤-lactam antibiotics. Linezolid, a new oxazolidinone antibiotic, can be used orally to treat cellulitis caused by MRSA (see Chapter 3). Patients started on a parenteral antibiotic may be switched to an oral agent when signs of systemic toxicity have abated, when leukocytosis has resolved, and when it is clear there are no local complications requiring surgery, such as abscess formation or the presence of necrotic tissue. It should be emphasized that changes in the ‘‘leading edge’’ of cellulitis or the intensity of erythema are often unreliable indicators of the adequacy of therapy. Erythema may persist well beyond the time when overall clinical improvement is evident. This is especially true when S. pyogenes is the pathogen. This phenomenon reflects tissue damage and residual inflammation induced by bacterial toxins, as opposed to ongoing infection. This may unnecessarily prolong hospitalization, prompt superfluous laboratory and radiographic testing, and lead to empirical ‘‘broadening’’ of antibiotic coverage. Duration of therapy is arbitrary; however, a two-week course is usually desirable, especially when there are local or systemic deficiencies of immune function.

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3.4

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Recurrent Cellulitis

Unfortunately, cellulitis is often a recurrent problem, especially when underlying lymphatic damage is present, as after axillary node dissection, saphenous vein harvest, lower extremity trauma, or previous episodes of cellulitis or deep venous thrombosis. S. pyogenes is usually the pathogen in such cases. The occurrence of more than two episodes of cellulitis over a period of several years should prompt consideration of use of prophylactic antibiotics. Treatment with oral penicillin VK at a dosage of 500 mg twice a day is quite effective in preventing recurrent episodes. Cephalexin is a suitable alternative for penicillin-allergic patients. The author’s practice is to continue therapy arbitrarily for 6 to 12 months, after which the antibiotic is stopped and the need for therapy is reassessed. 4

SUBCUTANEOUS INFECTIONS

A variety of terms are used to define a heterogeneous group of severe infections involving deep tissues of the skin and underlying structures (also see Chapter 2, Sec. 4). These infections are characterized by rapid progression, necrosis of subcutaneous tissues and overlying skin, and systemic toxicity. They may be caused by a single organism (S. pyogenes in particular) or by a mixture of pathogens, including anaerorbic bacteria. In all cases, prompt initiation of parenteral antibiotics coupled with surgical exploration is essential, with de´bridement of necrotic tissue as necessary. Streptococcal gangrene is a severe form of cellulitis in which there is spread of infection along fascial planes associated with extensive tissue necrosis, of both fascia and muscle. Trauma may or may not be a precipitating factor. Bacteremia and shock are often accompanying features. Production of extracellular toxins and enzymes by the organism appears to play a key role in pathogenesis. Thus antibiotics such as clindamycin that inhibit protein synthesis are preferred for this syndrome. Progressive bacterial synergistic gangrene usually occurs at the site of a surgical or traumatic abdominal wound. Mixed bowel flora, including anaerobic streptococci, Bacteroides fragilis, and aerobic GNRs, are usually involved. Anaerobic cellulitis is a necrotizing infection of devitalized subcutaneous tissues superficial to fascia and muscle. Anaerobic bacteria, such as Clostridium species (C. perfringens and C. septicum), and other anaerobic bacteria, such as Bacteroides spp. and Peptostreptococcus spp., often along with aerobic GNRs, gain access to subcutaneous tissues as a result of a traumatic injury or through contamination at the time of surgery. Gas production may be prominent, resulting in frank crepitus extending beyond the area of skin erythema. Involvement of deeper structures may be suggested by an elevated creatine kinase (CPK) level or by a magnetic resonance imaging (MRI) scan result suggesting muscle inflammation. It is often necessary to explore the area of involvement surgically to assess the degree of fascial and muscle involvement accurately. Surgical consultation is essential when faced with a patient with crepitant cellulitis, a rapidly spreading limb infection, a Gram stain result showing mixed flora, or an infection likely to have emanated from a bowel source. Empirical therapy must be directed against anaerobic bacteria, especially B. fragilis and Clostridium spp., streptococci, and aerobic GNRs (see Chapter 2, Table 4). 5

CHANCRIFORM LESIONS

Chancriform lesions are a heterogeneous group of infections involving multiple layers of skin. In developed countries, the most important of these are syphilis (Treponema palli-

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CHANCRIFORM LESIONS Primary syphilis Painless indurated ulcer at inoculation site Regional lymphadenopathy Sporotrichosis Gardeners and farmers Painless pustule that ulcerates Secondary lesions along lymphatics Tularemia Rodent or rabbit contact Painful papule that ulcerates M. marinum Contact with aquariums and fresh water Small papule that ulcerates Lymphangitic spread Anthrax Painless papule → necrotic ulcer → black eschar Associated edema, regional lymphadenopathy

dum), sporotrichosis (Sporothrix schenckii), anthrax (Bacillus anthracis), tularemia (Francisella tularensis), and atypical mycobacterial infection, especially with Mycobacterium marinum. The classic primary chancre of syphilis begins at the site of inoculation as a painless papule, which then erodes and becomes an indurated, painless ulcer with associated regional lymphadenopathy. Cutaneous sporotrichosis arises at sites of minor trauma, usually of a distal extremity, after inoculation of the fungus into skin. In the United States, this infection is most often seen among farmers and gardeners. Lesions often start as small papules or nodules, which then ulcerate, and raised, red borders develop. As in syphilis and anthrax, but in contrast to those of most bacterial infections, the lesions are not painful. A characteristic finding is secondary lesions that develop proximally along lymphatic channels. Ulceroglandular tularemia develops at the site of a tick bite or contact with an infected animal. The lesion starts as a painful papule, which subsequently undergoes necrosis to create a tender ulcer with an indurated border. It is associated with painful regional adenopathy. Infection with M. marinum follows contamination of minor wounds with the organism, which is found in aquariums and natural bodies of fresh water. The fingers and hands are most often infected. Lesions begin as small papules that subsequently enlarge and may ulcerate. Lymphatic spread may be seen, as in sporotrichosis. The point to emphasize is that a careful epidemiological history, including travel, animal exposure, occupational and avocational activities, and sexual activity, is critical in the evaluation of patients with this group of disorders (as with skin and soft tissue infections in general). B. anthracis derives its name from the Greek word for ‘‘coal,’’ anthrakis, because of the black eschar that is the hallmark of this infection. Historically, cutaneous anthrax has followed inoculation of open skin lesions with spores of B. anthracis after contact with anthrax-infected animals or contaminated animal products. Before the bioterrorism outbreak of anthrax in the United States in 2001, there were roughly 2000 cases of cutaneous anthrax per year worldwide, but only rare cases in the United States. The disease

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most commonly affects areas of exposed skin such as the face, neck, and arms. The lesion starts as a pruritic macule or papule, which quickly enlarges to form a round ulcer that may vesiculate and discharge serosanguineous fluid. Toxin production by the organism results in the development of a painless, depressed black eschar often associated with extensive edema. Lymphangitis, painful adenopathy, and systemic symptoms often occur concurrently with the primary lesion. In 2001 there were 11 confirmed or probable cases of cutaneous anthrax in the United States associated with dissemination of spores through the mail. The mean incubation period for these cases was 5 days, with a range of 1 to 10 days. None of the cases was fatal, although fatality rates as high as 20% have been reported in naturally occurring infections. In the United States, the major differential diagnosis would include arachnid bites, tularemia, ecthyma gangrenosum, a staphylococcal pustule or carbuncle with a necrotic eschar, and vasculitis. The diagnosis can be made readily, for untreated patients, by Gram stain and culture of vesicular fluid, or by punch biopsy of the lesion for immunohistochemical staining, and by polymerase chain reaction assays for patients who have already been started on antibiotics (see Chapter 44 for further discussion and treatment recommendations). 6

INFECTIONS OF ADNEXAL SKIN STRUCTURES

6.1 Folliculitis Folliculitis, one of the most common infections of skin, is an infection originating in hair follicles. The appearance is one of small, circumscribed pustules occurring in an area of nonglabrous skin. It may involve just one or several follicles and, hence, a small area of skin or become a generalized process. Systemic signs and symptoms of infection are

FOLLICULITIS, CARBUNCLES, AND PARONYCHIA Folliculitis Hair follicle infection that produces pustule No systemic toxicity S. aureus most often Topical therapy (see Table 3) Furuncles and carbuncles Painful abscess originating in hair follicles S. aureus most often Face, axilla, buttock most commonly Therapy Moist heat Drainage as needed Oral antibiotic for systemic symptoms, large or facial lesions (see Table 1) Paronychia Painful infection of nail bed or margin S. aureus most often Therapy Moist heat Drainage as needed Oral antibiotic for systemic symptoms, large or facial lesions (see Table 1)

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absent. S. aureus is the usual cause. Recurrent episodes may reflect persistent colonization with a pathogenic strain. Minor trauma may also predispose to recurrent episodes. P. aeruginosa and Candida spp. are occasional causes of folliculitis, the former after exposure to contaminated water (often in a swimming pool or whirlpool) and the latter in patients with mucocutaneous or intertriginous candidiasis often associated with antibiotic or corticosteroid use. Treatment of folliculitis consists of topical antibiotics (see Table 3). An attempt to clear staphylococcal carriage may be indicated in some cases of recurrent infection. 6.2

Furuncles and Carbuncles

A furuncle is a painful inflammatory nodule or abscess, also originating in a hair follicle but extending into deeper and adjacent tissues. A carbuncle is an even more extensive process extending into subcutaneous fat and representing multiple contiguous abscesses often with multiple areas of superficial drainage. S. aureus is the usual cause of both furuncles and carbuncles. Furunculosis occurs most often on the face, axillae, and buttocks. It commonly occurs in association with minor trauma such as that caused by shaving or abrasion from clothing. Whereas colonization with a virulent strain of S. aureus is sufficient to result in furunculosis in a normal host, obesity, treatment with steroids, and neutropenia or neutrophil dysfunction increases the likelihood of infection. Fever and constitutional symptoms may be present in addition to local pain. Bacteremia and secondary foci of infection may occasionally occur, especially after manipulation of the primary lesions. Application of moist heat is the cornerstone of therapy for furuncles, promoting localization and spontaneous drainage. Incision and drainage of localized lesions promote more rapid resolution of signs and symptoms. Patients with small furuncles or lesions that drain spontaneously without surrounding cellulitis do not require treatment with systemic antibiotics. Antibiotics are indicated, however, when there is fever, chills, or other systemic symptoms or when there is a significant degree of surrounding erythema or the lesions are large. Antimicrobial therapy is suggested for furuncles located on the head or face because of the small risk of intracranial complications or significant scarring, as well as for patients with impairment of host defenses and diabetes mellitus. Antibiotic therapy should be di-

Table 3 Topical Antibacterial Agents Drug Polymyxin B-neomycinbacitracin Mupirocin 2% oitment Clindamycin phosphate 1% gel Gentamicin sulfate 0.1% cream or ointment a

Trade name

Spectrum

Dosage

Costa

Neosporin

1–3 Times daily TID

3.5-g Tube $28.34 30-g Tube $39.45

Cleocin

Gram-positiveb Gram-negativec Gram-positiveb including MRSAd Gram-positiveb

BID

30-g Tube $30.76

Garamycin

Gram-negativec

TID–QID

15-g Tube $21.34

Bactroban

Average wholesale price. 2000 Drug Topics; Redbook. Staphylococcus, Streptococcus, Clostridium, Corynebacterium spp. c Escherichia coli, Proteus spp., Haemophilus influenzae, Pseudomonas spp., Serratia spp. d MRSA, methicillin-resistant Staphylococcus aureus. b

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rected against S. aureus. Because of the increasing prevalence of MRSA in most communities, even among patients without traditional ‘‘risk factors’’ for MRSA, abscess fluid should be cultured before initiation of antibiotics, if possible. Dicloxacillin and cephalexin are the usual empirical oral antibiotics of choice. Patients with allergy to these medications may be treated with clindamycin, trimethoprim/sulfamethoxazole, or linezolid. These latter drugs may also be useful in infection with MRSA. 6.3

Paronychia

An infection of soft tissues at the margins or bed of a fingernail or toenail is called a paronychia. Local trauma, such as that induced by an ingrown nail, usually precedes development of a paronychia. The vast majority of these infections are caused by S. aureus. Under circumstances of repeated immersion of hands or feet in water, Pseudomonas aeruginosa and Candida spp. can cause paronychia. Local treatment, including warm soaks and facilitated drainage of infected tissues, is often adequate therapy for a paronychia. Oral antistaphylococcal antibiotic is indicated if there are systemic signs of infection or extension of infection beyond the immediate margins of the nail. 7

SECONDARY BACTERIAL INFECTIONS

Skin and soft tissue infections often develop as complications of preexisting skin lesions, such as surgical or traumatic wounds, burns, bites, and cutaneous (including decubitus)

SECONDARY BACTERIAL INFECTIONS Lacerations and punctures Most often Staphylococcus and Streptococcus Can be caused by environmental contaminants such as Enterobacteriaceae, Pseudomonas spp., Aeromonas spp. Puncture through sneaker: P. aeruginosa Foul-smelling or associated with crepitus: Clostridium spp. Decubitus ulcers (see Chapter 41) Sacral Polymicrobic bowel flora most often Importance of deep wound culture to differentiate surface colonization Potential to penetrate to bone Magnetic resonance imaging (MRI) or surgical exploration Heel Staphylococcus and Streptococcus spp. Human bites Staphylococcus and Streptococcus spp. and mouth anaerobes Often involving the hand Tenosynovitis, arthritis, osteomyelitis Amoxicillin/clavulanate or ampicillin/sulbactam Animal bites (see Chapter 37) Staphylococcus and Streptococcus spp., anaerobes, and Pasteurella spp. Capnocytophaga spp. that cause sepsis in immune-compromised host Amoxicillin/clavulanate or ampicillin/sulbactam

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ulcers. The cause of infection may reflect the bacteriological characteristics of the upper respiratory tract (including streptococci and oral anaerobes) in the case of infections of the head or neck or after a human bite, or of the bowel (including streptococci, Bacteroides fragilis, and other anaerobes and aerobic GNRs); alternatively, environmental pathogens may be causative, especially after trauma and in the case of nosocomial infections. S. aureus is the most common organism causing secondary skin infections, and this is especially true among patients with staphylococcal colonization, the risk factors for which are discussed earlier. 7.1

Lacerations and Punctures

Patients with lacerations and puncture wounds that become secondarily infected typically experience some combination of pain, swelling, warmth, erythema, or drainage at the site of injury, often after the initial signs and symptoms of the injury have begun to subside. Fever and other systemic symptoms may or may not be present. S. aurerus and S. pyogenes are the most common causes of secondary infection. Gross contamination of lacerations by debris, especially from a moist environment, may result in infection with unusual organisms such as Aeromonas spp., Enterobacteriaceae, and Pseudomonas spp. A classic scenario is that of a puncture wound of the foot caused by a sharp object (usually a nail) that passes through the sole of a sneaker. The patient typically seeks medical attention several days later with some of the aforementioned symptoms, often after the infection has not improved with a course of an oral antibiotic. Infection under these circumstances is often caused by P. aeruginosa as this organism colonizes the space between the insole and the midsole of sneakers. The infection may spread to adjacent soft tissues or, not uncommonly, may cause osteomyelitis of the calcaneus, metatarsals, or other bones of the foot. An oral fluoroquinolone with activity against P. aeruginosa and S. aureus, such as levofloxacin, may be effective and obviate the need for parenteral therapy and surgical de´bridement. Once deep infection with P. aeruginosa has been established, de´bridement and parenteral therapy with a synergistic combination of drugs are necessary. Anaerobic bacteria, including Clostridium species, may also cause deep infections associated with puncture wounds. Clues to anaerobic infection include foul-smelling discharge, gas in tissues, and tissue necrosis, any of which should prompt urgent surgical evaluation. 7.2

Decubitus Ulcers

Decubitus ulcers (bedsores) occur most often in the sacral region and on the heels of bedridden patients (also see Chapter 41, Sec. 3.1). Sacral ulcers become colonized and then infected with bowel flora, including anaerobes (including B. fragilis), ␤ -hemolytic streptococci and enterococci, and aerobic GNRs. S. aureus may also be involved in this setting. These ulcers tend to be foul smelling and necrotic, reflecting their polymicrobial nature. Heel ulcers are more likely to be caused by staphylococci and streptococci. Differentiation between infecting and colonizing organisms is often difficult but is important in order to facilitate the targeting of antimicrobial therapy. Culture of deep tissue and bone obtained by surgical de´bridement is strongly recommended in equivocal cases. Decubitus ulcers may progress to involve contiguous bone. Differentiating between a deep bedsore and osteomyelitis is often difficult. Magnetic resonance imaging (MRI) scanning is useful in this setting, but false-positive and false-negative results occur. Bone biopsy for histopathological features and culture are often required for definitive diagnosis.

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Human Bites

Infections that follow human bites can be treacherous because of both their location and the microbiological characteristics involved. Human bites often result from a punch to the mouth and hence involve the hand. Hospitalization, use of parenteral antibiotics, and early surgical evaluation are advised for all but the most trivial infections. Infection may be complicated by compartment syndrome, vascular compromise, tissue necrosis, and osteomyelitis. Usual skin flora, especially S. aureus and S. pyogenes, are common pathogens; oral flora, including Peptostreptococcus, Fusobacterium, and Bacteroides species and Eikenella corrodens, are also commonly involved. This diversity of organisms may complicate empirical selection of an antibiotic and mandates the obtaining of cultures whenever possible. It is especially important to recognize the possibility of anaerobic infection and to treat accordingly. Ampicillin/sulbactam intravenously or amoxicillin/clavulanate orally is an excellent empirical choice. Clindamycin is useful in the case of penicillin and cephalosporin allergy, although it may have to be used in combination with a drug that targets GNRs. 7.4

Animal Bites

Animal bites may result in infection caused by the usual skin flora of the bitten host but also by oral flora of the involved animal (see Chapter 37, Sec. 3). Careful microbiological studies of dog and cat bites have shown that these infections are often polymicrobial in nature. The most important agent of infection after a dog or cat bite is Pasteurella multocida. This aerobic gram-negative bacillus causes cellulitis that is indistinguishable clinically from that caused by ␤ -hemolytic streptococci; infection is characterized by swelling, erythema, pain, and systemic signs of infection (see Sec. 3.2). Bacteremia may complicate infection, especially among immunocompromised hosts. Other organisms of animal origin that may cause infection after a bite are Capnocytophaga spp. and Fusobacterium spp. Capnocytophaga spp. can cause a disseminated infection and shock in immunocompromised hosts, especially asplenic patients or those with severe hepatic disease. Importantly, P. multocida is susceptible to penicillin but resistant to ␤ -lactamaseresistant penicillins and to first-generation cephalosporins; therefore, physicians must be aware of the inadequacy of the ‘‘usual’’ antimicrobial agents when treating infected animal bites. Amoxicillin/clavulanate or ampicillin/sulbactam (for oral and parenteral use, respectively) provides excellent coverage for most of the organisms that cause infection in this setting, including Pasteurella spp. Early treatment of animal bite wounds includes irrigation and removal of debris and devitalized tissue and assessment of rabies risk. It remains controversial as to whether antibiotics should be given to patients seen within hours of injury who are without signs of infection. The author recommends early empirical therapy for deep puncture wounds and for wounds involving the hands, face, and head because of the consequences of established infection in these areas. Obtaining purulent material or tissue for aerobic and anaerobic culture is especially important in this setting. 7.5

Surgical Site Infections

Surgical site infection remains a vexingly common problem even after ‘‘clean’’ or ‘‘cleancontaminated’’ procedures (see Chapter 24, Table 3). Complications of surgical site infection include wound dehiscence, prolonged hospitalization, and sepsis. Factors predisposing to infection include duration of the surgical procedure, extremes of age, diabetes, concomitant steroid therapy, obesity, and presence of devitalized tissue (including hematoma) after

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surgery. S. aureus and ␤ -hemolytic streptococci (especially groups A and B) are the most common pathogens. Nasal colonization with S. aureus before surgery is predictive of higher rates of surgical site infections. Measures to decrease presurgical colonization have met with some success in decreasing postoperative infection rates. Nosocomial infection with MRSA is a growing problem worldwide, and this increase has significant implications for both prophylaxis and empirical therapy. Aerobic GNRs, anaerobic bacteria (especially B. fragilis), enterococci, and Candida species may all cause wound infection or be present in mixed culture, especially after abdominal procedures. Wound management includes de´bridement of necrotic tissue, drainage of purulent material, and administration of antibiotics to which documented or presumed infectious agents are susceptible. For most infections, this involves therapy directed against S. aureus until culture results are available. Infections that follow bowel surgery or of sites that are likely to have become contaminated with bowel flora require empirical use of an agent or a combination of agents with activity against S. aureus, anaerobes, and aerobic GNRs. This may often be achieved by using piperacillin/tazobactam alone or ampicillin/sulbactam when there has not been antibiotic use before surgery. Other options include a carbapenem (imipenem or meropenem) or a combination of agents, including (1) metronidazole or clindamycin, (2) an aminoglycoside or fluoroquinolone, and (3) an antistaphylococcal antibiotic such as clindamycin, vancomycin, or nafcillin. Therapy can be tailored to the situation on the basis of culture results; maintenance of anaerobic coverage is important in most cases involving contamination by colonic flora. 7.6

Burns

Prevention and management of infections after severe burns are beyond the scope of this chapter. Briefly, such management may involve use of prophylactic antibiotics, both systemically and topically; full-thickness excision of wounds; de´bridement of necrotic material; and skin grafting. Prevention of contamination of wounds by nosocomial flora is obviously of paramount importance. Despite all the best efforts, infection after severe burns is not uncommon and remains one of the main causes of mortality in this setting. Signs of infection may include a change in appearance of the wound (hemorrhage, rapid eschar separation, or greenish discoloration of the wound), physiological changes consistent with sepsis (hypo- or hyperthermia, hypotension, leukocytosis, and oliguria), or changes in findings of quantitative tissue cultures (as practiced at some centers). The principal causes of infection of burns are S. aureus, including MRSA, and P. aeruginosa. 8

CUTANEOUS MANIFESTATIONS OF SYSTEMIC INFECTIONS

Systemic infections may involve skin secondarily, either by direct infection of skin by hematogenous dissemination or by the effects of bacterial toxins on skin and soft tissues (see Chapter 7). Cutaneous findings are often an early clue to the nature of an underlying infectious process and, hence, to a successful outcome. 8.1

Bacteremia and Candidemia

Bacteria may involve skin during the course of bacterial endocarditis as a result of microembolization from valvular vegetations (see Chapter 9, Sec. 4, and Chapter 7, Sec. 4). Emboli tend to lodge in peripheral sites, such as the distal extremities, especially the fingers and toes, but also palms and soles. Janeway lesions are small painless erythematous macules or nodular hemorrhages on the palms and soles. They represent small subcutaneous

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abscesses and are especially common in left-sided endocarditis caused by S. aureus. Osler nodes are tender indurated erythematous nodules that occur most commonly on the pads of the fingers or toes. Bacteremia, without embolization from an endovascular source, may cause skin lesions, especially during the course of infection with Neisseria gonorrhea and N. meningitidis. The lesions of gonococcemia consist of discrete papules and pustules, often with a hemorrhagic component; such lesions are located primarily on the extremities. Meningococcemia may be accompanied by a variety of purpuric lesions ranging from petechiae, located most often on the trunk and lower extremities, to large ecchymoses. Disseminated infection with Candida spp., which occurs principally in patients with chemotherapy-induced neutropenia, may result in scattered macronodular lesions, 0.5–1.0 cm in diameter, which reveal yeast forms on biopsy and stain results. Ecthyma gangrenosum is an uncommon but characteristic and ominous lesion that develops during the course of GNR sepsis, especially that caused by P. aeruginosa in the setting of neutropenia. It begins as a small macule, which becomes indurated and hemorrhagic and eventually sloughs to form a necrotic ulcer with a black eschar (from which the term gangrenosum derives) with a surrounding area of erythema. Such lesions may occur anywhere on the body and be single or multiple. Ecthyma reflects bacterial invasion of blood vessels within the dermis, ultimately resulting in dermal necrosis. The lesion, which can also be seen in candidemia, reflects serious infection in the setting of severely compromised immune function and heralds a poor outcome. 8.2

Bacterial Toxins

Several infections caused by toxigenic strains of S. aureus and S. pyogenes cause cutaneous findings that are the hallmark of specific syndromes (see Chapter 7, Sec. 4.2). Toxic shock syndrome (TSS) is an acute illness defined by the presence of fever, hypotension, multipleorgan-system dysfunction, and rash with desquamation occurring during convalescence. TSS is caused by toxins produced by S. aureus during the course of infection or mucosal colonization with this organism. Although the disease is widely known for its association with tampon use during menstruation, the fact is that at least half of all cases occur in other settings, in both males and females. Common settings for TSS include upper and lower respiratory tract infection, surgical or traumatic wound infection, secondary infection of other preexisting skin lesions (such as varicella or shingles), use of barrier contraceptives, and the postpartum state. The disease is especially common in children, who are more likely than adults to lack protective antibody to the TSS toxins (TSSTs). Menstrual TSS is almost always caused by the toxin TSST-1, whereas the staphylococcal enterotoxins and TSST-1 may cause nonmenstrual TSS. The acute rash of TSS most often appears as a diffuse, sunburn-like erythroderma, but the rash may be subtle, patchy, or evanscent and appear before or after a patient has gastrointestinal, musculoskeletal, and/or nonspecific constitutional symptoms. It is important to emphasize that desquamation, one of the defining clinical features of TSS, occurs during convalescence, 1 to 2 weeks after the onset of illness; in the author’s experience this is a frequent source of confusion among health care providers and may result in delayed or missed diagnosis of this serious infection. Treatment of TSS consists of removal of any foreign device or material, administration of intraveneous fluids, parenteral antimicrobial therapy directed against S. aureus, and hemodynamic and ventilatory support as needed. There are theoretical, experimental, and anecdotal clinical data suggesting that use of an antibiotic that blocks protein synthesis, such as clindamycin, may be preferred to use of cell wall–active agents in the treatment

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of TSS. Administration of intravenous immunoglobulin, preparations of which have high titers of neutralizing antibody to TSS toxins, is also recommended in severe cases. A single dose of 400 mg/kg has been shown to be effective in reversing the hypotension and other serious manifestations of this illness. A similar picture may be seen during the course of infection with S. pyogenes. The rash of scarlet fever is classically described as a punctate erythroderma, appearing on the trunk and then spreading diffusely with sparing of the palms and soles. The causative toxin of scarlet fever is one of the streptococcal pyrogenic exotoxins (A–C). These toxins are also capable of causing what is now known as streptococcal TSS in a susceptible individual; this syndrome may or may not be accompanied by rash. It may be challenging to differentiate among the rashes of TSS, scarlet fever, and streptococcal TSS. Staphylococcal scalded skin syndrome (SSSS) is caused by a staphylococcal exfoliative or epidermolytic toxin. This disease is primarily seen in children. The onset is abrupt, with fever, skin tenderness, and an erythematous rash. There is subsequent development of large, flaccid, clear bullae, which rupture, resulting in the separation of sheets of skin, a process that exposes large areas of bright red skin. Exfoliation occurs during the acute illness. Healing is complete and without scarring. SSSS and a morphologically identical syndrome caused by an adverse drug reaction, seen mainly in adults, are often grouped together under the term toxic epidermal necrolysis (TEN). 8.3

Spirochete Infections

Worthy of brief mention are two spirochetal illnesses with prominent cutaneous manifestations: Lyme disease, caused by infection with Borrelia burgdorferi, and syphilis, caused by infection with Treponema pallidum; these diseases are further discussed in Chapters 17, 18, and 30. The characteristic lesion of Lyme disease is erythema migrans (EM). EM begins as a painless red macule or papule, most often at the site of the bite of the vector of Lyme disease, an Ixodes sp. tick. The lesion subsequently evolves into an expanding area of redness, often with partial central clearing. The centers of early lesions occasionally become intensely erythematous and may have a vesicular or necrotic quality, which may confound the diagnosis. Within several days of the primary lesion, multiple secondary annular lesions, which are usually smaller than the original lesion, may develop. EM is often accompanied by symptoms of malaise, fatigue, headache, fever, myalgias, and arthralgias. The differential diagnosis of EM includes cellulitis, ringworm, urticaria, exaggerated local reaction to an insect bite, erythema multiforme, and other macular erythrodermas. The characteristic lesion of primary syphilis, the chancre, is described earlier. Secondary (disseminated) syphilis is often marked by the emergence of multiple painless skin lesions, which may appear as macular, maculopapular, papular, or pustular lesions in various combinations. Involvement of the palms and soles strongly suggests the diagnosis. Constitutional symptoms, including low-grade fever, malaise, sore throat, anorexia, weight loss, arthralgias, and generalized lymphadenopathy, are often present during the course of secondary syphilis. Because of its varied presentation, the diagnosis of syphilis is missed unless it is suspected and tested for. Dark-field examination of mucocutaneous lesions is the quickest and most direct laboratory method of establishing the diagnosis. Tissue obtained by skin biopsy can show spirochetes on silver stain or more specific immunofluorescence or immunoperoxidase staining. Serological tests for syphilis usually have positive results at this stage of infection.

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BACTERIAL INFECTIONS OF MUSCLE

Muscles are relatively uncommonly infected because of their rich blood supply and their relative isolation from direct inoculation by bacteria (see Chapter 2, Sec. 4.2.3–4.2.4). In tropical areas of the world, the vast majority of pyomyositis is caused by S. aureus, and this organism causes a sizable majority of muscle infections in North America as well. A wide variety of other organisms can cause muscle infection under specific circumstances, including Streptococcus milleri, group A streptococcus, and rarely, GNRs. Infection of muscle may result from either spread from contiguous focus, such as osteomyelitis, decubitus ulcers, and penetrating wounds, or bacteremic seeding. In the case of hematogenous pyomyositis there is often a history of previous muscle injury; presumably, injury increases the susceptibility of muscle to infection during the course of what might otherwise be a transient bacteremia. Psoas abscess was, at one time, a not infrequent cause of fever of unknown origin; the sensitivity of computed tomography (CT) scanning for this process has made diagnosis of this condition relatively straightforward. S. pyogenes can cause not only cellulitis and necrotizing fasciitis, as discussed, but also necrotizing myositis. Differentiation between fasciitis and myositis requires surgical exploration and direct examination of involved tissues, although MRI scanning may suggest the presence or absence of muscle involvement. Gas gangrene (clostridial myonecrosis) is a rapidly progressive infection most often caused by C. perfringens. Penetrating trauma, bowel surgery, and arterial insufficiency of an extremity are predisposing factors; the existence of devitalized tissue strongly favors development of this illness after inoculation by Clostridium spp. The patient experiences severe pain (usually of an extremity), and examination reveals tense edema and local tenderness, often with crepitus, accompanied by systemic toxicity and rapid progression to refractory shock. There is rapid destruction of muscle tissue, and a fatal outcome is inevitable without definitive early intervention. Treatment consists of prompt de´bridement of devitalized tissue (usually consisting of amputation) and adjunctive antibiotic therapy. Penicillin has historically been the treatment of choice; some authorities now recommend treatment with a combination of penicillin and clindamycin. There may be a role for hyperbaric oxygen for some patients, especially when resection of all involved tissues is not possible, but surgical de´bridement should never be delayed in anticipation of employing this mode of therapy. BIBLIOGRAPHY Archer GL. Staphylococcus aureus: A well-armed pathogen. Clin Infect Dis 26:1179–1181, 1998. Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med 334:240– 245, 1996. Davies HD, McGeer A, Schwartz B, Green K, Cann D, Simor AE, Low DE. Invasive group A streptococcal infections in Ontario, Canada: Ontario Group A Streptococcal Study Group. N Engl J Med 336:547–554, 1996. Eriksson B, Jorup-Ronstrom C, Karkkonen K, Sjoblom AC, Holm SE. Erysipelas: Clinical and bacteriologic spectrum and serological aspects. Clin Infect Dis 23:1091–1098, 1996. Simonart T, Simonart JM, Derdelinckx I, Dobbeleer G, Verleysen A, Verraes S, de Maubeuge J, Van Vooren JP, Naeyaert JM, de la Brassine M, Peetermans WE, Heenen M. Value of standard laboratory tests for the early recognition of group A beta-hemolytic streptococcal necrotizing fasciitis. Clin Infect Dis 32:E9–E12, 2001. Swartz MN. Recognition and management of anthrax—an update. N Engl J Med 345:1621–1626, 2001. Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJ. Bacteriologic analysis of infected dog and cat bites. N Engl J Med 340:85–92, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

20 Nonbacterial Infections of the Skin Anita Licata University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

The skin may be the window of a systemic infection, as seen with the rashes of the tickborne diseases or the exanthems associated with bacterial toxins. The skin may also be the source of localized infections by a number of organisms, ranging in size from the smallest viral particle to a grossly visible insect. This chapter discusses some of the most common infections, including ectoparasite infestations by arthropods such as lice and scabies, fungal infections from dermatophytes and yeasts, and viral infections such as warts, molluscum, and herpesviruses.

2

INFESTATIONS

2.1

Pediculosis

Pediculosis is the infestation with Phthirius pubis (crab or pubic louse) or Pediculus humanus (body or head louse), the two species of blood-sucking lice specific to the human host. The body louse (P. humanus var. corporis) and the head louse (P. humanus var. capitus) are similar in appearance, measuring 2–4 mm in length with flat, gray-white elongated bodies. The pubic louse is wider and shorter. Lice are transmitted by personal contact or via clothing, towels, bedding, or brushes. The injection of saliva and feces into human skin during feeding causes an immune reaction that results in pruritis and rash, which appears approximately 30 days after a primary infection. In addition to causing cutaneous disease, the body louse, but not the head or pubic louse, is capable of transmitting rickettsial epidemic typhus, trench fever, and relapsing fever. 2.1.1

Body Lice

Body lice may cause pruritis, erythematous macules and papules, and urticaria in individuals forgoing bathing and laundry. The lice are not found on the skin but in the seams of the clothing. They only attach to the host for a blood meal and then return to clothing. Treatment of the patient is therefore not necessary. Washing clothing in hot water, drying on high setting, and/or ironing clothes are generally sufficient to kill lice. Chronic infestations can lead to generalized hyperpigmentation and dermal thickening. 393

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INFESTATIONS Lice Pruritic eczematous rash Scalp dandruff Therapy Head: NIX or RID Body: washing of clothes; no therapy for patient Pubic: NIX, Lindane, Elimite to affected areas Scabies Pruritic papules, burrows Therapy: Table 1 Fleas Pruritic papules Therapy: treatment of pets and rugs, furniture contacted

2.1.2

Head Lice

Adult head lice lay eggs (nits), which firmly attach to the hair shaft. They are most easily found above the ears and in the occiput. The nits, oval and grayish dots on the hair shaft, are laid very close to the scalp and hatch in about 7–9 days before the hair has grown more than 1/4 inch. The adult female louse has a lifespan of about 25 days and lays about 10 eggs a day. Away from a host, lice die in about 10 days. Most affected individuals have scalp pruritis and eczematous inflammation. Cervical or occipital adenopathy may be present and secondary impetigo is common. Recently, head lice have appeared to become more resistant to standard over-thecounter (OTC) treatment and initial treatment failures are exceedingly common. The first line of treatment remains OTC 1% permethrin cream rinse (NIX) or A-200 pyrinate liquid (RID). They should be applied to wet towel-dried hair and left on at least 10 minutes. After treatment, hair should be combed meticulously with a special fine-toothed nit removing comb to remove any viable nonhatched nits. All personal headgear, scarves, coats, and bed linen should be disinfected by machine washing in hot water and drying on the hot cycle of a dryer for at least 20 minutes. Combs and brushes should be soaked in hot water (above 130⬚F) for 5 to 10 minutes. Thorough vacuuming of rooms is also recommended. Many schools have a ‘‘no nit’’ policy, which requires there be no visible nits before returning to school. Reapplication of medication is only necessary if nits are seen at the hair-scalp junction. Nits seen >1/2 inch from the scalp represent empty eggshells. Treatment alternatives for NIX- or RID-resistant lice may include the following: Ovide (5% malathione lotion): apply to dry hair; do not cover. Wash out in 8–12 hours. Caution: it is flammable. Elimite (5% permethrin cream): apply to wet hair at bedtime, wrap in towel, and wash out the next morning. Lindane: apply to wet hair at bedtime, wrap in towel, and wash out in the morning. Trimethoprim-sulfamethoxazole (Bactrim DS): take once orally every day for 3 days; repeat in 10 days.

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Petrolatum or mayonnaise: thickly applied, it should be covered with a shower cap overnight. Shampoo out with Dawn dish detergent. Shave hair. 2.1.3

Pubic Lice

The chance of acquiring Phthirius pubis from a single sexual contact is about 95%. Pubic, thigh, and eyelash hair may be infected. The lice attach tightly to the bases of hair and clinically resemble multiple small freckles. Patients complain of pruritis in affected areas. Erythematous macules and papules may be present along with excoriations. Occasionally, feeding sites develop peculiar slate blue colored macules that may persist for many months. Partners should be treated and the possibility of other sexually transmitted diseases investigated. Clothing and bedding should be washed as described for head lice. Treatment for pubic lice may include the following: Lindane lotion applied to affected areas overnight NIX applied to affected areas as for head lice and repeated in 10 days Elimite cream applied to affected areas overnight Shaving of hair The preceding treatments should not be applied to the eyelids or lashes. Treatment for eyelashes may include thick application of petrolatum twice a day for 10 days and mechanical removal of nits. Symptomatic pruritis can be treated with antihistamines or topical corticosteroids. 2.2

Scabies

Scabies is caused by infestation with the mite Sarcoptes scabiei var. hominis. These arthropods belong to the class Arachnida. The adults are 1/3 mm long, are rounded, and have four pairs of legs. Scabies is generally transmitted through close personal contact with an infected individual, although rarely transmission via clothing or linens may occur. The incubation period is about 1 month. The female mites burrow superficially into the stratum corneum and lay eggs daily for several weeks before dying. Larvae hatch in a few days and then molt to adults, which then deposit more eggs. Infections therefore may persist for long periods if untreated. The itch of scabies is severe and generally worst at nighttime. Affected individuals have many small red papules, excoriations, and dermatitis prominent on the hands, axilla, breasts, abdomen, and genitalia. Pruritic red papules on the penis should be considered scabies until proved otherwise. Very close inspection is needed to see the characteristic small burrows best noted between the fingers and on the wrists. Only about 10 mites are present on the average host and are best found in these burrows. Definitive diagnosis requires demonstrating the characteristic mite and/or eggs or feces in a skin scraping. 2.2.1

Scabies Preparation Technique

A number 15 scalpel blade should be used to shave the superficial epidermis firmly over burrows and papules between the fingers and on the wrists. Proper sampling often causes a small amount of bleeding. Multiple sites should be scraped and the material put together on one slide. Add one drop of mineral oil or KOH and cover with a coverslip. Mites, eggs, and feces are easily visible at 10⫻ magnification. Because many forms of dermatitis mimic scabies clinically, a scraping should always be performed. If a skin scraping finding is negative and clinical suspicion of scabies is

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high, empirical treatment may be undertaken. However, if empirical treatment fails, an alternative diagnosis should be considered. After successful eradication of the mites, pruritis and rash may continue for up to 4 weeks as part of the so-called postscabetic syndrome. Symptoms after this time should prompt reinvestigation for continued infestation. Crusted or Norwegian scabies may be seen in immunocompromised or immobile patients; it is characterized by thick, crusted plaques that may resemble psoriasis. These individuals are extremely infectious as the lesions are teeming with mites. Treatment is more difficult and usually must be repeated numerous times until clearing. The treatment of choice for scabies is permethrin 5% cream (Elimite) applied before bedtime to the entire cutaneous surface except the face and scalp with meticulous attention to the hands, including under the nails. It is essential that the instructions for application are understood and that medication is applied to all skin and not just symptomatic areas. In the morning, the bed linens should be removed and washed. Mites generally die within 48 hours off a human host so avoidance of usual clothing or furniture for 1–2 days after treatment may decrease the potential for reinfection. Disinfection of furniture or other clothing is generally not necessary. It is important that all close contacts be treated, preferably at the same time, even if they are asymptomatic. Lindane is now used less frequently, partly because of concerns about potential neurotoxic side effects. Toxicity, however, only results from excessive and inappropriate usage and does not occur if the medication is used as directed. Symptomatic treatment with antihistamines and topical anti-itch preparations including topical steroids should also be given as needed. For individuals with resistant disease and particularly those with crusted scabies, oral ivermectin (Stromectol) can be used. It is now available in the United States and is indicated for the treatment of onchocerciasis and Strongyloides sp. infections. Studies in humans show that two doses 1 week apart are effective for uncomplicated infestation and are equal in efficacy to a single application of permethrin cream (see Table 1). 2.3

Other Mites

A variety of mites may be found on most animals and plants, where they generally complete their life cycle. On occasion, these mites may temporarily try to burrow or bite into

Table 1 Treatment of Scabies FDA indication

Pregnancy category

Permethrin 5% cream (Elimite)

Yes >6 months of age

B

Lindane 1%

Yes

B

Ivermectin

No

C

Medication

a

Directions Apply at night to all skin; repeat in 1 week Apply at night to all skin; repeat in 1 week 200 ␮g/kg as a single dose, repeat in one week

Costa $24.00 (60 g)

$15.00 (60 ml)

$10.00 (6-mg tab) $5.00 (3-mg tab)

Average wholesale price, 2000 Drug Topics Red Book. FDA, U.S. Food and Drug Administration.

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a human, often causing an immune reaction in the process. The most common of these are fleas and chiggers. 2.3.1

Fleas

Fleas exist universally among animals and humans and may be vectors of serious disease, particularly the rat flea, which serves as the vector of plague and endemic typhus. Currently in the United States, however, the most common problem associated with fleas is the cutaneous irritation caused by bites from Pulex irritans, the human flea; Ctenocephalides felis, the cat flea; and Ctenocephalides canis, the dog flea. Fleas are small brown wingless insects about 1 mm long and are extraordinary jumpers. Bites are most common around the legs and waist and are often in clusters. Not everyone reacts to flea bites, and in some households, only one individual may be affected. In some sensitized individuals, a generalized pruritic eruption of red papules, sometimes called papular urticaria, may occur. In addition to treatment of affected pets, all infested areas such as pet bedding, carpets, and furniture need to be treated. Successful eradication often requires multiple treatments. 2.3.2

Chiggers

The trombiculid mites known as chiggers, harvest mites, or red bugs are common in the southern United States. Mites are about 0.5 mm long and live in hay, grass, and bushes. They are the potential vectors of scrub typhus. Shortly after contact, they cause hemorrhagic punctae surrounded by erythema and sometimes urticaria. The mite usually then drops off and is not seen. Bites are most frequent under constrictive clothing such as at the beltline or around the ankles. Treatment is symptomatic with oral antihistamines or topical corticosteroids. 2.3.3 Cheyletiella Species Also called ‘‘walking dandruff,’’ Cheyletiella spp. are parasites on dogs, cats, and rabbits. They cause small itchy red bumps, generally on the arms of humans who handle animals. The pet should be examined and treated by a veterinarian.

FUNGAL INFECTIONS Dermatophytes (tinea) Circular scaly plaques, dandruff on scalp, thickened discolored nails Therapy Cutaneous: treat topically (Table 3) Hair: treat orally (Table 5) Nails: treat orally (Table 6) Candidal infections Bright red, oozing, painful rash in intertriginous areas Therapy Topical (Table 3) If severe, orally (Table 6) Pityriasis Large coalescing white, red, or brown painless macules Therapy: Table 7

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FUNGAL INFECTIONS

Superficial fungal infections of the skin can be caused by either dermatophytes or yeast. Infection with the dermatophyte or ringworm fungi cause the ‘‘tinea’’ infections. The most common yeast infections are caused by Candida sp. and by Pityrosporum ovale, the causative agent of pityriasis versicolor. 3.1

Dermatophyte Infections (Ringworm or Tinea)

The dermatophytes are molds that include three genera (Trichophyton, Microsporum, and Epidermophyton) and 39 species that may be acquired from other humans, animals, or soil. They invade the stratum corneum of the skin, most commonly in the groin and on the feet, but may also invade hair and nails. Humans become infected after contact with the fungal arthrospore, which then invades the skin. These vegetative spores can live outside the host for 15 months. Therefore, host-to-host contact is not necessary. Classically, the tinea infections are circular lesions with raised scaling edges that may be inflamed. Infections may be asymptomatic, but generally pruritis is prominent. The name of the infection is completed by the location of the fungus on the body: scalp (tinea capitis), face (tinea facei), body (tinea corporis), groin (tinea cruris), hands (tinea manuum), feet (tinea pedis), and nails (onychomycosis). A secondary rash (id reaction) may develop as an immunological reaction to the dermatophyte infection. These id reactions may occur during therapy. Rarely, dermatophyte infections invade deeper tissues in immune compromised hosts, leading to edema and subcutaneous nodules. See Table 2 for a clinical description and diagnostic approach. The diagnosis is made by the characteristic lesions and by skin scraping that demonstrates the organisms on KOH preparation or by culture. Some species of dermatophyte, particularly those acquired from animals, may show green fluorescence on Wood’s light examination. However, very few dermatophyte infections can be diagnosed with this method. 3.1.1

Potassium Hydroxide Preparation Technique

Scrape the skin tangentially with a number 15 scalpel blade and collect a good amount of white scales on a microscope slide. Add 1 to 2 drops of 10% KOH and cover with a coverslip. Heat for 5 seconds (a flame under the slide is sufficient) and view. Hyphae are long, slender, frequently branching filaments that cross several keratinocytes. They are much smaller than keratinocytes and are only faintly seen at 10⫻. Easily identifiable ‘‘filaments’’ at 10⫻ are clothing fibers. As an alternative, chlorazole black is a fungusspecific stain that does not need to be heated and stains fungi a light green color. Apply 1 drop of this, cover with a coverslip, and wait 5 minutes before viewing. Dermatophyte infections of the skin often respond to topical therapy. See Table 3 for a listing of topical antifungal preparations. Clotrimazole (Lotrimin) and terbenafine (Lamisil) cream are the most effective OTC products available. Treatment may take up to 4–6 weeks (longer than suggested on the product label). Occasionally widespread or resistant cases may need oral therapy (see Table 4). Tinea capitis (Table 5) and onychomycosis (Table 6) require systemic therapy. Almost 100% of fingernails and a majority of toenails show improvement with oral therapy. Toenail infections require 12 weeks of daily therapy, whereas fingernail infections may respond in 6 weeks. Ten completely normal toenails, however, can only be achieved about 30% to 50% of the time. Recurrences are common and may approach 50% by 3 years. Almost all individuals with onychomycosis have chronic tinea pedis as well; al-

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Table 2 Dermatophyte (Tinea) Infections Location (name) Scalp (tinea capitis)

Clinical

Red boggy plaque(s), often initially misdiagnosed as impetigo, folliculitis, or contact dermatitis Body (tinea corporis; Annular plaques with ringworm) central clearing and peripheral scale

Hand (tinea manuum)

Feet (tinea pedis)

Nail (onychomycosis)

Comments

1. 2.5% Selenium sulfide shampoo for patient and contacts to decrease infectivity 2. Reinfection common; may need to treat contacts Almost always from an Pluck hairs and send animal; look for liveswab from vigorous stock or pets with scraping of pustules for mange fungal smear and culture 1. Obtain KOH from pe- DDX: Nummular dermatitis—especially if riphery of lesion more than a few le2. Send skin scrapings to sions present or nonlab for fungal smear response to therapy and culture 1. Obtain KOH from pe- Examine feet; treating riphery of lesion chronic tinea pedis decreases recurrences 2. Send skin scrapings to lab for fungal smear and culture

Usually resembles diffuse Fungus lives inside hair; pluck several hairs to dandruff; may have send to lab from the scaling, inflammation, edge of a bald spot or and alopecia; more diffusely scaling area common in children of scalp

Face (tinea facei)

Groin (tinea cruris)

Diagnosis

Pink patch with peripheral scale in inguinal area; does not involve scrotum; if scrotum involved, potentially candidal Fine white scaling of palms prominent in skin creases; often unilateral; fingernails often involved Type 1 ‘‘chronic’’: often asymptomatic; fine dry scaling of soles of feet (‘‘athlete’s foot’’) Type 2 ‘‘acute’’: red itchy patches with peripheral scaling, sometimes blisters Type 3 ‘‘interdigitale’’: redness, fissures, and pain between toes Raised nails with subungual debris

Also known as ‘‘two feet, 1. Obtain KOH one hand disease’’; 2. Send skin scrapings to both feet generally lab for fungal smear show chronic white and culture scaling as well 1. Obtain KOH from pe- Type 3 usually has superinfection with yeast riphery and bacteria; to clear 2. Send skin scrapings to infection, important to lab for fungal smear aerate and separate toes and culture with cotton

Send nail clippings and subungual debris (remove with curette) for fungal smear and culture

High rate of false-negative culture results; if positive test result desired, may need to be repeated

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Table 3 Activity of Topical Antifungal Preparations

Clotrimazole (Lotrimin) Econazole (Spectazole) Naftifine (Naftin) Nystatin Terbinafine (Lamisil) Tolnaftate 2.5% Selenium (Selsun Rx)

Tinea/ dermatophyte

Pityriasis versicolor

Candidal

⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺

⫹ ⫹ ⫺ ⫺ ? ⫺ ⫹

⫹ ⫹ ⫺ ⫹ ? ⫺ ⫺

though it is not proved, many believe that recurrences may be decreased by regular prophylactic application of topical antifungals to the feet. 3.2

Yeast Infections

There are two major yeastlike fungi that cause skin disease: candidal and pityrosporum. 3.2.1

Candidal Infections

Candida albicans is a normal commensal organism of the skin, mucous membranes, and gastrointestinal tract that may become pathogenic under certain conditions. These conditions include increased moisture, maceration and occlusion, and host factors such as diabetes mellitus, pregnancy, immunosuppression, or antibiotic use. Common sites of infection include the intertriginous areas, axillae, and areas beneath the breasts and in the groin and genitals. Although both candida and dermatophytes can infect the inguinal creases, only candida involves the scrotum and penis—a clinical finding that can help differentiate the two. Classic candidal infections are bright red, glistening, or oozing and have characteristic red papules and pustules at the periphery of the plaques (‘‘satellite lesions’’). The diagnosis can be made by a KOH preparation showing budding spores and/or by culture. Candida sp. grows quickly and culture results are often available in about 48 hours. For most labs, a bacterial culturette swab with ‘‘Fungus culture, suspect yeast’’ written on the requisition slip is recommended. If both bacteria and yeast are in the differential, a bacterial culture should be requested and two swabs sent with a note on the slip that yeast is also suspected. Most available topical antifungal preparations treat both yeast and dermatophyte infections; however, some agents have primarily antidermatophyte activity and these

Table 4 Oral Treatment for Dermatophyte Skin Infections Agent Fluconazole (Diflucan) Griseofulvin Itraconazole (Sporanox) Terbinafine (Lamisil) a

Dose

Duration

Costa

150–300 mg one dose/wk 500 mg qd 200–400 mg qd 250 mg qd

4–6 Weeks 4–8 Weeks 7 Days 10 Days

$72–$144 $37–$75 $99–$198 $76

Average wholesale price, 2000 Drug Topics Red Book.

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Table 5 Treatment of Tinea Capitis Cost (for 20-kg child)a

Drug

Daily dose

Duration

Griseofulvin Itraconazole (Sporanox)

20–25 mg/kg 5 mg/kg

Fluconazole (Diflucan)

6 mg/kg 5 mg/kg 10–20 kg–62.5 mg 20–40 kg–125 mg >40 kg–250 mg

6–8 Weeks 4–6 Weeks 1 week/month pulse for 3 months 20 Days 4–6 Weeks 2–4 Weeks

Terbinafine (Lamisil)

$200 $140

$170 $60

a

Average wholesale price, 2000 Drug Topics Red Book.

should not be prescribed when a yeast is suspected (see Table 3). For severe or widespread infections or for severely eroded skin, oral therapy with fluconazole or ketoconazole 100– 200 mg/day for 1–5 days or itraconazole 200 mg/day for 5 days may be used. For candidal infections, care should be given to addressing the underlying physical causes (occlusion, maceration, etc.) to minimize recurrences. 3.2.2

Pityriasis Versicolor

In some individuals, under stimulation from heat and sweat, the normal and ubiquitous follicular commensal yeast Pityrosporum ovale changes from its usual spore form to a mycelial form and becomes the agent of pityriasis versicolor (PV). PV is sometimes also

Table 6 Treatment of Onychomycosis Drug

Dose

Duration

Penlac (topical) Terbinafine

Daily 250 mg/day 250 mg bid ‘‘Pulse’’

Fluconazole

150–400 mg; one dose/wk 200 mg/day 200 mg bid ‘‘Pulse’’

Until clear 12 Weeks For 7 days, then off 21 days; repeat for a total of four ‘‘pulses’’ for toenails and three pulses for fingernails 3–12 months (continue until clear) 90 Days For 7 days, then off 21 days; repeat for a total of three ‘‘pulses’’ for toenails and two pulses for fingernails

Itraconazole

a

Average wholesale price, 2000 Drug Topics Red Book.

Improvement rate, %

Costa

20 70–80

$90 $644 $350

50–80

$143–$1269

60–85

$1287 $600

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called tinea versicolor, which is an unfortunate misnomer since Pityrosporum ovale (previously called Malassezia furfur) is not a tinea (dermatophyte) but a yeastlike organism. PV is more common in the summer and in tropical climates. PV is characterized by white, pink, or brown macules, which may or may not have obvious scale. The spots coalesce into larger patches and are classically located in the sebaceous areas of the torso, particularly on the upper back, anterior chest, and upper abdomen. The fungus secretes a chemical that prevents pigmentation of the underlying skin. For this reason, white spots remain after treatment, particularly in tanned individuals. They can be reassured that their skin color will normalize with the fading of the tan. Diagnosis can easily be made by a KOH preparation that shows abundant small fat hyphae and spores (‘‘spaghetti and meatballs’’). The organism does not grow in routine culture media. The fungus is fairly easy to eradicate; however, recurrences are guaranteed. Treatment options are summarized in Table 7. PV generally responds to topical azole creams. A single 400-mg dose of ketoconazole may suffice, though 5–10 days of 200 mg/day is sometimes needed.

4

VIRAL INFECTIONS

Viral infections localized to the skin include molluscum contagiosum and herpes family viruses including Herpes simplex and varicella zoster. 4.1

Warts

Warts are epidermal neoplasms caused by human papillomavirus (HPV). Characteristically, warts are raised exophytic nodules that are generally asymptomatic but may be painful or bleed. HPV is only found on humans; although it is contagious, transmission is rather difficult. There are at least 89 serotypes of HPV, most of which have a predilection for specific anatomical areas. For example, types 1 and 2 cause plantar warts; types 3 and 10 cause flat warts. Although HPV-induced warts are generally considered benign, infection has been implicated in the development of some squamous cell carcinomas (SCCs), particularly cervical carcinoma (see Chapter 16 concerning genital HPV), anal carcinoma in patients with human immunodeficiency virus (HIV) and SCC in patients who have had organ transplantation. Since death from SCC is a major concern for patients on long-term immunosuppression, it is reasonable to make an attempt to eradicate warts prior to transplantation. However, it must be noted that studies have not been done to prove this therapy effective and that warts can be notoriously difficult to eradicate.

Table 7 Treatment of Pityriasis Versicolor Agent Ketoconazole Clotrimazole cream 2.5% Selenium sulfide lotion a

Dose 400 mg ⫻ 1 dose; repeat if necessary bid ⫻ 1 Month Daily for 10 minutes, shower off; ⫻ 7 days

Average wholesale price, 2000 Drug Topics Red Book.

Pregnancy category

Costa

C

$6

B C

$8 (16-g Tube) $13 (120 ml)

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VIRAL INFECTIONS Warts Nodules may be verrucous or flat, generally painless, caused by HPV Treatment: may resolve spontaneously Over-the-counter (OTC) salicylic acid topically Destruction by liquid nitrogen, laser, cautery Molluscum contagiosum Small flesh-colored or red papules with umbilication Contagious Treatment: may resolve spontaneously Topical treatment with imiquimod Mechanical removal Herpes simplex Usually recurrent vesicles or ulcerations on lips, face, genitals, or buttocks Treatment: Table 8 Varicella zoster Chickenpox possibly followed by shingles in later age or in immune compromised host Treatment: Table 9

Individuals without clinical evidence of warts show an active immune reaction and cytotoxic response against HPV that prevent its expression. Although individuals with clinical warts initially do not show much response to HPV-infected cells, almost all children and a majority of adults with warts eventually mount a successful immune reaction if followed over several years. Clinically, this is represented by a spontaneous and fairly rapid disappearance of lesions. 4.1.1

Common Wart (Verruca Vulgaris)

One or multiple warty papules may be present anywhere but are most frequent on the hands, around the fingers, and on the extensor extremities. Some lesions may have multiple black-tipped finger-like projections. 4.1.2

Flat Warts

Flat warts are characterized by small, red-brown, 1- to 3-mm nonscaling papules that are usually found in clusters. They are common on the face, especially in the beard area; on the backs of the hands; and on the legs. Shaving with a metal razor causes spreading and should be avoided. Acceptable alternatives to a razor blade include an electric razor (which does not shave as closely) and chemical depilatories. The warts can be treated with a light application of liquid nitrogen; however, possible permanent hyper- or hypopigmentation may occur. Approved for use in genital warts, topical imiquimod (Aldara) can be useful for widespread infections; however, the cost may be prohibitive. 4.1.3

Plantar Warts

Often it is difficult to determine whether a keratotic lesion on the sole of the foot is a wart or a corn or callus. This is usually best resolved by paring the top of the lesion. A wart has small black dots representing virally altered blood vessels, whereas a corn has

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a single glassy kernel-like center. It is important to make this distinction because a corn cannot be removed by destructive methods. Plantar warts are often painful as a result of the thick overlying callus. Paring or sanding away this material may be sufficient to provide relief and the patient can be instructed to repeat this as needed for comfort. Treatment is not always necessary, particularly if the lesions are asymptomatic. Reassurance alone is often appropriate, particularly in children. Multiple treatments, all of which have significant limitations, are available (discussed later). OTC salicylic acid should be tried as a first-line agent. Destruction by nitrogen, cautery, or laser is painful, creates open wounds, and may leave permanent pigmentation changes or scars. 4.1.4

Therapy of Warts

Liquid Nitrogen. Apply with a cotton applicator or spray gun until the entire lesion turns white and remains white for 20 to 60 seconds, allow to thaw, and then repeat. Multiple freeze/thaw cycles are superior to one. Blistering is to be expected. Risks include permanent pigmentation changes as well as scarring. Treatments should be repeated every 2 to 4 weeks as necessary. The 3-month cure rate is 40%–80%. Salicylic Acid. Salicylic acid is available OTC as a paint-on liquid or as patches in strengths from 17% to 40%. The stronger concentrations should be used with occlusion for plantar warts. The cure rate is 30%–70%. Cautery. After achieving local anesthesia, the wart can be removed with a curette and the base cauterized. This has a cure rate of about 70% for a single treatment and leaves a permanent scar. Laser. The carbon dioxide laser is often used as a treatment of last resort. This causes a significant thermal injury and wounds are quite slow in healing. Risks include significant pain during recovery and a permanent scar. The cure rate is about 80%. The pulse dye or vascular laser may also be used. It is fairly painful and usually causes blistering but rarely causes scarring or pigment changes. It is most practical for treating multiple lesions on the hands. Cimetidine. There are several anecdotal reports of oral cimetidine at doses of 20– 40 mg/kg for 3 to 4 months. It is theorized that this medication works by stimulating host immune responses. Placebo-controlled studies, however, have shown no statistically significant benefit. Imiquimod (Aldara). Imiquimod topical cream is approved for the treatment of genital warts with a cure rate of about 65% at 4 months. It is an immune-response modifier, which up-regulates host recognition and destruction of HPV infected cells. There are anecdotal reports of benefit in flat warts and some common warts. It is applied three times a week for 3 to 4 months. It does not penetrate keratin, so thick warts need to be pared or pretreated with salicylic acid and the medication applied under occlusion. The cost is about $100/month. 4.2

Molluscum Contagiosum

Molluscum contagiosum is a flesh- to red-colored papule with a characteristic central depression or ‘‘dell’’ in some but not all papules. It is caused by the molluscum contagiosum virus, a deoxyribonucleic acid (DNA) virus of the Poxviridae family. Young children are most frequently affected; although lesions may occur anywhere on the body, they are most common on the head and face. Children with atopic dermatitis appear to be particularly prone, often with more widespread and longer-lasting lesions. As

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the name suggests, they are contagious and are readily spread to siblings and other children. Occasionally a lesion becomes severely inflamed, presenting as a red, painful, large (up to 1 cm) and sometimes purulent nodule. Genital and perianal lesions may be present in children and frequently represent autoinoculation; however, sexual abuse should be considered. In children, routine treatment is generally discouraged since the natural history is that most infections spontaneously clear in 6 to 9 months. Indications for treatment are pain, inflammation, rapid spreading of lesions, or secondary infection. Studies suggest that topical Aldara applied three times a week may clear 80% of infections in 2–3 months. Lesions can also be treated by curettage, light electrocautery, or liquid nitrogen; however, these therapies carry a small risk of permanent pigmentation changes or scarring. Also, destructive procedures may be traumatic for small children as they often require the use of physical restraint. Molluscum contagiosum in adults is almost always sexually transmitted with lesions primarily seen on the genitalia, pubis, abdomen, and thighs. The latent period from acquisition of the virus to the appearance of clinical lesions is around 30 days. In adults, treatment is recommended, and often several office visits are necessary to eradicate all lesions. Liquid nitrogen is generally the treatment of choice. Partners need to be treated to prevent reinfection. Evaluation for other sexually transmitted diseases should be considered. In contrast to that in children, molluscum on the face of an adult is highly unusual and HIV infection should be strongly suspected. Effective antiretroviral therapy is the only successful treatment for HIV-related molluscum. 4.3

Herpes Family Infections

The Herpesviridae is a family of large DNA viruses that include Herpes simplex virus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus, Epstein-Barr virus, human herpes 6, 7, and 8 viruses, and simian B virus. The major causes of cutaneous infections in adults are HSV and VZV. These latter infections are characterized by a severe primary infection (primary mucocutaneous lesions or chickenpox, respectively), followed by a clinically silent latency and then episodic recurrence in the form of less severe infections (orolabial or genital ulceration or zoster, respectively). Humans are the only reservoir for HSV and VZV. 4.3.1

Herpes Simplex Virus

There are two types of herpes simplex viruses. HSV-1 predominately affects the oral cavity; HSV-2 affects the genitals. There is wide overlap of anatomical location, and patients may have HSV-1 genital ulcerations and/or HSV-2 oral lesions. Ninety percent of adults are infected with HSV-1 by the age of 50 years. Recurrent herpes infection affects up to 40% of the U.S. population. HSV is spread by direct contact from individual to individual. See also Chapters 11, 16, and 17. Primary or first-episode herpetic gingivostomatitis is a severe orofacial infection characterized by erosions and crusting of the lips, tongue, buccal mucosa, nasal mucosa, hard and soft palate, and/or pharynx. Fever, pain, and cervical lymphadenopathy are common. Resolution generally occurs within 7–14 days. Recurrent oral lesions are characterized by grouped painful vesicles that readily rupture, leaving small ulcerations. These generally occur on the vermilion border of the lips. The recurrence is never as severe as the primary infection and, unless the patient is immunosuppressed, does not involve the tongue, buccal mucosa, or pharynx. Recurrent ulcers in these locations are most likely aphthous ulcers and should not be treated with antiviral

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therapy. The number of recurrences ranges widely but generally decreases in frequency over time. Recurrent cutaneous infections may occur at any site and are most common on the cheeks, neck, buttocks, and thighs. Most cases of presumed recurrent herpes zoster are actually recurrent cutaneous HSV infections. Excessive sun exposure, illness, immunosuppression, and stress are often associated with occurrences. Clinically, one commonly sees a thick serum crust, resembling impetigo. Under the crust are multiple coalescent 1to 2-mm punched-out ulcerations. Only rarely are the initial small tense vesicles seen. An underlying herpes infection should always be considered in all cases of ‘‘impetigo.’’ It is important to recognize that patients may shed HSV during an asymptomatic recurrence. In these occurrences, ulcers or vesicles are not present but the patient is still potentially contagious. Recurrences in immune compromised hosts, such as people with HIV or recipients of organ transplantation, may be more frequent and severe. Transmission to any mucosal surface or abraded cutaneous surface can occur either between people or as autoinoculation. An example of this is herpetic whitlow, an HSV-1 or -2 infection of the finger due to direct contact of the patient with active HSV lesions or secretions in the case of health care workers. Whitlow is manifested as pain and swelling associated with a purulent or vesicular lesion generally of the finger tip. Fever and regional lymphadenopathy may be present. It may be difficult to differentiate from a bacterial infection such as a paronychia, cellulitis, or abscess. Eczema herpeticum is a form of widespread cutaneous HSV infection that occurs in individuals with atopic dermatitis and clinically somewhat resembles chickenpox. Hundreds of crusted papules and erosions may be seen on the face, torso, and extremities, sometimes coalescing into large plaques. It is usually painful (in contrast to the usual itch of atopic dermatitis) and individuals may be febrile. The diagnosis of HSV infection is generally based on the clinical appearance of the eruption. Antibody detection is not helpful because of the common occurrence of positive serological results. Confirmation of a herpes infection and typing (HSV-1 vs. HSV-2) can be accomplished as outlined later. Detection of HSV and VZV requires the collection of cells from the base of lesions. Several skin lesions should be scraped with a number 15 scalpel blade or a Papanicolaou smear spatula. This scraping should be fairly firm; collecting blister fluid or wiping a culturette swab over skin lesions is insufficient. Cells can be sent for cytological examination (Tzanck test smear). HSV- or VZVinfected cells appear as distinctive multinucleated giant cells, and this finding is reported as a positive viral change. A Tzanck test preparation can be obtained rapidly and has a sensitivity of about 70%. Viral culture is needed to distinguish the type of infection (VZV, HSV-1, or HSV2). For culture, cells must to be sent in viral transport media (obtain from your local lab and keep refrigerated). HSV grows in 2–7 days, whereas VZV often takes 7–14 days. With optimal collection and handling, the sensitivity is about 90%. In some areas (check with your local lab), detection by direct fluorescent antibody test (DFA) can be performed with rapid results. Treatment of both primary and recurrent infections is usually accomplished orally (see Table 8). Occasionally, intravenous therapy may be required for a severe primary infection that is not responding to oral treatment. Topical medications, though less effective than oral agents, can reduce the duration of symptomatic outbreaks. Systemic therapy with intravenous acycolvir (5 mg/kg q8h) is indicated for eczema herpeticum and in severe outbreaks in the immune compromised host.

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Table 8 Treatment of Cutaneous Herpes Simplex Virus Infections Agent

Dose

Penciclovir ointment (Denavir) Acyclovir

Apply q2h while awake 200 mg 5/d ⫻ 5 days

Pregnancy category

Costa

B B

$23 (1.5-g Tube) $25

or 400 mg tid ⫻ 5 days

$30

or Valacyclovir (Valtrex) Famciclovir (Famvir)

800 mg bid ⫻ 5 days 500–1000 mg bid ⫻ 3 days 250–500 mg bid ⫻ 5 days

B B

$38 $33–$44 $35–$70

a

Average wholesale price, 2000 Drug Topics Red Book.

Frequent relapses can be suppressed by chronic use of acyclovir (400 mg bid), valacyclovir (500 mg/day), or famciclovir (250 mg/day). Occasionally higher doses are necessary. 4.4 4.4.1

Varicella Zoster Virus Infections Chickenpox

Chickenpox or primary varicella infection is acquired through respiratory particles primarily in the winter and spring. The incubation period is 10–23 days. A person is infectious from 1 day before the rash appears until all lesions have crusted (approximately 7– 10 days). A child may not attend school or day care until all lesions have crusted. A prodrome of fever and sore throat may precede the appearance of pink macules, which tend to be more dense on the torso and scalp than on the face and extremities. Within 24 hours, small tense clear vesicles appear and resemble ‘‘dew drops on rose petals.’’ The vesicles quickly become cloudy and then crust. New crops of lesions appear for several days so that the three variations of lesions (vesicles, pustules, and crusting) are seen simultaneously. Prior to the release of the OKA varicella vaccine, 90% of cases were seen in children less than 10 years old. The vaccine is recommended by the American Academy of Pediatrics for all children and can be given at 1 year of age. Antiviral therapy (discussed later) of mild, uncomplicated infections is not indicated; however, therapy should be used for severe cases and for immunocompromised patients. Attention should be given to frequent skin cleansing to prevent secondary staphylococcal infection. If a bacterial infection is suspected, oral antibiotics should be promptly initiated. 4.4.2

Zoster (Shingles)

VZV is neurotropic. In most individuals, after a primary infection, the virus enters a dormant state in the dorsal root ganglia of the cranial, cervical, thoracic, or lumbrosacral spinal nerves. Zoster or shingles is the reemergence of active virus from these sites, causing pain along the sensory nerve and cutaneous lesions in the nerve’s dermatome. The lesions are chickenpox-like vesicles and pustules that then crust over. Complications of facial infection include deafness, tinnitus, vertigo, or facial palsy (Ramsey Hunt syndrome), pharyngeal and/or laryngeal lesions. Ophthalmic zoster is a medical emergency because of VZV involvement of the first branch of the fifth cranial nerve characterized by keratitis, conjunctival lesions, or uveitis (characteristic large dendritic cells seen on slit lamp examination). A clue to the presence of keratitis is the presence

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Table 9 Treatment for Varicella Infections Agent Acyclovir Valacyclovir (Valtrex) Famciclovir (Famvir)

Dose 800 mg PO 5 times/day ⫻ 7 days 10 mg/kg IV q8h 1 g tid ⫻ 7 days 500 mg tid ⫻ 7 days

Pregnancy category

Costa

B

$45

B B

$92 $164

a

Average wholesale price, 2000 Drug Topics Red Book.

of lesions on the tip of the nose, indicating involvement of the first branch of the fifth nerve. Immediate ophthalmological evaluation is indicated when there is any suspicion of ophthalmic involvement. Treatment (see Table 9) initiated within 72 hours of the start of the cutaneous lesions decreases pain, the number of lesions, and time to healing. However, other than analgesics and good local care, an uncomplicated infection in an individual below age 50 does not necessarily require treatment. In contrast, after the age of 50, there is evidence that treatment may decrease the risk of postherpetic neuralgia. In the very old or immunocompromised patient, early systemic therapy is indicated to reduce the risk of disseminated infection. For pain during acute zoster, oral analgesics can be used. Topical lidocaine gel may also be effective. Topical capsacin (Zostrix) should be avoided if the skin is not intact. Pain after zoster is common and the risk increases with age. For most individuals below age 60, pain has resolved by 6 months. However, of those older than age 60, a significant number experience pain lasting over 1 year. There is evidence that, in addition to antiviral therapy, prophylactic treatment of high-risk patients (elderly, severe infections) with a lowdose tricyclic antidepressant may be effective in decreasing the incidence of postherpetic neuralgia. Amitriptyline or desipramine 10–25 mg at bedtime for 1–3 months is recommended. Several studies have investigated whether a short course of oral steroids during acute zoster is helpful in decreasing subsequent pain, unfortunately with contradictory results. For pain remaining when the skin lesions have cleared, topical lidocaine or capsacin (Zostrix) may be tried. First-line treatment for established postherpetic neuralgia is usually tricyclic antidepressants (increase dose every 5–7 days till effective or maximal dose is obtained) or neurontin (300–3600 mg/day). Other possibilities include anticonvulsants and referral for neural blockade. BIBLIOGRAPHY Allen AL, Siegfried EC. What’s new in human papillomavirus infection. Curr Opin Pediatr 2000 Aug; 12(4):365–369. Benton EC. Therapy of cutaneous warts. Clin Dermatol 15:449–455, 1997. Chosidow O. Scabies and pediculosis. Lancet 355:819–826, 2000. Goldstein AO, Smith KM, Ives TJ, Goldstein B. Mycotic infections. Geriatrics 55:40–52, 2000. Hengge UR, Esser S, Schultewolter T, Behrendt C, Meyer T, Stockfleth E, Goos M. Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum. Br J Dermatol 2000 Nov; 143(5):1026–1031. Johnson R. Herpes zoster—predicting and minimizing the impact of post-herpetic neuralgia. J Antimicrob Chemother 2001 Feb; 47 Suppl T1:1–8. Wood AJJ. Post-herpetic neuralgia. N Engl J Med 335:32–42, 1996. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

21 Ocular Infections Martin Mayers Bronx Lebanon Hospital Center and Albert Einstein College of Medicine, Bronx, New York, U.S.A.

Essene Bell Bronx Lebanon Hospital Center, Bronx, New York, U.S.A.

Michael H. Miller Albany Medical College, Albany, New York, U.S.A.

1

INTRODUCTION

Differentiating infectious from noninfectious causes of eye disease is a challenging yet crucial task for primary care providers. Regardless of whether the cause of the ocular disease is infectious or noninfectious, patients with diseases of the anterior segment of the eye and adnexae often experience a ‘‘red eye’’ and varying degrees and qualities of ocular discomfort. Diseases limited to the posterior segment of the eye (e.g., vitreous, retina, and choroid) generally do not cause redness or discomfort but do cause visual disturbances and rarely pain. The goal of this chapter is to help the primary care provider identify those situations that can be appropriately treated without referral and those requiring prompt care by an ophthalmologist (see Table 1). A diagram of the eye is provided to assist the primary care provider with the language of ophthalmological infections (see Figure 1).

2

APPROACH TO THE PATIENT WITH ‘‘RED EYE’’

Although most patients with a ‘‘red eye’’ do not have a vision-threatening problem, a red eye may be a warning sign of potential visual loss secondary to acute glaucoma, uveitis, scleritis, or keratitis. All patients with ocular complaints should have their visual acuity measured, a close examination of the external eye with a penlight, instillation of fluorescein into the tear film to look for abnormalities in the corneal epithelium, and measurement of intraocular pressure. An overview of the differential diagnosis of the red eye is presented in Table 2. Differentiating the pattern of inflammation is critical in determining the cause of a ‘‘red eye.’’ The eye becomes noticeably red or injected when the superficial blood vessels of the conjunctiva, episclera, or sclera become dilated in response to vasoactive mediators. The primary site of the inflammation may be either these tissues or an adjacent site such as eyelid, cornea, iris, or ciliary body. 409

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Table 1 Patients with ‘‘Red Eye’’ Requiring Immediate Referral to an Ophthalmologist Symptoms, signs, or risks Visual acuity decreased to less than 20/25 Pain Photophobia Contact lens use Recent eye surgery Pupil middilated or nonresponsive Hyperpurulent conjunctivitis Circumlimbal injection Corneal opacity Corneal edema Hypopyon Elevated intraocular pressure

Comment Suggestive of uveitis or angle closure glaucoma Conjunctivitis potentially uncomfortable, not painful Symptom of keratitis or anterior uveitis Risk of severe keratitis (e.g., Pseudomonas, Acanthamoeba spp.) Risk of postoperative endophthalmitis Concern for acute glaucoma or anterior uveitis; measure intraocular pressure Possibility of gonorrheal conjunctivitis Sign of keratitis or anterior uveitis Sign of corneal infection Sign of angle closure glaucoma Sign of uveitis and endophthalmitis ‘‘Normal’’ ⱕ21 mm Hg

Diffuse hyperemia with relatively less redness in the perilimbal area (the conjunctiva adjacent to the cornea) is the typical pattern of inflammation in common bacterial and viral conjunctivitis (see Figure 2). Ciliary flush refers to primarily circumlimbal (surrounding the cornea) hyperemia and is suggestive of corneal inflammation or iridocyclitis (anterior uveitis or iritis) (see Figure 3). Focal or sectoral hyperemia is localized injection that can be seen in episcleritis (inflammation of the connective tissue between the sclera and conjunctiva) and scleritis. Inflammation of a pterygium (a triangular patch of fibrovascular tissue often found extending from the inner canthus onto the cornea) or a pinguecula (connective tissue thickening of the conjunctiva appearing as a yellowish spot on either side of the cornea) can also cause a focal hyperemia. Unilateral hyperemia that lasts more than 2 days suggests that the disease process is not conjunctivitis. Although conjunctivitis may be asymmetrical, a unilateral inflamed eye should be promptly referred to an ophthalmologist. 3

CONJUNCTIVITIS

Conjunctivitis refers to inflammation of the moist, translucent mucous membrane that covers the sclera (bulbar conjunctiva), the undersurface of the eyelids (palpebral conjunctiva), and the interconnecting forniceal conjunctiva (see Figure 4). It is classified on the basis of cause (infectious, allergic, toxic, or tear insufficiency). Infectious conjunctivitis is commonly called ‘‘pink eye’’; the term has been variously associated with S. pneumoniae in temperate climates, H. aegyptius in hot climates, and viral conjunctivitis (adenoviral) on the Internet. Bulbar conjunctival injection, varying degrees of bulbar and forniceal conjunctival edema (chemosis), and a papillary reaction on the tarsal conjunctivae are general findings in conjunctivitis. Papillae are composed of a tiny central fibrovascular core of vessels that vasodilate in response to inflammatory chemical mediators. Eversion of the lids to inspect for a papillary response is requisite to making the diagnosis of conjunctivitis. On slit lamp examination papillae appear as fine elevated nodular areas of inflammation. Although papillae are a nonspecific sign of conjunctival inflammation their

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Figure 1 Anatomical characteristics of the normal eye: (A) external anatomical characteristics; (B) cross section of the eye illustrating the anterior and posterior sections of the globe.

absence on the tarsal, especially upper tarsal, conjunctiva precludes a diagnosis of conjunctivitis. Examination of a normal upper lid tarsal conjunctiva reveals distinct blood vessels running perpendicular to the lid margin. Obscuration of these blood vessels by hyperemia and papillae is the basis of a grading scale.

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‘‘RED EYE’’ Most often benign but may represent sight-threatening infection When to refer to an ophthalmologist (Table 1) Differential diagnosis (Table 2) Examination Close examination of external eye Visual acuity Intraocular pressure Fluorescein test of cornea Bacterial and viral conjunctivitis with diffuse hyperemia Circumlimbal hyperemia suggestive of iridocyclitis Unilateral hyperemia lasting >2 days not suggestive of viral conjunctivitis but should prompt ophthalmological consultation

P1: distinct outline of blood vessels (see Figure 5) P2: blood vessels that appear partially obscured (see Figure 6) P3: blood vessels obscured by overlying hyperemia and papillae Giant papillae (>1 mm) give the tarsal conjunctiva a cobblestone appearance and are suggestive of allergic mechanisms (vernal conjunctivitis or contact lens–related giant papillary conjunctivitis [GPC]).

Table 2 Differential Diagnosis of ‘‘Red Eye’’a Conjunctivitis Conjunctival erythema Discharge Chemosis Decreased vision Pain Photophobia Corneal opacity/ulcer Ocular pressure Pupillary reaction Hypopyon a

⫹⫹⫹c

Blepharitisb

Keratitis

⫹⫹ to ⫹⫹⫹e ⫹⫹⫹ ⫺ ⫹/⫺ ⫹/⫺ ⫺ N N

⫹⫹ (eyelid margin) ⫹ ⫹⫹ ⫺ ⫹/⫺ ⫹ ⫺a N N

⫹⫹d ⫹ to ⫹/⫺ ⫹ to ⫹ to ⫹ to ⫹ to N N

⫺

⫺

⫺ to ⫹⫹

⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹⫹

Anterior uveitis

Acute angle glaucoma

⫹⫹d

⫹ to ⫹⫹d

⫺ ⫺ ⫹⫹ ⫹ to ⫹⫹⫹ ⫹⫹⫹ ⫺ N Miotic, sluggish ⫺ to ⫹⫹

⫺ ⫺ ⫹⫹ ⫹ to ⫹⫹⫹ ⫹⫹ ⫺ ⇑ Middilated ⫺

Symptoms may occur concurrently, such as blepharoconjunctivitis, keratoconjunctivitis, or blepharokeratoconjunctivitis. ⫹, mild; ⫹⫹, moderate; ⫹⫹⫹, severe; ⫺, not present; N, normal. b May be associated with recurrent or chronic chalazia or styes. c Diffuse hyperemia. d Circumlimbal hyperemia. e Bacterial is generally purulent, viral generally watery.

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Figure 2 Diffuse bulbar conjunctival hyperemia with less inflammation near the limbus, suggestive of conjunctivitis.

Follicles are small lymphocytic aggregates that appear clinically as pale, round-oval elevated structures. Presence of a few follicles in the fornix is of little clinical importance. Finding numerous follicles on the bulbar or palpebral conjunctiva is clinically significant as they are not found in routine bacterial conjunctivitis. Follicular conjunctivitis is a sign of viral infection (adenovirus, Herpes simplex, and Molluscum contagiosum), chlamydial infection, Lyme disease, and occasionally Moraxella conjunctivitis (see Figure 7). The distinct properties of membranous layers that form in some patients with conjunctivitis help to differentiate among causes. ‘‘True’’ membranes are more adherent and when removed cause extensive bleeding; they may form in conjunctivitis caused by Corynebacterium diphtheriae, Neisseria gonorrhoeae, and S. pyogenes or be associated with Stevens-Johnson syndrome. A pseudomembrane is a less adherent inflammatory co-

Figure 3 Circumlimbal injection with less inflammation distal to limbus, suggestive of iritis or keratitis. Not the pattern of inflammation seen in conjunctivitis.

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CONJUNCTIVITIS Differential diagnosis (Table 2) Bulbar conjunctiva injection Papillary reaction of tarsal (especially upper tarsal) conjunctiva (Figure 4) Grading system based on extent of obscuration of upper plate conjunctiva (Figures 5 and 6) Follicular conjunctivitis suggestive of viral, Chlamydia sp., Lyme disease, or Moraxella sp. (Figure 7) May have concomitant keratoconjunctivitis or blepharokeratoconjunctivitis Viral Unilateral to bilateral in 2–10 days Commonly caused by adenovirus Epidemic keratoconjunctivitis Pharyngoconjunctival fever Also enterovirus, herpes simplex virus (HSV), and influenza virus Treatment Topical lubricants Steroids used cautiously (Table 3) Bacterial Unilateral to bilateral in 24 hours Hyperacute: N. gonorrhoeae, N. meningitidis, Streptococcus spp., Staphylococcus spp. Acute to subacute: Streptococcus spp., Staphylococcus spp., H. influenzae Chronic: Staphylococcus spp., S. pneumoniae, Moraxella spp. Topical therapy (Table 4)

agulum and bleeds less than a true membrane when removed. Pseudomembranes may occur with severe viral or bacterial conjunctivitis and alkali burns. Many of the pathogens that cause conjunctivitis may also cause simultaneous infection in the cornea (keratoconjunctivitis), eyelid (blepharoconjunctivitis), or all three areas (blepharokeratoconjunctivitis). In addition, conjunctivitis may be acute or chronic and be predominantly follicular or papillary in nature. 3.1 3.1.1

Viral Conjunctivitis Symptoms and Signs

Patients who have viral conjunctivitis experience acute onset of redness, tearing, or light mucoid discharge, irritation or foreign body sensation, and mild to moderate light sensitivity. There may be recent or current symptoms of upper respiratory infection (URI) as well as a history of exposure to sick contacts. Viral conjunctivitis typically begins unilaterally with involvement of the contralateral eye within 2 to 10 days. On careful examination, conjunctivitis shows a follicular response. The bulbar conjunctiva shows hyperemia, varying degrees of chemosis, and petechial or subconjunctival hemorrhages. Pseudomembranes may occur on the forniceal or tarsal conjunctival surfaces. Superficial keratitis can be the cause of decreased vision. The eyelids become edematous, and a preauricular lymphadenopathy is to be expected.

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Figure 4 Normal eye with limbus, bulbar conjunctiva, forniceal conjunctiva, and lower tarsal conjunctiva identified.

3.1.2

Cause

Acute follicular conjunctivitis is commonly caused by adenovirus, including such syndromes as epidemic keratoconjunctivitis (EKC) and pharyngoconjunctival fever (PCF). PCF is characterized by conjunctivitis, low-grade fever, pharyngitis, lid edema, and preauricular lymphadenopathy. Other causes of acute follicular conjunctivitis include acute hemorrhagic conjunctivitis caused by enterovirus 70, coxsackievirus, and primary herpes simplex virus (HSV). Influenza virus infection is associated with a watery conjunctivitis in 40%–60% of patients that accompanies the usual symptoms of cough, fever, and myalgia. Other less common viral causes of conjunctivitis include varicella zoster virus (VZV or chickenpox), human papillomavirus (warts), measles and mumps viruses, and Newcastle’s disease due to paramyxovirus. 3.1.3

Course and Management

Viral conjunctivitis is generally a self-limited illness of 10 days or less. Occasionally patients with adenovirus keratoconjunctivitis may have a foreign body sensation and reduced vision lasting weeks to months. Treatment is supportive with topical lubricants or vasoconstrictors and cold compresses. There is no commercially available ophthalmic antiinfective preparation for treating adenovirus. In EKC, topical corticosteroid use is controversial but may be prescribed

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Figure 5 Normal upper tarsal conjunctiva exposed after eversion of upper eyelid. Easily identifiable blood vessels running perpendicular to lid margin categorize this as a P1 reaction.

Figure 6 Upper tarsal conjunctiva in a patient with bacterial conjunctivitis. The obscuration of blood vessels by the micropapillary hypertrophy categorize this as a P2 reaction.

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Figure 7 Follicular conjunctivitis.

by the ophthalmologist to decrease corneal opacities and pseudomembranes after a definitive diagnosis has been made. Corticosteroids should be used cautiously by patients with conjunctivitis (see Table 3). Although HSV conjunctivitis may be self-limited, it is generally associated with keratitis. Use of topical trifluridine is appropriate. Oral acyclovir, famciclovir, or valacyclovir should decrease the rate of recurrence when taken on a long-term basis. Topical corticosteroid use is contraindicated in patients with herpes simplex keratoconjunctivitis. Viral conjunctivitis is highly contagious, and patients should be instructed to employ strict hygiene, including hand washing, avoidance of sharing of towels and bedding, and absence from school, work, and direct personal contact in general for at least the first 7 days. Spread can also occur in an office or clinic setting so health care workers should take precautions to prevent spread to other patients and themselves. It is important to keep in mind that a viral conjunctivitis–like illness with recent upper respiratory tract infection and conjunctival pseudomembrane formation may also occur with streptococcal infections. 3.2

Bacterial Conjunctivitis

Bacteria infect the conjunctiva from airborne fomites, upper respiratory tract secretions, hand to eye contact, and least commonly contiguous spread from a facial infection. The

Table 3 Caveats Regarding the Use of Corticosteroid-Containing Eyedrops Do not use when the diagnosis is uncertain. Never use if herpes simplex virus is in the differential diagnosis until ruled out. Do not use if corneal ulceration is present. They can cause open angle glaucoma in patients at risk. They can cause posterior subcapsular cataracts if used for extended periods. By suppressing the immune response, they increase the risk for infection.

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onset of bacterial conjunctivitis can be classified as hyperacute (onset <24 hours), acute or subacute (days to weeks), or chronic (>3–4 weeks). 3.2.1

Signs and Symptoms

Symptoms usually begin unilaterally and become bilateral within 24 to 48 hours. Severity of symptoms, inflammation, and discharge vary with pathogen and host. Patients generally complain of irritation, tearing, redness, and mucopurulent or purulent discharge. Vision should not be significantly affected. Hyperacute conjunctivitis presents with abrupt onset of profuse purulent discharge, lid edema, chemosis, subconjunctival hemorrhages, and preauricular lymphadenopathy. If there is an associated keratitis, progression of corneal ulceration can lead to corneal perforation in <48 hours. Acute, subacute, and chronic bacterial conjunctivitises are characterized by varying degrees of conjunctival injection and chemosis, papillary conjunctival reaction, and mild to moderate purulent discharge; generally preauricular lymphadenopathy is not present. 3.2.2

Cause

In hyperacute bacterial conjunctivitis the clinician must take care to rule out Neisseria gonorrhoeae. Less often N. meningitidis, Streptococcus species, and Staphylococcus species are the cause. In adults with acute or subacute bacterial conjunctivitis, S. aureus, coagulase-negative Staphylococcus spp., Streptococcus pneumoniae, and Haemophilus influenzae are common agents. Chronic bacterial conjunctivitis is often due to S aureus, Moraxella lacunata, Proteus spp., Enterobacteriaceae, and Pseudomonas spp. Frequently, chronic bacterial conjunctivitis has an associated blepharitis (staphylococcal blepharoconjunctivitis). In addition to gonorrhea, sexually transmitted inclusion conjunctivitis caused by Chlamydia trachomatis can occur. Trachoma is a nonsexually transmitted infection due to C. trachomatis. Although very uncommon in the United States (cases have been reported in Native Americans), trachoma remains one of the leading causes of blindness throughout the world. In repeated or chronic infections, superior tarsal scarring causes an inturning of the eyelid margin with entropion leading to keratitis and pannus formation over the cornea, which eventually results in blindness. 3.2.3

Management

Gonococcal conjunctivitis is an ocular emergency that must be referred immediately and treated promptly to prevent corneal perforation. Therapy for gonococcal conjunctivitis without corneal involvement is a single dose of ceftriaxone 1 g intramuscularly. Patients should be admitted and treated with ceftriaxone 1 g intravenously every 12 hours for 3 days if corneal ulceration has started. Cephalosporin-allergic patients can be treated with intramuscular spectinomycin or an oral fluoroquinolone. Local therapy should include frequent copious irrigation with normal saline solution. After irrigation, topical ophthalmic antibacterial eyedrops or ointments should be applied (bacitracin, erythromycin, ciprofloxacin, ofloxacin, or tetracycline). Since these patients are often coinfected with Chlamydia sp., treatment for this infection should also be provided (see Chapters 16 and 17). Testing for other sexually transmitted diseases such as syphilis and human immunodeficiency virus (HIV) infection should also be performed. Bacterial conjunctivitis that has a less acute course is usually self-limited. Empirical treatment with broad-spectrum topical ophthalmic antibiotic preparations in both eyes often results in improved clinical resolution (see Table 4).

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Agents that have both aerobic gram-negative rod and gram-positive coccus activity should be used. In severe cases a topical aminoglycoside (e.g., gentamicin or tobramycin) or quinolone (e.g., ciprofloxacin, ofloxacin, or levofloxacin) can be used in combination with erythromycin, bacitracin, or polymixin B with trimethoprim. Neomycin with polymixin has both gram-positive and gram-negative bacterial activity, but neomycin is a common cause of contact hypersensitivity reactions. Initial instillation of topical antibiotic preparation should be every 2 to 4 hours for the first 2 days followed by less frequent administration to four times daily for days 3 through 7. Conjunctival swabs for cytological evaluation and culture and sensitivity testing in recent-onset untreated patients are generally not of clinical value. Bacterial conjunctivitis usually shows dramatic improvement within 3 to 5 days of treatment. Patients with poor response to empirical treatment should be promptly referred to an ophthalmologist. Inclusion conjunctivitis due to Chlamydia sp. infection can be treated with oral doxycycline 100 mg twice daily. Topical erythromycin or tetracycline can be added to the regimen. Treatment of chronic staphylococcal blepharoconjunctivitis is reviewed later. 4

BLEPHARITIS

Blepharitis is inflammation of the eyelid margins. It is among the most common causes of external ocular inflammation. Although it can be acute and unilateral, it is more often chronic and bilateral. It causes burning, irritation, redness, and pruritis. It often occurs concomitantly with conjunctivitis. Anterior blepharitis, affecting the base of the eyelids predominantly, is caused by S. aureus or seborrhea. Posterior blepharitis is an inflammation of the meibomian glands of the eyelid. A chalazion is a chronic noninfectious lipogranulomatous inflammation of the meibomian glands. It presents as a localized nodule on the eyelid. Infection of the gland is referred to as an internal hordeolum. With the lid everted, it appears as a yellowish nodule seen through the tarsal conjunctiva. In contrast, an external hordeolum or stye is an infection of the glands of Zeis that are connected to the eyelash follicles. The most common bacterial causes of blepharitis include S. aureus, coagulase-negative Staphylococcus spp., Propionibacterium spp., and Corynebacterium spp. Nonbacterial causes of blepharitis commonly include seborrheic dermatitis, allergy, and rosacea (see Figure 8). 4.1

Staphylococcal Blepharitis

Staphylococcal blepharitis patients most often present with redness of the tarsal conjunctiva, burning, mild light sensitivity, tearing, and crusting of the eyelids, especially on awakening. Examination reveals inflammation of the lid margin, crusting and scaling on the lashes and lid margins, poliosis (white lashes), madarosis (loss of lashes), trichiasis (misdirection of lashes), ulceration at the base of lashes, and conjunctival injection. There may also be styes, chalazia, and internal hordeola. Staphylococcal blepharitis can lead to chronic papillary conjunctivitis and keratitis. Corneal involvement can manifest as a superficial epithelial keratitis or a peripheral infiltration of white cells leading to corneal ulceration and/or superficial neovascularization (i.e., pannus formation); involvement is typically seen in the inferior third of the cornea. 4.2

Differential Diagnosis

Seborrheic blepharitis and acne rosacea with meibomian gland dysfunction are common causes of eyelid disease. Less commonly local infection with HSV, Molluscum conta-

Gentak

Gentamicin

Drop Ointment

Ointment Ointment

1% 0.5%

Ilotycin

Erythromycin 0.3% 0.3%

Drop

0.5%

Chloroptic

Ointment

Terramycin

Ointment

1.25 mg/10,000 units/ 0.025 mg/ml 5 mg/g–10,000 U/g

Neosporin

1.75 mg/g–10,000 U/ml–400 U/g

Neosporin

Drop

Ointment Ointment

Formulation

Neomycin with polymixin B and oramicidin Oxytetracycline with polymyxin B Chloramphenicolb

10,000 U/ml–0.1%

500 U/g (0.5%) 500 U/g–10,000 U/ml

Concentration

Polytrim

Polysporin

Bacitracin Bacitracin with polymixin B

Polymyxin B with trimethoprim Neomycin with polymixin B and bacitracin

Trade name

Generic name

Table 4 Topical Ophthalmic Antibiotics

Gram-positive bacteria, Neisseria gonorrhoeae, Chlamydia trachomatis Gram-negative bacteria

Covers gram-positive and gram-negative bacteria, including Pseudomonas spp. Covers gram-positive and gram-negative bacteria

Covers gram-positive and gram-negative bacteria, including Pseudomonas spp., but not Serratia spp. Gram-negative, Pseudomonas spp., and gram-positive Covers gram-positive and gram-negative bacteria, including Pseudomonas spp., but not Serratia spp.

Comments

$9.62 For 5 ml $14.60 For 3.5 g

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$9.54 For 3.75 g

$28.34 For 3.5 g

$17.50 For 10 ml

$28.95 For 3.75-g tube

Costsa

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Ciloxan

Quixin

Chibroxin

Ocuflox

Generic

Ciprofloxacin

Levofloxacin

Norfloxacin

Ofloxacin

Sulfacetamide

Drop

Ointment

10%

Drop

10%, 15%, 30%

0.3%

Drop

Ointment Drop

0.3% 0.5%

0.3%

Drop Ointment Drop

0.3% 0.3% 0.3%

Covers gram-positive and gram-negative bacteria, including Pseudomonas spp. and Serratia spp. Covers gram-positive and gram-negative bacteria, including Pseudomonas spp. and Serratia spp. Covers gram-positive and gram-negative bacteria, including Pseudomonas spp. and Serratia spp. Covers gram-positive and gram-negative bacteria but not Pseudomonas spp. and Serratia spp.

Gram-negative bacteria with some staphylococcal and streptococcal activity

Gram-negative bacteria

b

Average wholesale price, 2000 Drug Topics REDBOOK. Serious blood dyscrasias, including aplastic anemia, thrombocytopenia, and granulocytopenia, have been reported.

a

Tobrex

Tobramycin

$5.09 For 3.5 g (10%)

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$29.00 For 5 ml

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$29.46 For 5 ml $31.38 For 3.5 g $30.30 For 5 ml

Ocular Infections 421

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BLEPHARITIS Usually chronic and bilateral Anterior S. aureus Seborrhea Posterior Chalazion Internal hordeolum Staphylococcal Tarsal conjunctiva hyperemia Abnormalities of eyelid and lashes May lead to corneal ulceration Differential diagnosis: seborrhea, rosacea May be associated with keratoconjunctivitis sicca Therapy Lid hygiene Topical ophthalmic erythromycin, bacitracin (Table 4)

Figure 8 Rosacea blepharitis. Note loss of lower eyelid lashes (madarosis), irregular lid margin, stye on lower lid, chalazion on upper lid, and facial telangiectasia.

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giosum (MC), Moraxella spp., or Phthirus pubis (pubic lice or crabs) can occur. Since HSV can cause blepharokeratoconjunctivitis, evaluation for corneal disease is imperative and is a contraindication to the use of topical corticosteroids. MC commonly causes either a unilateral or a bilateral follicular conjunctivitis with round, waxy, pearly white nodules on the lid margin. Patients infected with the HIV are prone to MC infection; therefore, MC patients should be tested for HIV infection. Moraxella spp. can also cause a blepharoconjunctivitis with crusting and ulceration of the skin in the lateral canthal angle. Keratoconjunctivitis sicca (KCS) or ‘‘dry eye syndrome’’ can exist concomitantly with blepharitis. Signs and symptoms can be similar to those of blepharitis though corneal staining involves the interpalpebral zone (keratitis sicca). 4.3

Management

Lid hygiene with warm water or baby shampoo scrubs on awakening and at bedtime may be supplemented by topical application of an ophthalmic antibiotic ointment such as erythromycin or bacitracin. In acute cases, ointment should be applied twice daily then nightly for chronic therapy as needed. Rarely a short course of a topical steroid may be necessary during initial therapy, but steroids are discouraged for long-term care (see Table 3). In cases associated with acne rosacea, long-term treatment with oral tetracycline, doxycycline, minocycline, or erythromycin may be needed. 5

KERATITIS

Keratitis is inflammation of the cornea and may be described on the basis of distribution, depth, location, and shape. The cornea is an avascular structure composed of a surface layer of epithelial cells and a thick central layer or stroma that constitutes most of the cornea. By using a penlight or Finoff transilluminator abnormalities of the corneal epithelium can be detected as irregularities in the pattern of light reflected off the cornea. Corneal opacities may indicate inflammation of the corneal stroma. The combination of an irregular light reflex and corneal haziness or opacity is suggestive of a corneal ulcer (see Figure 9).

KERATITIS Inflammation of cornea Ocular pain, photophobia, decreased vision Circumlimbal conjunctiva hyperemia Urgent referral to ophthalmologist Viral Adenovirus Herpes simplex virus (HSV) (blepharoconjunctivitis) Varicella zoster virus (VZV) (fifth cranial nerve dermatome) Bacterial (65%–95%) Trauma and contact lens Hypopyon, miosis, synechiae Staphylococcus spp., gram-negative rods (GNRs), Pseudomonas spp., Moraxella spp. Topical ciprofloxacin and bacitracin with polymyxin B (Table 4) Fungal, parasitic; uncommon

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Figure 9 Pseudomonas sp. corneal ulcer. Note mucopurulent discharge, corneal infiltrate, and hypopyon.

Patients experience ocular pain, a foreign body sensation, photophobia, and decreased vision if the visual axis is involved. Physical examination reveals circumlimbal hyperemia, punctate epithelial keratopathy, corneal opacities or infiltrates of variable morphological characteristics, and corneal ulceration in severe cases. Bacteria are the most common cause of keratitis, accounting for 65%–95% of all corneal infections, followed by viruses and fungi. Parasitic causes of keratitis such as onchocerciasis, African trypanosomiasis, and leishmaniasis can be seen in persons in tropical areas. Acanthamoeba sp., a free-living amoeba associated with water contact, has a worldwide distribution but is fortunately a rare cause of chronic keratitis. All patients suspected of having keratitis should be immediately referred to an ophthalmologist. Keratitis can cause vision loss as well as corneal ulceration, leading to perforation of the globe and potential loss of the eye. 5.1 5.1.1

Viral Adenovirus

In the early stage of adenoviral keratoconjunctivitis there is a diffuse epithelial keratitis that progresses to a focal epithelial keratitis by 1 week. Subepithelial opacities develop after 2 weeks and can cause reduced vision. These infiltrates generally regress spontaneously. If they cause significant or persistent decrease in vision, a short course of topical steroids may be considered despite the risk of development of steroid dependency. Even in healthy eyes, protracted topical steroid use causes cataract formation and may induce glaucoma. 5.1.2

Herpes Simplex Virus

Herpes simplex virus (HSV) is the most common cause of corneal blindness in developed countries and the most common cause of unilateral corneal blindness in the world. Primary

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ocular HSV disease appears as a unilateral blepharokeratoconjunctivitis. Symptoms include redness, pain, photophobia, tearing, foreign body sensation, and possibly decreased vision. Vesicles occur on the periocular skin. An ipsilateral preauricular lymph node may be palpable. The conjunctiva displays a follicular response and may develop a pseudomembrane. Most patients have a scattered punctate epitheliopathy and/or a dendritic epithelial keratopathy. Instillation of fluorescein dye and examination of the cornea with a blue filtered light make the dendritiform and geographical epithelial defects stand out (see Figure 10). Diagnosis can be confirmed by viral culture. Uncommonly corneal stromal inflammation or uveitis occurs in primary ocular HSV. Recurrent ocular HSV disease can be manifested as blepharoconjunctivitis, dendritic or geographical epithelial keratitis, stromal keratitis, and anterior uveitis. Patients with a history of HSV corneal disease often have reduced corneal sensation; for that reason some patients with recurrent dendritic disease may be relatively asymptomatic. Stromal keratitis can be necrotizing or nonnecrotizing and can cause significant ocular morbidity. Stromal HSV is thought to be due to an immune response to residual viral antigen in the cornea stroma. Topical steroid use has increased the incidence of HSV keratitis. Treatment is with topical trifluorothymidine (trifluridine [Viroptic ophthalmic solution) or 9-B-arabinofuranosyl (vidarabine [Vira-A]) ophthalmic ointment and systemic antivirals such as acyclovir 400 mg five times daily, famciclovir 500 mg twice daily, or valacyclovir 500–1000 mg twice daily. Recurrent ocular HSV occurs in up to 32% of patients who are not maintained on oral acyclovir prophylaxis during the initial year. Treatment with oral acyclovir 400 mg twice daily reduces the rate of recurrent HSV ocular

Figure 10 Herpes simplex virus keratitis with dendrite.

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disease to 19%. Topical steroid use is contraindicated in patients with HSV epithelial disease. 5.1.3

Herpes Zoster Ophthalmicus

Activation of latent VZV from the trigeminal (fifth cranial nerve) sensory ganglion with development of dermatitis in the dermatome of the ophthalmic division (V1) is referred to as herpes zoster ophthalmicus (HZO). Ocular involvement can also result when VZV occurs in the maxillary (V2) or mandibular (V3) dermatomes. Corneal involvement occurs in two-thirds of patients with HZO. Shingles of the eye is a vesicular eruption generally confined to the forehead and upper eyelid. Even in the absence of Hutchinson’s sign, a lesion on the tip of the nose indicating involvement of the nasociliary branch of the ophthalmic division and possible corneal involvement, the eye may be involved. The pain accompanying zoster usually decreases as the acute dermatitis resolves, though discomfort may persist for months. Paradoxically corneal anesthesia can be profound and cause a neurotrophic keratitis. HZO can severely damage every part of the eye and adnexa. Patients should be referred promptly to an ophthalmologist to assess the degree of ocular involvement. Systemic antivirals should be started immediately. Beginning treatment after 72 hours of the onset of the dermatitis has not been shown to ameliorate the incidence and severity of complications. Therapeutic options are oral acyclovir 800 mg five times daily, valacyclovir 1 g three times daily, or famciclovir 500 mg three times daily for 7 to 10 days. Commercially available ophthalmic antiviral preparations in the United States have not been shown to be beneficial. 5.2

Bacterial

Bacterial keratitis is a relatively common infection that can rapidly lead to corneal ulceration and visual loss. Risk factors for development of bacterial keratitis include contact lens use (especially of ‘‘extended-wear’’ type), any type of trauma including what might be considered minor, contaminated ophthalmic solutions, and any ocular condition that damages the corneal epithelium, such as corneal abrasions, neurotrophic keratitis, exposure keratitis, and postoperatively exposed sutures. Patients have ocular erythema, pain, conjunctival and lid swelling, and decreased vision. In addition to a corneal infiltrate, physical examination may reveal corneal stromal edema, hypopyon (pus in the anterior chamber seen clinically as a white layer against the lower cornea obscuring the inferior iris), and a miotic pupil. The most common pathogens include S. aureus, coagulase-negative Staphylococcus spp., P. aeruginosa, S. pneumoniae, and other gram-negative rods, including the Enterobacteriaceae and Moraxella spp. P. aeruginosa is the most common cause of contact lens– related corneal ulcers. It is the most common cause of keratitis in the southern United States, whereas staphylococci are the more common pathogens in the northern United States. Untreated N. gonorrhoeae conjunctivitis can involve the cornea without antecedent trauma and lead to a rapidly progressive keratitis. Corneal specimens should be obtained for cytological evaluation, Gram stain, and culture. These specimens can be obtained by corneal scraping, using slit lamp microscopy. Sampling of the cornea with a moistened calcium alginate swab for culture and sensitivity may also be used. Ideally, initial therapy should be guided by the results of Gram stain. Initial empirical therapy often consists of frequent (every-30-minute) instillation of a fluoroquinolone ophthalmic solution such as ciprofloxacin or ofloxacin. Since ciproflox-

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acin does not adequately cover streptococcal infections, the addition of bacitracin with polymyxin B ophthalmic ointment is suggested. After the first 48 hours the dosing interval can be gradually extended. Therapy can be modified by the results of the cultures. If no organisms or differentiating types of bacteria are seen, broad-spectrum antibiotic therapy with a ‘‘fortified’’ aminoglycoside (gentamicin 1.4% or tobramycin 1.4%) and cephalosporin (cefazolin 5%) solution can be prescribed. These solutions can be prepared by special compounding pharmacies and are most often used by cornea specialists. 5.3

Fungal

Fungal keratitis occurs much less commonly than bacterial keratitis. Both filamentous fungi such as Fusarium spp., Aspergillus spp., and Alternaria, Curvularia, and Penicillium spp. and yeasts forms such as Candida spp. can cause corneal infections. Filamentous fungal keratitis occurs more commonly in warmer and humid climates, whereas yeast keratitis is more common in the cooler locales. Common risk factors for development of fungal keratitis include trauma with plant material and topical steroid use. The initial stages of fungal keratitis generally produce milder signs and symptoms than occur in bacterial keratitis. Filamentous fungal infiltrates typically are grayish white with feathery edges. Yeast keratitis tends to appear as focal infiltrates resembling gram-positive bacterial corneal infections. The infrequency of fungal keratitis mitigates against initial empirical antifungal therapy. Treatment for most filamentous keratitis is topical natamycin 5% suspension (pimaricin). Amphotericin B deoxycholate 0.15% eyedrops are recommended for yeast and Aspergillus sp. keratitis. This solution, though, can be toxic to corneal epithelium. Topical therapy may need to be supplemented with ketoconazole for filamentous keratitis and fluconazole for yeast keratitis. Itraconazole has good activity against Aspergillus spp. and can be used to treat keratomycosis due to this organism. 6

PERIOCULAR INFECTIONS

Infection of the periocular soft tissues may result from trauma or skin infection, hematogenous spread, or, more commonly, direct extension from infected sinuses. Cellulitis is classified as preseptal or orbital on the basis of whether the infection is anterior or posterior to the orbital septum, respectively. The septal fascia extends from the orbital rim periosteum to structures in the upper and lower eyelids. Both preseptal and orbital cellulitises are more common in children than in adults. On the basis of temporal, clinical, and anatomical considerations, infections posterior to the orbital septum can be further differentiated into subperiosteal abscess, orbital cellulitis, orbital abscess, superior orbital fissure syndrome, and cavernous sinus thrombosis. Any periocular infection may have serious complications, including loss of vision, intracranial extension, and death. Appropriate management requires prompt diagnosis, appropriate subspecialty referral, systemic antibiotic therapy, and possible surgical intervention. 6.1

Preseptal Cellulitis

Preseptal cellulitis patients often report recent onset of swelling of the eyelids associated with varying degrees of discomfort. History may elicit an anteceding stye, chalazion, bite, trauma, or URI. On examination, the eyelid is erythematous, edematous, tender, and warm. There should not be signs of retroseptal disease such as pupillary, extraocular muscle, or optic nerve dysfunction, and the eyeball should not be involved. Reduced vision, proptosis,

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PERIOCULAR INFECTIONS Preseptal cellulitis Pain and swelling of eyelids and surrounding tissue Eyeball and ocular function normal Staphylococcus and Streptococcus spp. Computed tomography (CT) scan to rule out orbital involvement Orbital cellulitis Infection posterior to orbital septum Eyelid erythema, swelling, pain Ocular pain, decreased vision Most often due to extension of sinusitis Hospitalization, intravenous antibiotics, and possibly surgery Orbital apex syndrome Visual loss Ophthalmoplegia Cavernous sinus thrombosis Septic thrombophlebitis of ophthalmic veins draining into cavernous sinus Diplopia, photophobia, orbital swelling, exophthalmos, abnormal pupillary reflex

abnormalities of extraocular muscle movements, and pupillary changes point to retroseptal (i.e., orbital) involvement and require emergency intervention. Before the introduction of the conjugate vaccine H. influnzae was the most common cause of childhood preseptal and orbital cellulitis. S. pneumoniae, S. aureus, S. epidermidis, and mixed anaerobic and aerobic pathogens are common. S. aureus and S. pyogenes are commonly isolated in cases due to trauma and skin infection. In human or animal bites anaerobes such as Peptococcus, Peptostreptococcus, and Bacteroides species must be considered in addition to Pasturella multocida. Local allergic reactions, facial trauma, blepharochalasis (redundancy of the upper lid with a resultant skinfold hanging down concealing the tarsal margin), dacryoadenitis (inflammation of the lacrimal gland), maxillary sinusitis, angioneurotic edema, and autoimmune diseases such as systemic lupus erythematosus are among the conditions that can mimic preseptal cellulitis. Computed tomography (CT) of the orbit and sinuses is helpful in diagnosing sinusitis as well as confirming that the infection is limited to the preseptal space. Gram stain results of the discharge or wound can direct the choice of initial antibiotic therapy. The results of culture and sensitivity testing can then be used to modify the initial empirical therapy. Older children and adults with mild preseptal cellulitis due to an obvious superficial cause such as styes and chalazia often respond quickly to oral antibiotics. In mild cases, cephalexin, dicloxacillin, or amoxicillin with clavulanate can be used. If the patient has a severe penicillin allergy, oral clindamycin or trimethoprim & sulfamethoxazole can be used. Hospitalization for intravenous therapy is indicated for patients who are moderately or severely ill, in situations in which poor adherence may be an issue, and for patients not improving on oral therapy. Initial empirical therapy should include a ␤ -lactam/␤ -

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lactamase inhibitor combination (ampicillin with sulbactam, or piperacillin with tazobactam). Addition of vancomycin should be considered if epidemiological factors suggest either a methicillin-resistant S. aureus or penicillin-resistant S. pneumoniae. If a localized abscess develops, surgical drainage is indicated. Topical antibiotics and tetanus toxoid should also be administered when indicated. 6.2

Orbital Cellulitis

Orbital cellulitis is an acute infection posterior to the orbital septum. In addition to the symptoms of preseptal cellulitis, patients often have ocular pain and decreased or double vision. Findings may include fever, decreased vision, pain on eye movement, limitation of eye movement, proptosis, pupillary abnormalities, conjunctival injection with chemosis, and congestion of retinal vessels (see Figure 11). In most patients with orbital cellulitis, sinusitis is the source of the infection. Trauma and surgery are less common causes. The same bacteria that cause preseptal cellulitis are the common pathogens for orbital cellulitis. Rhinocerebral mucormycosis (zycomycosis) and aspergillosis are rare but devastating infections (see later discussion). Patients with orbital cellulitis should be immediately hospitalized. Specimens for Gram stain and culture should be obtained from any discharge or wounds. CT of sinuses and orbit as well as otolaryngology consultation are indicated. Blood cultures, lumbar puncture, and an infectious disease consultation should be obtained if meningitis or extension into the central nervous system is suspected. Intravenous antibiotic therapy with ceftriaxone and clindamycin or piperacillin plus tazobactam should be initiated. Orbital abscess development requires surgical intervention. 6.2.1

Subperiosteal Abscess

When pus from a contiguous infected sinus erodes through the orbital wall and collects beneath the periosteum, a subperiosteal abscess is formed. Since the ethmoid and frontal

Figure 11 Orbital cellulitis with loss of globe.

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sinuses are the most common primary sites of infection, the orbital contents may be displaced laterally or inferiorly, respectively. In addition to erythema, edema, and lid tenderness, conjunctival chemosis and a fever are common. Antibiotic therapy is similar to that for orbital cellulitis. Surgical de´bridement may be needed. 6.2.2

Orbital Apex Syndrome

Orbital apex syndrome is manifested with visual loss (cranial nerve II) and ophthalmoplegia (cranial nerves III, IV, and VI). If it is subacute, signs of infection may be lacking. It is often due to chronic ethmoid or sphenoid sinusitis. Since the same cranial nerves traverse the orbital apex and the anterior cavernous sinus, disease has similar clinical manifestations in these two locations. Antibiotic therapy is similar to that for orbital cellulitis. Surgical de´bridement may be needed. 6.2.3

Cavernous Sinus Thrombosis

Cavernous sinus thrombosis is a dreaded complication of preseptal and orbital cellulitis as well as facial furunculosis and bacterial sinusitis. The superior and inferior ophthalmic veins drain the orbit into the cavernous sinuses. Septic thrombophlebitis of these vessels results in cavernous sinus thrombosis. Patients report diplopia, photophobia, and orbital swelling. Examination reveals exophthalmos, chemosis, papilledema, deceased pupillary and corneal reflex, and ocular palsies. Complete external and internal ophthalmoplegia may occur. Any of the structures coursing through the cavernous sinus can be compromised, including cranial nerves III, IV, V, and VI; the internal carotid artery; and the orbital sympathetic nerves. Spread may be rapid to the contralateral sinus, causing bilateral illness. Urgent magnetic resonance imaging (MRI) is required. 6.2.4

Phycomycosis

Zygomycosis (mucormycosis) is an invasive fungal infection that can involve the orbit, periorbital tissue, and central nervous system. Although diabetics in ketoacidosis are among the most common patients at risk, immunosuppression and systemic malignancy are also risk factors. Initially, clinical manifestations may be subtle. Patients may at first note nasal discharge, epistaxis, lacrimation, ocular or periocular pain or numbness, and headache. As adjacent structures are invaded, signs of orbital apex syndrome or cavernous sinus thrombosis may develop. Thrombosis of the internal carotid artery can result in contralateral hemiplegia. Diagnosis is made by demonstration of nonseptate hyphae on biopsy of involved tissue. Treatment includes extensive surgical de´bridement and administration of amphotericin B. 7

INFECTIONS OF THE INNER EYE

Uveitis is inflammation of the uveal tract, which consists of the iris, ciliary body, and choroid. Uveitic conditions are generally labeled as to their anatomical location. Inflammation may be anterior (iritis, iridocyclitis), in the intermediate region including the pars plana of the ciliary body (pars planitis), posterior (choroiditis or chorioretinitis, retinitis or retinochoroiditis), or diffuse (panophthalmitis). Infectious processes can enter the globe and cause endophthalmitis through exogenous routes such as surgery or perforating trauma or endogenously through the bloodstream. Symptoms and signs of intraocular infection vary with the anatomical sites of inflammation. Prompt diagnosis and treatment can prevent loss of vision. All cases of

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UVEITIS Inflammation of iris, ciliary body, and choroid Anterior (iridocyclitis) Pain, photophobia, blurred vision Usually not infectious Infectious causes: herpes simplex virus (HSV), varicella zoster virus (VZV), syphilis, tuberculosis (TB), Lyme disease Intermediate (pars planitis of ciliary body) Floaters, blurred vision TB, Lyme disease, syphilis, Toxocara spp. Posterior (retinitis) Decreased vision, floaters Cytomegalovirus in patients with advanced acquired immunodeficiency syndrome (AIDS) HSV (acute retinal necrosis) Toxoplasma spp. Reactivation of congenital infection most common Toxocara spp., syphilis, TB

suspected intraocular inflammation or infection deserve immediate ophthalmologic consultation. 7.1

Uveitis

Patients with acute iridocyclitis (anterior uveitis) experience pain, photophobia, blurred vision, redness, and tearing. Findings on examination include blepharospasm (squinting), reduced vision, circumlimbal injection, corneal endothelial precipitates (keratic precipitates), white blood cells and proteinaceous flare in the aqueous humor (hypopyon, when layered), and a meiotic sluggish pupil. Most causes of anterior uveitis are not infectious. However, herpes simplex, herpes zoster, syphilis, tuberculosis, Lyme disease, and leprosy can cause anterior uveitis. Posterior inflammations can spill over into the anterior segment, causing symptoms and signs of anterior uveitis. Anterior uveitis can mask a posterior uveitis. Patients with intermediate uveitis tend to have symptoms of floaters and blurred vision. The patients do not appear to be in pain, and the external eye does not appear inflamed. On dilated examination of the internal periphery of the eye, evidence of inflammation can be seen in the region of the pars plana of the ciliary body, the peripheral choroid and retina, and the contiguous vitreous humor. Infectious causes include tuberculosis, syphilis, Lyme disease, and toxocariasis. Pain and external signs of inflammation are uncommon in patients with posterior uveitis. Visual complaints are the most common. If the macula is involved, the vision may be 20/200 or worse. Although any systemic infection can be manifested ophthalmologically, infectious agents that can target the posterior segment of the eye include herpes family viruses such as HSV, VZV, and cytomegalovirus (CMV); Toxoplasma gondii; Toxocara canis; Treponema pallidum; Mycobacterium tuberculosis; Candida species; and other fungi.

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Necrotizing Herpetic Retinitis (Acute Retinal Necrosis)

Necrotizing herpetic retinitis or acute retinal necrosis (ARN) is a fulminant necrotizing infection of the retina. It may occur bilaterally. These patients often report ocular pain and reduced vision. On dilated fundus examination occlusive retinal arteriolitis, vitritis, and multifocal yellow-white peripheral retinal lesions are classically seen. Varicella-zoster virus, herpes simplex virus type 2, and cytomegalovirus have also been associated with ARN. In addition to systemic acyclovir and steroids, aspirin and other anticoagulation therapy have been tried. Retinal breaks and detachments are common. Prognosis is poor. 7.1.2

Cytomegalovirus

CMV retinitis is the most common ocular opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). It can also be seen in patients with other forms of immunosuppression. Patients often complain of floaters and decreased vision. Early CMV retinitis may appear as cotton-wool spots. Retinal periphlebitis can occur. Dilated funduscopic examination reveals retinal opacification with hemorrhage, exudates, and necrosis said to resemble a ‘‘pizza pie.’’ Initial treatment options include intravenous ganciclovir, foscarnet, or cidofovir. Intravitreal injections of ganciclovir and foscarnet can be administered. Patients who cannot tolerate systemic drug therapy or who show progression may benefit from surgical placement of a ganciclovir implant. Valganciclovir hydrochloride, a prodrug of ganciclovir with excellent oral bioavailability, holds promise as an oral agent for the treatment of acute CMV retinitis and chronic suppression for patients with immune compromise. 7.1.3

Toxoplasmosis

Toxoplasma gondii primarily causes an exudative focal retinitis. It can also involve the choroid: hence the term retinochoroiditis. It is an obligate intracellular parasitic protozoon that is a major cause of posterior segment infection throughout the world. The patient may report floaters or poor vision. If the inflammation is severe, it can spill over into the anterior segment to cause signs and symptoms of anterior uveitis. The acute yellow or gray-white focal retinitis lesion, obscured by inflammatory cells in the vitreous, results in a ‘‘headlight in the fog’’ appearance on dilated funduscopic examination. After the inflammation subsides, a chorioretinal scar persists. Ingestion of contaminated food, cat feces, or congenital acquisition results in human infection. Although most cases of toxoplasmic retinochoroiditis have been presumed to be caused by reactivation of congenitally acquired infection, acquired systemic toxoplasmosis is perhaps a more common cause than previously appreciated. Seroprevalence of toxoplasmosis increases with increasing age of the population. U.S. studies suggest that between 3% and 70% of the population is seropositive, depending on age, geographical locale, and employment. Thus a positive immunoglobulin G (IgG) antibody titer finding does not confirm the diagnosis but may help to corroborate it. A negative serological finding would help rule out the infection. Institution of treatment depends on the patient as well as on the location and severity of the retinitis. If there is a vision-threatening infection, treatment is indicated. The standard treatment regimen includes pyrimethamine, sulfadiazine, folinic acid, and prednisone. Trimethoprim & sulfamethoxazole has been used as a substitute for sulfadiazine. Clindamycin can be used in patients intolerant of sulfonamides. Therapy is given for 6 weeks. Since the parasite can exist in an encysted latent state, recurrence of retinochoroiditis can occur, especially in immunocompromised patients, for whom chronic suppressive therapy is needed.

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Toxocariasis

Toxocara canis is a common canine intestinal roundworm that causes visceral larval migrans. Ocular infection can follow ingestion of T. canis ova–contaminated soil or vegetables. Young children who are exposed to puppies or have a history of geophagia are at highest risk. Ocular toxocariasis is usually unilateral, appearing most commonly as a posterior pole granuloma. It can also take the form of a peripheral granuloma, leukocoria with chronic endophthalmitis, or a diffuse unilateral subacute neuroretinitis. Although definitive diagnosis requires demonstration of the larva in the eye, serum antibody is helpful in diagnosis. Systemic and/or periocular steroids help reduce the inflammation. Thiabendazole and diethylcarbamazine have been used to treat visceral larval migrans but may cause increased ocular inflammation when antigenic proteins are released from the dead parasite: the Mazzotti reaction. Rather than use of anthelmintic agents, vitrectomy is often preferred. If the nematode is visible, direct laser photocoagulation is an option. 7.1.5

Syphilis

Infection with Treponema pallidum can affect any structure within the eye. The inflammation can be anterior with symptoms of pain, redness, and photophobia; posterior with symptoms of floaters and blurred vision; or diffuse (panuveitis). Diagnosis is based on serological results (see Chapters 16 and 17). Specific treponemal tests such as the FTAABS or MHA-TP are always reactive but do not indicate active disease. Syphilitic chorioretinitis usually indicates central nervous system involvement. A lumbar puncture should therefore be performed. High-dose parenteral penicillin is the treatment of choice. 7.1.6

Tuberculosis

Mycobacterium tuberculosis more commonly affects the posterior segment than the anterior segment of the eye. When the posterior segment is involved, the symptoms are floaters and blurred vision. A dilated funduscopic examination reveals vitritis and chorioretinitis. Diagnosis and treatment of ocular tuberculosis are the same as for pulmonary disease (see Chapter 13). 7.2

Endophthalmitis

7.2.1 Candida Species Candida sp. endophthalmitis is a complication of candidemia that results in seeding of the choroid with secondary involvement of the retina and vitreous (chorioretinitis). Individuals who are at risk include the immunosuppressed, those with central venous catheters (patients receiving total parenteral nutrition are at particular risk), and persons using intravenous drugs. Ocular involvement is insidious with symptoms of worsening vision. The fluffy yellowish white choroidal lesions seen on examination are not pathognomonic for Candida sp. infection and may appear similar to those seen in toxoplasmic choroiditis. Diagnosis in the absence of positive blood culture results may require vitreous aspiration or vitrectomy. Despite poor penetration of amphotericin B into the vitreous humor, early chorioretinal disease responds well. Amphotericin used in combination with 5-fluorocytosine may have a synergistic effect. Although there is less experience with azole derivatives, they are known to penetrate the eye more readily and have been used in nonimmunosuppressed patients with early disease. Azoles can decrease the fungicidal activity of amphotericin B; they should not be use together in the treatment of Candida albicans.

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ENDOPHTHALMITIS Candida species Secondary to candidemia Immunocompromised host Patients with central venous catheters Insidious worsening of vision Bacterial Most often postoperative Early onset (<6 weeks postoperative) Acute onset of blurred vision, pain Staphylococcus spp., gram-negative rods (GNRs) Late onset (>6 weeks postoperative) Coagulase-negative Staphylococcus spp., propionibacterium spp., fungi Need for intraocular antibiotics

7.2.2

Bacterial

Most cases of bacterial endophthalmitis occur after intraocular surgery. Bacteremia leading to endophthalmitis is much less common. Postoperative endophthalmitis is divided into early (<6 weeks post operatively) and late (>6 weeks). Organisms that most commonly cause early-onset postoperative endophthalmitis include coagulase-negative Staphylococcus spp., S. aureus, Streptococcus species, and assorted gram-negative rods. Late endophthalmitis can be caused by the introduction of less virulent pathogens in surgery or postoperatively as pathogens enter the eye through a wound, as may occur in glaucoma filtration surgery. Late postoperative endophthalmitis is often due to Propionibacterium acnes, coagulase-negative Staphylococcus sp., or fungi. Late infections associated with glaucoma filtration surgery are commonly due to Streptococcus spp., Haemophilus spp., and assorted gram-positive bacilli. Almost all patients with early postoperative endophthalmitis present acutely with blurred vision. Although most complain of pain, 25% do not. There may also be conjunctival hyperemia, chemosis, and swelling of the eyelid. A layering of white blood cells in the anterior chamber obscuring the inferior aspect of the iris (hypopyon) is the most common finding, followed by poor visualization of the posterior pole. The approach to treatment depends on the level of vision. If the vision is limited to hand movements or better, the patient should have a vitreous aspiration or biopsy and intravitreal injection of antibiotics. If vision is reduced to only light perception, the patient should have an immediate vitrectomy followed by intravitreal antibiotic injection. Intravitreal injections suggested by the National Eye Institute–Endophthalmitis Vitrectomy Study (NEI–EVS) (1995) include vancomycin, amikacin, and dexamethasone. Intravenously administered amikacin and ceftazidime penetrate the blood–ocular barrier poorly and are of limited benefit. Fluoroquinolones such as ciprofloxacin do penetrate the blood– ocular barrier and their use appears reasonable. Topically applied vancomycin, amikacin, prednisolone, and atropine were used in the NEI–EVS.

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BIBLIOGRAPHY Chandler JR, Langenbrunner DJ, Stevens ER. The pathogenesis of orbital complications in acute sinusitis. Laryngoscope 80:1414–1428, 1970. Chung C, Cohen E. Bacterial Conjunctivitis. Clinical Evidence. 3:305–310, 2000. Endophthalmitis Vitrectomy Study Group. Results of the Endophthalmitis Vitrectomy Study: A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 113(12):1479–1496, 1995. Herpetic Eye Disease Study Group. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. N Engl J Med 339(5):300–306, 1998. Kanski JJ, Nischal KK. Ophthalmology: Clinical Signs and Differential Diagnosis. Edinburgh: Harcourt Publishers Limited, 2000. Ostler HB. Diseases of the External Eye and Adnexa. Baltimore: Williams & Wilkins, 1993. Van Heuven WAJ, Zwaan J. Decision Making in Ophthalmology. St. Louis: Mosby, 2000.

22 Infectious Diarrhea Beth D. Kirkpatrick University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

As the intestine’s response to a wide variety of infectious and noninfectious insults, diarrhea is a common outpatient problem. Whether diarrhea is a self-limited inconvenience or a life-threatening systemic infection depends on both the cause and the host. This chapter focuses on the approach to the patient with diarrhea and discusses common pathogens and two special situations (antibiotic-associated diarrhea and diarrhea in the patient with acquired immunodeficiency syndrome [AIDS]). Terminology that overlaps with infectious diarrhea deserves clarification. Gastroenteritis, a term generally used to describe diarrhea with vomiting and abdominal pain, often is due to noninflammatory infections, but similar symptoms may be due to noninfectious causes. Food-borne disease frequently causes upper gastrointestinal symptoms after a short incubation period, especially from ingestion of preformed bacterial toxins (e.g., Staphylococcus aureus and Bacillus cereus). Dysentery is a constellation of symptoms due to infection with an invasive colonic pathogen and includes small-volume stools containing blood and mucus, usually in association with fever and severe abdominal cramping. Most infectious diarrheas are acquired through fecal-oral transmission of pathogens from water, contaminated food, or person-to-person contact. Food-borne disease or food poisoning represents a significant percentage of cases of infectious diarrhea and gastroenteritis. A wide variety of pathogens may cause food-borne diseases, which occur sporadically or in outbreaks. Globalization of the food supply has increased the risks for foodborne disease, including disease from newly recognized pathogens such as Cyclospora cayatenesis and Escherichia coli 0157:H7. The approach to the patient with infectious diarrhea requires an astute history, including clinical and epidemiological clues; assessment of severity of disease; and appropriate use of laboratory testing. In recognizing the increasing array of pathogens associated with diarrhea and the need for cost containment, practice guidelines on the management of infectious diarrhea have been published by the Infectious Disease Society of America.

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EPIDEMIOLOGICAL CHARACTERISTICS AND PATHOGENS OF INFECTIOUS DIARRHEA Common, often self-limited illness Elderly patients at risk for more severe and life-threatening illness Increased risk of acquisition of diarrhea: international travelers, those exposed to day care centers, immunocompromised hosts, hospitalized patients, and those engaging in oralanal sexual practices Most often due to food-borne transmission 81% of cases of food-borne disease due to nondiagnosed infection Norwalk and Norwalk-like viruses common causes 90% of diagnosed cases of food-borne diarrheal illnesses due to Campylobacter, Salmonella, Shigella spp., and Clostridium perfringens

2

EPIDEMIOLOGICAL CHARACTERISTICS

Infectious diarrhea is a global problem of enormous significance, particularly for children in less-developed nations and patients with immunocompromising conditions, such as AIDS. Throughout the world, diarrhea causes approximately 4–6 million deaths per year. Infectious diarrhea is thought to cause approximately 200 million cases of diarrhea in North American adults each year or 1.2–1.9 cases of diarrhea per person each year (children and adults). Most cases of diarrhea are self-limited and never reach medical attention. In contrast, select populations are at risk for severe and life-threatening disease. In the United States, 85% of deaths of diarrhea occur in the elderly. Examination of the risk factors and exposures to intestinal pathogens are essential in determining the cause of diarrhea, especially in a community or food-borne outbreak. Special groups at high risk for diarrhea illnesses include travelers, adults with exposure to infants and young children in diapers or day care, immunocompromised patients including those with AIDS and malignancies, hospitalized patients, patients taking antibiotics, and people engaging in sexual practices with oral-anal contact. Many of the food-borne diseases (‘‘food poisoning’’), including gastroenteritis, are caused by the same pathogens that cause infectious diarrhea. Approximately 76 million cases of food-borne disease occur annually in the United States, resulting in 325,000 hospitalizations and approximately 5000 deaths. Of interest, 81% of all food-borne illnesses are thought to be due to unknown pathogens. The elderly and patients with chronic diseases have increased susceptibility to these infections. In 1996 the Centers for Disease Control and Prevention (CDC) in cooperation with local state health departments and the United States Department of Agriculture established the Foodborne Disease Active Surveillance Network (FoodNet). This national program is designed to investigate and report food-borne illnesses in the United States. 3

PATHOPHYSIOLOGICAL CHARACTERISTICS

Diarrhea is caused by an alteration of fluid absorption and secretion by the small and/or large intestine. In health, approximately 10 liters of fluid enters the intestines daily. Of this fluid 99% is absorbed and <150 ml of water is lost in the stool. Mechanisms for diarrhea include osmotic water retention in the intestinal lumen, active electrolyte secretion, structural damage to the bowel wall, and increased intestinal motility. Pathogens may

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initiate diarrhea after adherence to intestinal epithelium (with or without mucosal damage), with mucosal invasion of epithelial cells and/or production of enterotoxins or cytotoxins. Toxins released by bacterial pathogens are often enterotoxins or cytotoxins; cytoskeletonaltering toxins and toxins with neural activity are also described. Enterotoxins stimulate net secretion into the intestinal lumen without histological evidence of intestinal damage. Vibrio cholerae, the classic example of enterotoxin-producing bacteria, causes a profuse watery diarrhea (cholera) via chloride and bicarbonate secretion into the lumen of the intestine. Strains of enterotoxigenic E. coli (ETEC) produce a heat-labile (LT) enterotoxin similar to cholera toxin as well as a heat-stable toxin (ST) that causes excess fluid secretion. Other organisms that produce secretory enterotoxins include Salmonella spp. and Shigella spp. (not S. dysenteriae). Cytotoxins produce intestinal cell or tissue damage, usually with cell death, and are often associated with bloody diarrhea or dysentery. Shiga toxin, produced by Shigella dysenteriae, is a well-described cytotoxin. E. coli 0157:H7 (enterohemorrhagic E. coli [EHEC]) also produces Shiga–like toxins and similar clinical disease. Pathogens classically associated with food poisoning such as Clostridium perfringens and Staphylococcus aureus also cause diarrhea in association with cytotoxin or enterotoxin production, respectively.

4

SELECTED PATHOGENS THAT CAUSE DIARRHEA AND FOOD-BORNE DISEASE

A wide diversity of enteric pathogens cause diarrhea and food-borne disease. In an outpatient practice, however, the majority of infections are caused by only a few pathogens. For example, approximately 90% of the documented (i.e., culture-proven) cases of food poisoning are caused by Campylobacter, Salmonella, and Shigella spp. and Clostridium perfringens. Select pathogens of particular importance are described later, and food-borne disease syndromes are described in Table 1.

Table 1 Food-Borne Diseases Incubation 1–6 Hours 8–16 Hours 8–16 Hours

Common symptoms Nausea, vomiting

Associated pathogens and toxinsa Preformed toxins of Bacillus cereus and Staphylococcus aureus Preformed toxins of C. perfringens, B. cereus Clostridium botulinum toxin

Abdominal cramps, diarrhea Nausea, vomiting, diarrhea, descending paralysis 16–48 Hours Fever, abdominal cramps, diarrhea Salmonella, Shigella, Campylobacter spp.; Vibrio parahemolyticus; Yersinia enterocolitica 16–72 Hours Abdominal cramps, watery diarETEC, V. cholerae and parahemolyticus, rhea Campylobacter, Salmonella, Shigella, Listeria spp. 24–48 Hours Gastroenteritis, headache Norwalk and Norwalk-like viruses 72–120 Hours Bloody diarrhea E. coli 0157:H7

a

ETEC, enterotoxigenic E. coli; E. coli 0157:H7, enterohemorrhagic E. coli.

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Kirkpatrick

Campylobacter Species

Campylobacter jejuni infection is the most common cause of documented (i.e., identified on culture) food-borne disease in the United States (2.4 million cases annually). The most commonly implicated foods include milk and undercooked poultry. Infection can occur year round but peaks in the spring and fall. Campylobacter spp. are curved aerobic gram-negative rods (GNRs). C. jejuni can invade the jejunum, ileum, and colon, causing a spectrum of illness from mild watery diarrhea to severe inflammatory enteritis or colitis. After an incubation period of 2–4 days, clinical symptoms begin with a prodrome of fever and headache, followed by diarrhea, malaise, abdominal pain, and myalgias. Symptoms concentrated in the right lower quadrant can mimic appendicitis. Presumptive diagnosis is made with phase-contrast microscopy that shows the characteristic motile curved bacterium. Culture of stool is performed with selective media, incubated under reduced oxygen content. Treatment is rarely necessary in normal hosts, except patients with systemic infection, severe diarrhea, or immunosuppression. A Reiter’slike reactive arthritis can occur in those who are human leukocyte antigen B27–(HLAB27)-positive. 4.2

Nontyphoid Salmonella Species

Salmonella spp. are facultative anaerobic GNRs and commensal bacteria of domesticated and wild animals. Nontyphoidal species include S. enteritidis and S. typhimurium. Agents of typhoid fever (S. typhi and S. paratyphi) do not generally cause a prominent diarrhea. Nontyphoidal Salmonella species cause an estimated 1.4 million cases of diarrhea and gastroenteritis annually. They are transmitted by contaminated food, usually poultry, eggs, beef, and pork. Eggs may be infected after contamination of the shells from infected chickens. Raw or partially cooked eggs have emerged as a significant source of salmonellosis. Other food sources have included contaminated orange juice, tomatoes, and alfalfa sprouts. Salmonella spp. infections are most common in the summer and fall months, in children less than 5 years of age, and in patients with altered intestinal flora or decreased gastric acid (from antacid and H2 blocker use), lymphoproliferative diseases, or AIDS. After an incubation period of 6–48 hours the disease manifests itself with abdominal pain, fever, chills, and diarrhea. Grossly bloody diarrhea is uncommon. The illness is usually self-limited with resolution within a week. Patients may continue to harbor Salmonella spp. in their stools for 4–6 weeks after resolution of symptoms. Approximately 0.2%– 0.6% of patients become long-term carriers, defined as having persistent Salmonella spp. infection after 1 year. The treatment of salmonellosis is a source of confusion and deserves special mention (see Table 7). In healthy adults without signs of systemic toxicity, salmonellosis is a selflimited infection and should not be treated with antibiotics. Treatment may increase the risk of becoming a Salmonella spp. chronic carrier and contribute to antibiotic resistance. However, Salmonella spp. have a propensity to invade vascular sites and can cause systemic toxicity in immunocompromised patients. Therapy is indicated for patients with any of the following: systemic toxicity or bacteremia, age below 6 months or above 50 years, prosthetic joints, heart valves, vascular grafts, severe atherosclerosis, malignancy, human immunodeficiency virus/AIDS (HIV/AIDS), or uremia.

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Shigella Species

Shigella spp. are aerobic GNRs. There are four major species/serogroups: serogroup A (Shigella dysenteriae, the agent of bacillary dysentery), B (S. flexneri), C (S. boydii), and D (S. sonnei, the most common species in the United States). Shigella spp. are extremely contagious: ingestion of <100 bacteria in some species can cause infection. Because of the small inoculum, shigellosis can be transmitted directly (from person to person) as well as through contaminated food. Raw vegetables, cheeses, and eggs are common sources of infections, which occur predominantly in the summer and fall seasons. Shigellosis is an inflammatory colitis, characterized by dysentery (small-volume stools with abdominal cramping, fever, and tenesmus). Systemic signs of fever, toxicity, and lower abdominal tenderness are often present, although bacteremia is rare. Routine stool cultures detect the organism and fecal leukocytes are present on direct examination of the stool. Unlike Salmonella spp. patients, all patients with confirmed shigellosis should be treated (Table 7). 4.4

Escherichia coli

Escherichia coli are aerobic GNRs that are normal inhabitants of the human small and large intestines. Strains of E. coli cause distinct clinical manifestations that are due to the different toxins and virulence factors produced. Enterotoxigenic E. coli (ETEC) produces a well-known syndrome, traveler’s diarrhea, and is a common cause of diarrhea in less-developed countries (see Chapter 40). In healthy individuals this infection is characterized by watery diarrhea with nausea and abdominal cramping but is self-limited. Enterohemorrhagic E. coli (EHEC) strains cause a hemorrhagic colitis associated with the hemolytic uremic syndrome in children. EHEC serotype E. coli 0157:H7 has been associated with several large-scale food and water outbreaks. Unlike the other strains of E. coli, EHEC is commonly described in developed countries. Enteroinvasive E. coli (EIEC) cause a Shigella sp.–like dysentery. Enteropathogenic E. coli (EPEC) are an important cause of persistent diarrhea in young children. 4.5

Norwalk and Norwalk-Like Viruses

Norwalk and Norwalk-like viruses are among the most common etiological agents causing noninflammatory diarrhea in adults (rotavirus is much more common in children). This broad group of viruses causes food-borne disease without seasonal variation, often in institutional settings and associated with undercooked shellfish and contaminated water. Norwalk-type viruses, although not usually isolated in the clinical laboratory, are by far the most common cause of gastroenteritis, estimated at 23 million cases annually. After an incubation period of 1–3 days, clinical illness is abrupt in onset. Patients have abdominal cramps, vomiting, fever, and watery diarrhea. Treatment is supportive, but symptoms may be shortened with the use of bismuth subsalicylate (Pepto-Bismol). Resolution occurs after 48–72 hours.

5 5.1

CLINICAL EVALUATION History and Physical Examination

The initial clinical evaluation of the patient with diarrhea should determine whether the patient is systemically ill, whether he or she is moderately to severely dehydrated, and

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EVALUATION AND MANAGEMENT Approach to the patient with diarrhea (Figure 1) Elderly and immunocompromised patients at risk for severe illness (fever, blood or mucus in stool, >6 stools/day) Epidemiological clues (Table 3) Diarrheal syndrome (Table 4) Chronic diarrhea (>2 weeks) usually noninfectious of parasitic (Table 2) Diagnostic testing (Table 5) Yield of stool culture low (<2%) without symptoms/signs of inflammatory diarrhea Management Oral rehydration (Table 6) Antibiotics (Table 7) For confirmed pathogens Empirically for International travelers Patients with acute inflammatory diarrhea Suspected giardiasis

whether hospitalization or empirical antibiotic therapy is needed (see Figure 1). Most mild cases of diarrhea are managed at home without physician involvement. Specific patient populations require close medical evaluation: the immunocompromised or elderly; any patient with fever, blood, or mucus in the stool; and individuals with illnesses that last over 48 hours or with profuse diarrhea (more than six stools in 24 hours). Patients with persistent diarrhea (>14 days) or chronic diarrhea (>30 days) usually have illnesses of lower toxicity and are less likely to be infectious. Protozoan infections, including Giardia lamblia infections, are common causes of persistent and chronic diarrhea (see Table 2 for a comprehensive list of causes). A broad range of pathogens cause chronic diarrhea in immunocompromised patients with AIDS (discussed later). Evaluation of the patient includes a detailed history of the symptoms of the diarrheal illness, to help determine the severity of clinical illness and possible microbial causes. Patients should be asked about the onset and duration of diarrhea and associated fever, cramps, tenesmus, or vomiting. Additional important clinical clues to the diagnosis of diarrhea include a food and water intake history, timing of symptoms (duration and onset), season, geographical location, medications, sexual practices, and history of chronic illnesses and hospitalizations (see Table 3). Physical examination of the patient with diarrhea is often nonspecific. Careful evaluation of the vital signs, including orthostatic blood pressure and heart rate, yields important clues to the degree of dehydration. Skin tenting and mucous membrane dryness may not be reliable indicators of dehydration in an adult. In the elderly, lethargy is often a manifestation of severe dehydration. Fever and tachycardia may indicate systemic infection. Abdominal tenderness on examination is often found with inflammatory colitis. Most diarrheal illnesses can be organized into syndromes, classified by common symptoms, frequency and volume of stools, and infectious causes (see Table 4). This approach often helps guide diagnostic tests and management.

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Figure 1 Approach to the patient with diarrhea. Patients should be assessed for degree of toxicity and dehydration. Risk factors and epidemiological clues should be gathered from the history and physical examination. Most patients with acute diarrhea do not need laboratory work-up or antibiotic therapy. Patients with systemic toxicity or inflammatory diarrhea should be rapidly evaluated with fecal leukocytes and stool cultures. Empirical therapy may be begun, though caution is suggested since some pathogens (e.g., Escherichia coli 0157:H7) should not be treated with antibiotics. (1) Fecal leukocytes can be identified by direct stain of the stool or by demonstration of lactoferrin. (2) Ova and parasites should be added if risk for exposure to Giardia spp., homosexual sex, or international travel. (3) Stool should be sent for C. difficile toxin assay for those who are currently on or recently received antibiotics. O&P, ova and parasite; ELISA, enzyme-linked immunosorbent assay.

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Table 2 Causes of Chronic Diarrhea Infectious or presumed infectious Protozoa (e.g., Cryptosporidium, Giardia spp.) ‘‘Bacterial overgrowth’’ syndrome Tropical sprue Whipple’s disease Intestinal tuberculosis Noninfectious Noninflammatory Laxatives, alcohol Antibiotics Celiac sprue Partial bowel obstruction or resection Hormone-producing tumors (e.g., carcinoid, gastrinoma, medullary carcinoma of the thyroid) Addison’s disease Lactase deficiency Irritable bowel syndrome Pancreatic exocrine deficiency Food allergies Inflammatory Inflammatory bowel disease Collogenous colitis Eosinophilic gastroenteritis Radiation enterocolitis Chronic graft-versus-host disease Behc¸et’s syndrome

5.2

Diagnostic Testing

A specific microbial diagnosis and tailored antimicrobial therapy are the goal of the diagnostic work-up for diarrhea (see Table 5). This is increasingly important in light of increasing bacterial antibiotic resistance (particularly in Salmonella, Shigella, and Campylobacter spp.), the risks of empirical therapy [i.e., hemolytic-uremic syndrome after antibiotics are given for E. coli 0.157:H7, prolongation of the Salmonella spp. carrier state and suprainfections after antibiotic use (C. difficile colitis, Candida spp. vaginitis)]. With these principles in mind, however, diagnostic tests are not always indicated, useful (e.g., viral pathogens), or cost-effective. Clinical evaluation and examination of the patient also determine when empirical therapy is necessary before diagnostic test results are available (see later discussion). Routine stool cultures, using a variety of agars, are designed to detect Salmonella, Shigella, Campylobacter, and Yersinia spp. and E. coli 0157:H7. Vibrio spp. can be detected when stool is plated onto specific (thiosulfate-citrate-bile salts [TCBS]) media. When stool cultures are indiscriminately ordered for patients with diarrhea, however, the yield of these cultures is very low (<2% in patients with acute diarrhea) and the costs high. Stool cultures should be limited to those cases of inflammatory diarrhea suspected on the basis of fever, tenesmus, and bloody/mucoid stools. Inflammation can be confirmed

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Table 3 Clues to the Diagnosis of Infectious Diarrheaa History and epidemiological features History Antacid or H2 blocker use Recent antibiotic use or hospitalization Chronic care facilities Liver disease Epidemiological risk Travel to a developing region Travel to mountainous areas Contact with children in diapers Male homosexual Diarrhea after social gathering Contact with domestic and agricultural animals Consumption of raw and undercooked shellfish a

Pathogens Increased risk for all enteric pathogens C. difficile C. difficile, Aeromonas spp., viral pathogens Vibrio spp. Enterotoxigenic E. coli, Shigella, Salmonella, Campylobacter, Giardia, Cholera spp. Giardia, Cyclospora spp. Cryptosporidium, Giardia, Campylobacter, Shigella spp.; Rotavirus; Norwalk virus HSV, N. gonorrhoeae, Campylobacter spp., amebiasis Salmonella, Campylobacter spp.; Norwalk virus; Bacillus cereus; Clostridium perfringens Yersinia enterocolitica Vibrio parahaemolyticus

HSV, herpes simplex virus; H2, type 2 histamine.

by documenting the presence of fecal leukocytes by Gram or methylene blue staining of diarrhea or detecting the presence of neutrophils by lactoferrin testing (Leukotest; Techlab). Stool should be tested for E. coli 0157:H7 in all patients who have acutely bloody diarrhea. Routine stool cultures (as well as ova and parasite exams) should be avoided in hospitalized patients in whom diarrhea develops after 3 or more days of hospitalization. This ‘‘3day rule’’ may not apply to neutropenic patients, the elderly, and those with AIDS. Examination of stool for parasites should be limited to patients with an appropriate clinical illness or epidemiological risk. Parasitic intestinal infection should be considered in those with persistent diarrhea (>2 weeks); exposure to infants or day care; potential exposure to a water-borne outbreak, including shallow home wells; international travelers; and homosexual men. Ova and parasite (O&P) exams are useful in the identification of helminth eggs, G. lamblia, and Entamoeba histolytica (amebiasis), but not of other protozoan pathogens such as Cryptosporidium or Cyclospora spp. or Isospora belli. In the United States, the most common pathogen detected on O&P examination is G. lamblia. A downfall of the inappropriate use of ova and parasite examinations is the confusion caused by the identification of a wide variety of protozoa that are believed to be nonpathogenic (e.g., Blastocystis hominis and Entamoeba coli). Commercially available diagnostic techniques such as enzyme immunoassays may be more sensitive than microbial studies and are available for the evaluation of Cryptosporidium spp., G. lamblia, and E. histolytica. Viral cultures are rarely indicated in the assessment of infectious diarrhea. If diarrhea is of public health importance (i.e., the initial case in a potential outbreak), a microbial cause should always be sought and the health department notified.

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Table 4 Infectious Diarrhea Syndromes Syndrome

Common symptoms

Location

Select microbial causesa Many noninflammatory enteric pathogens, including viruses, Giardia spp., and ETEC Shigella, Campylobacter, Salmonella spp.; E. coli 0157:H7; EIEC; E. histolytica; C. difficile

Acute watery diarrhea

Large-volume stools Abdominal cramps

Small intestine

Colitis, dysentery

Frequent small-volume stools Tenesmus Blood and mucus in stools Fever, cramps Same as colitis

Colon

Proctitis

Persistent (>14 days) and chronic (>4 weeks) diarrhea

Gastroenteritis (in foodborne disease) a

Variable, usually watery diarrhea May have signs of weight loss Vitamin deficiency Vomiting, nausea Watery diarrhea

Rectum

Small intestine and/or colon

Stomach, small intestine

N. gonorrhoeae, herpesviruses, Chlamydia trachomatis, syphilis Protozoa (Cryptosporidium, Cyclospora, Isospora, Microsporidium spp.), EPEC Preformed toxins of S. aureus, B. cereus, and viral pathogens

ETEC, enterotoxigenic E. coli; E. coli 0157:H7, enterohemorrhagic E. coli; EPEC, enteropathogenic E. coli; EIEC, enteroinvasive E. coli.

Table 5 Diagnostic Tests Pathogen/marker

Diagnostic testa

Salmonella spp. Shigella spp. Campylobacter spp. E. coli 0157:H7

Routine stool cultures, including special media for Campylobacter spp. (at 42 C), E. coli 0157:H7

Vibrio cholerae Yersinia species C. difficile

Stool culture for Vibrio spp. (TCBS agar) Stool culture with cold enrichment C. difficile toxin assay or culture

Cryptosporidium parvum Cyclospora species Isospora belli

Acid-fast stain (Kinyoun) of stool

Giardia lamblia Cryptosporidium parvum

Stool antigen assay (may be offered together or as separate tests)

Giardia lamblia Entamoeba histolytica

Ova and parasites

Fecal leukocytes Fecal blood

Lactoferrin test, stool stained for WBC Guaiac testing of stool

a

TCBS, thiosulfate-citrate-bile salts; ELISA, enzyme linked immunosorbent assay; WBC, white blood cells.

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MANAGEMENT

6.1

Rehydration

The cornerstones of therapy are the restoration and maintenance of adequate hydration. This is particularly important in the elderly or immunocompromised patient. In otherwise healthy patients with mild to moderate diarrhea, increasing intake of most fluids is usually adequate to replace fluid losses. In moderate to severe diarrhea, juices and sports drinks may not adequately replace electrolyte losses. For dehydrating diarrhea, aggressive rehydration with electrolyte solutions or intravenous fluids is required. The formulation of ‘‘oral rehydration solutions’’ as determined by the World Health Organization (WHO) includes the addition of sodium, potassium, chloride, citrate, and glucose to meet fluid and electrolyte needs. Home recipes, which approximate WHO recommendations, are listed in Table 6. Use of these solutions may help preclude the need for intravenous fluid administration. 6.2

Antimotility Agents

Antimotility drugs, such as loperamide (Imodium), can be used safely for symptomatic relief in most cases of acute diarrhea. The number of diarrheal stools is reduced by 80% with this agent. Lomotil (diphenoxylate hydrochloride; atropine sulfate) should be avoided because of the central opiate effect, risk of overdosage, and anticholinergic effects of the atropine, including urinary retention, mucosal and cutaneous dryness, tachycardia, and hyperthermia. All antimotility drugs should be avoided when there are symptoms of dysentery (fever, cramps, blood and pus in stool). In general, when fever or other systemic signs are present with diarrhea, antimotility drugs should only be used concurrently with appropriate antibiotic therapy. The antisecretory properties of salicylate in bismuth subsalicylate (Pepto-Bismol) can decrease diarrheal stools by 50% and are effective in decreasing symptoms of vomiting due to enteric viral infections. Salicylate overdose and bismuth encephalopathy have occurred after excessive use of bismuth subsalicylate. 6.3

Antibiotic for Specific Pathogens

Specific antimicrobial therapy is used when a pathogen is confirmed and in selected cases of empirical treatment (discussed later). Agents and dosages are listed in Table 7. Diagnosis and treatment of Entamoeba histolytica are reviewed in Chapter 32.

Table 6 Home Recipes for Oral Rehydration Solutions Recipe 1 3/4 teaspoon salt 1 teaspoon baking soda 1 Cup orange juice or two bananas 4 Tablespoons sugar Add to 1 liter of clean water Recipe 2 Mix in one cup

Mix in another cup Drink alternately from the two cups

8 ounces of orange or apple juice 1/2 teaspoon of honey 1 pinch salt 8 ounces clean water 1/4 teaspoon baking soda

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Table 7 Therapya Pathogen

Antimicrobial agent

Special circumstances

Bacterial Nontyphoid Salmonella species

Not recommended routinely

Campylobacter species

Erythromycin 500 mg PO bid ⫻ 5 days for severe disease Co-trimoxazole ds PO bid ⫻ 3 days (if sensitive) Ciprofloxacin 500 mg bid ⫻ 3 days, if resistant

Shigella species

Escherichia coli ETEC

E. coli 0157:H7 Yersinia species

Vibrio cholerae

Clostridium difficile

Ciprofloxacin 1.0 g PO ⫻ 1 or 500 mg PO bid ⫻ 3 days Not recommendedc Antibiotics not required

Doxycyline 300 mg PO ⫻ 1 or Ciprofloxacin 1 g PO ⫻ 1 Metronidazole 500 mg PO tid ⫻ 10–14 days

Ciprofloxacin 500 mg PO bid for 5 days Treat 14 days if patient immunocompromisedb

Treat immunocompromised patient ⫻ 7–10 days

For serious infections or bacteremia: ciprofloxacin IV or PO or Doxycycline with aminoglycoside

For severe infections, vancomycin 125 mg PO qid ⫻ 10–14 days Metronidazole 500 mg IV q8hd ⫻ 10–14 days

Parasitic Cryptosporidium parvum

Giardia lamblia Cyclospora cayentanenis Isospora belli a

No therapy useful Self-limited illness in immunocompetent hosts Metronidazole 250 mg PO tid ⫻ 5–10 days Co-trimoxazole DS bid ⫻ 3 days Co-trimoxazole 2 DS PO bid ⫻ 2–4 wk

Immunocompromised hosts: try paromomycin 500 mg PO tid ⫻ 2–4 wk

ETEC, enterotoxigenic E. coli; E. coli 0157:H7, enterohemorrhagic E. coli; DS, double-strength. See text for recommendations. c Increased risk of hemolytic uremic syndrome. d If unable to take orally. b

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Empirical Therapy

Several practice guidelines including those of the American College of Gastroenterology (1997) and the Infectious Disease Society of America (Guerrant et al., 2001) support the use of empiric antibiotic therapy in the treatment of diarrhea in three specific patient populations: (1) patients with traveler’s diarrhea, (2) suspected giardiasis, and (3) patients with acute inflammatory diarrheas. Traveler’s diarrhea is frequently due to enterotoxigenic E. coli. In acute, moderate, to severe travel-related diarrhea, empirical therapy with a quinolone antibiotic is appropriate, without stool culture (see Table 7). In giardiasis, patients often have watery diarrhea that lasts 10 days to more than 4 weeks but do not have fever or symptoms of dysentery. Empirical therapy with metronidazole may be considered in these patients. Finally, patients with fever and acute inflammatory diarrhea (confirmed by lactoferrin testing) and signs of systemic illness should also be considered for empirical antibiotic therapy, usually with ciprofloxacin 500 mg bid orally, while confirmatory microbiological results are pending. This decision should be carefully made in cases of bloody diarrhea that may be due to E. coli 0157:H7.

7 CLOSTRIDIUM DIFFICILE AND ANTIBIOTIC-ASSOCIATED DIARRHEA Almost all antibiotics can cause diarrhea. The majority of cases are benign and resolve on discontinuation of the antibiotic. The organism best known to cause antibiotic-associated diarrhea (AAD) is Clostridium difficile, the second most frequently isolated enteric pathogen, after Campylobacter jejuni. C. difficile accounts for 10%–20% of cases of AAD and is the most common cause of nosocomial diarrhea. However, most cases of AAD, especially in outpatients, are not due to C. difficile. The cause of non–C. difficile AAD has not been fully elucidated, although both S. aureus and Candida species have been implicated in association with altered metabolism of carbohydrates and fatty acids.

ANTIBIOTIC-ASSOCIATED DIARRHEA Can be caused by any antibiotic Often resolves with discontinuation of antibiotic 10%–20% Due to C. difficile C. difficile–associated diarrhea Increased risk in elderly, immune suppressed, hospitalized, and those undergoing gastrointestinal (GI) surgery Abdominal pain, fever, blood/mucus in stool Leukocytosis Fecal leukocytes possibly present Diagnosis by immunoassay on stool for toxin A and B, endoscopy, or stool culture Therapy (Table 8) Relapse in 20% of patients Associated with Continued antibiotic use Elderly, recent GI surgery, renal failure patients

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C. difficile is a toxin-producing obligate anaerobic gram-positive bacillus. It is not part of the normal adult intestinal flora; only 1%–3% of normal hosts are colonized with C. difficle. C. difficile is able to survive in the environment in a spore form for up to 5 months on a hospital floor. The organism is thought to be acquired from the environment after alteration of protective gut flora by antibiotics rather than from antibiotic-enhanced overgrowth of a natural carrier state. The majority of hospitalized patients who acquire C. difficile are clinically asymptomatic and undiagnosed, thus representing a reservoir for nosocomial transmission. Almost all antibiotics have been linked to C. difficile–associated diarrhea (CDAD), including vancomycin and metronidazole, the usual treatments for the infection. The most commonly implicated agents are clindamycin and the cephalosporins. Risk factors for acquiring CDAD include advanced age, immunosuppression, hospitalization, and alteration of intestinal flora or motility. A strong link between gastrointestinal surgery, hospitalization, and narcotic-impaired gastrointestinal motility has been made with pseudomembraneous colitis (PMC). The pathogenesis of CDAD depends on disruption of normal bowel flora by antibiotics, acquisition of C. difficile, and secretion of toxins A (an enterotoxin) and B (a cytotoxin). After attaching to intestinal epithelium, the toxins cause disruption of the cellular skeleton, cell death, mucosal inflammation, and increased intracolonic secretion of fluid. Toxin A is thought to cause most of the clinical manifestations of CDAD, but synergy of the two toxins may be necessary for disease expression. 7.1

Clinical Manifestations

Symptoms of AAD often begin 5–10 days after the onset of antibiotic use. The majority of patients have mild diarrhea, which abates spontaneously with discontinuation of the antibiotic. Patients with CDAD often experience more severe symptoms and signs. Crampy abdominal pain, nausea, and vomiting are common. Diarrhea may occur 10–20 times a day and is often associated with mucus and blood in the stool. Fever and leukocytosis (up to 20,000 white blood cells/mm3) is expected. In leukemoid reactions the white blood cell (WBC) count may exceed 40,000/mm3. Cases of toxic megacolon or colonic perforation are rare. Clinically these patients may have rebound tenderness and lack of bowel sounds on physical examination. 7.2

Diagnosis

CDAD should be suspected in all patients in whom diarrhea develops while they are receiving antibiotics or shortly afterward. The presence of fever, systemic toxicity, and leukocytosis should further raise concern. Inflammatory cells (as indicated by either lactoferrin or fecal leukocyte examination) may be present in the stool, although a negative test finding does not exclude the diagnosis of CDAD. Megacolon with mucosal thumbprinting may be seen on plain radiograph. Computed tomography (CT) scans may reveal colonic thickening and pericolonic inflammation. CT scans may be especially helpful in those who have abdominal pain without diarrhea and right-sided colonic involvement. Diagnosis of CDAD by visualization of pseudomembranes is useful, and sigmoidoscopy is often adequate. Colonoscopy may be needed, however, if right-sided involvement of the colon is suspected. On endoscopy, most CDAD patients have normal or mildly inflamed mucosa. In those with colitis, friable, red, and edematous mucosa is found in the left colon in 70%–95% of cases. Classic patchy pseudomembranous plaques are 2–5 mm and are limited to the colon. The pseudomembranes are composed of neutrophils, sloughed epithelial cells, mucus, and fibrin. Though pseudomembranes may be extensive, histolog-

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ical findings do not necessarily correlate with severity of symptoms. CDAD should be differentiated from other pathogens that cause a dysentery-like illness, inflammatory bowel disease, and ischemic colitis. With the use of selective media, culture for C. difficile is a sensitive test but is not performed in many hospital labs. Since many hospitalized patients are colonized with C. difficile, a positive culture result is not equivalent to clinical disease. Latex agglutination assays for detection of the C. difficile bacterium in stool are rapid and simple to perform but are not sensitive or specific and do not differentiate toxin-producing from non-toxinproducing strains. Clinically, the diagnosis of CDAD is usually made by demonstrating the presence of C. difficile toxin A or B in stool from a patient with diarrhea. The gold standard toxin assay is a test for tissue cytotoxicity. Although sensitive and specific, this assay is cumbersome and expensive. Most clinical laboratories use a straightforward enzyme-linked immunosorbent toxin assay (ELISA) to detect toxin A or A and B. These tests are very specific but miss 10%–20% of cases. Some authors have suggested that repeating the ELISA two or three times may increase the sensitivity. Assays that detect both A and B toxins have a higher sensitivity than those assays that detect only toxin A. 7.3

Treatment

The initial step in treatment of ADD is to discontinue antibiotic therapy whenever possible. Up to 25% of patients respond to this measure alone. Asymptomatic carriers of C. difficile should not be treated, since colonization is usually transient. The initiation of therapy for CDAD should depend on the clinical severity of the illness and confirmation of the diagnosis by ELISA, cytotoxicity assay, or endoscopy. The presence of fecal leukocytes or lactoferrin in a patient with a history compatible with CDAD may warrant empirical therapy while awaiting laboratory confirmation. Therapy is aimed at using antibiotics effective against C. difficile, eliminating toxins, and restoring gut flora (see Table 8). Antimotility agents such as Imodium should be avoided.

Table 8 Treatment of Clostridium difficile Colitis Drug Metronidazole orally Vancomycin orally Bacitracin

Metronidazole intravenouslyc Vancomycin intrarectally a

Costsa

Comment

500 mg qid ⫻ 7–10 days 750 mg tid ⫻ 7–10 days 125 mg qid ⫻ 7–14 days

$12.00–$18.00 $19.00–$28.99 $239.00–$478.00

500 mg qid ⫻ 7–10 days 20,000–25,000 U PO qid ⫻ 10 days

$602.00–$860.00 $76.00

Considered the drug of choice For patients unable to tolerate metronidazoleb Severely ill patients Less effective than metronidazole or vancomycin Associated with more relapses Inability to take oral antibiotics Less effective than oral

Dose

500 mg q8h ⫻ 7–10 days 500 mg q4–8h ⫻ 7–10 days

Average wholesale price. 2000 Drug Topics Red Book. Continued alcohol use or pregnancy, severe nausea, and vomiting. c Add oral vancomycin by nasogastric tube if possible. b

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Both metronidazole and vancomycin are highly efficacious. Metronidazole is less expensive and generally considered the drug of choice. In very ill patients, however, highdose oral vancomycin is preferred. When oral antibiotics cannot be used, intravenous (IV) metronidazole is the best choice since IV vancomycin penetrates the colon poorly and should not be used. Nasogastric tube delivery of vancomycin and vancomycin retention enemas have been used with success. With successful therapy, patients often feel better within 2–3 days with cessation of diarrhea within 1 week. Results of tests for toxin, however, remain positive for weeks, and a ‘‘test for cure’’ is not indicated. Surgical intervention is infrequently necessary but is a critical step for patients with toxic megacolon unresponsive to antibiotics or perforation. The operative mortality rate of patients with perforations due to severe colitis is high. Despite appropriate antibiotic therapy, approximately 20% of patients with C. difficile colitis relapse after discontinuation of therapy. Risk factors for CDAD relapse include the continued use of antibiotics despite the presence of C. difficile infection, advanced age, recent abdominal surgery, chronic renal failure, and community-acquired disease. Retreatment with the same regimen is effective in about half of these patients. A variety of other approaches are used for patients with repeated relapses, including ‘‘pulsing’’ or tapering of vancomycin, combinations of vancomycin and rifampin, use of anion-exchange resins (cholestyramine), rectal infusions of bacteria or feces (often avoided for aesthetic reasons), and oral probiotics such as Lactobacillus GG and Saccharomyces boulardii to restore normal flora. Except Lactobacillus sp. therapy, is the only therapy approaches that has been subjected to clinical trial. For patients admitted to the hospital, infection control is very important. The main techniques of preventing nosocomial spread are isolation of patients, handwashing (before and after patient contact), contact precautions with gloves and gowns, and environmental decontamination. 8

ACQUIRED IMMUNODEFICIENCY SYDROME

Approximately 50% of AIDS patients have gastrointestinal tract involvement with a wide variety of pathogens. In the early 1990s, 30%–60% of patients with AIDS reported diarrhea, frequently associated with malnutrition and progressive weight loss. Unlike in other populations, diarrhea is often (⬃30%) due to more than one pathogen and specific causes are difficult to determine. The use of highly active antiretroviral therapy (HAART) has

ACQUIRED IMMUNODEFICIENCY SYNDROME–RELATED DIARRHEA Approach to patient (Figure 2) Common with protease inhibitors Infection associated with advanced immune suppression (CD 4 < 100) Increased risk for nontyphoidal Salmonella spp. Protozoan infections common cause of chronic, noninflammatory diarrhea Cryptosporidium, Cyclospora, Isospora spp. diagnosed with acid-fast stain (Kinyuon) of stool Microsporidia diagnosed by biopsy/electron microscopy, histopathological evaluation, or stool trichrome stain

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Figure 2 Approach to the patient with AIDS and diarrhea. Patients with advanced immune suppression are at highest risk for infectious diarrhea. Protease inhibitors commonly cause diarrhea. If there are signs of an inflammatory process (fever, fecal leukocytes) in a patient with acute-onset diarrhea, then empirical therapy with ciprofloxacin should be initiated. If the diarrhea is persistent and undiagnosed, then upper endoscopy for parasites or mycobacterium pathogens should be done. Upper or lower endoscopy with biopsy may be needed to make a diagnosis. (1) Patients with CD4 >200–300 cells/mm3 usually can be managed as immunologically normal hosts (Figure 1). (2) Short duration of several days; may last up to 14 days. (3) More than 14 days. (4) Large-volume, watery diarrhea without blood or mucus. (5) Small, frequent stools with tenemus; blood or mucus may be present. AIDS, acquired immunodeficiency syndrome; EM, electron microscopy; O&P, ova and parasite; AFB, acid-fast bacillus; CMV, cytomegalovirus.

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markedly decreased the incidence of gastrointestinal opportunistic infections. However, debilitating diarrhea can be caused by HAART, especially as a result of the use of protease inhibitors. Figure 2 demonstrates a basic algorithm for evaluating acute diarrhea in patients with AIDS. Several pathogens are more common in patients with AIDS, predominantly as a result of changes in cell-mediated immunity. Leading causes of diarrhea in patients with AIDS include cytomegalovirus, Cryptosporidium spp., Microsporidium spp., E. histolytica, G. lamblia, Salmonella spp., Campylobacter spp., Shigella spp., C. difficile, Vibrio parahaemolyticus, and Mycobacterium spp. Before the era of HAART, Cryptosporidium parvum infected up to 20% of patients with very low CD4 counts (<100 cells/mm3). It frequently causes a chronic profuse watery diarrhea and was associated with dehydration, weight loss, and a poor prognosis. Diagnosis of Cryptosporidium sp. is made through acid-fast stain or auramine-orange stain of the stool or by stool ELISA to Cryptosporidium spp. antigen. Other protozoan pathogens including Isospora belli and Cyclospora spp. cause a similar chronic illness and also are diagnosed by acid-fast stain. Unlike C. parvum, however, both Cylcospora spp. and Isospora spp. can be treated with co-trimoxazole. Microsporidium spp. also cause a watery diarrhea but cannot be seen under light microscopy. Diagnosis of microsporidiosis requires intestinal biopsy analysis by electron microscopy or chemofluorescent stains. Nontyphoidal Salmonella spp. are 20-fold more common in patients with AIDS and produce a more severe diarrheal illness. Cytomegalovirus is the most common viral opportunistic infection in patients with AIDS (affecting up to 44% of patients before HAART therapy) and a common cause of colitis and diarrhea (12%–45% of cases) in patients with advanced AIDS. Enteric viruses such as calcivirus, picornavirus, and adenovirus may cause up to 12% of cases of diarrhea in HIV-positive patients. In addition to patients with low CD4 counts, homosexual men engaging in anal sexual activities are at risk for a variety of enteric and sexually transmitted pathogens, including G. lamblia, E. histolytica, Campylobacter spp., Shigella spp., N. gonorrhoeae, and herpes simplex virus. BIBIOGRAPHY Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 346:334–339, 2002. Centers for Disease Control and Prevention. Diagnostics and management of food-borne illness: A primer for physicians. MMWR Morb Mortal Wkly Rep 50(RR-1):241–246, 2001. Cheney DP, Wong KH. Acute infectious diarrhea. Med Clin North Am 77(5):1169–1196, 1993. DiJohn D, Levine M. Treatment of diarrhea. Infect Dis Clin North Am 2(3):719–745, 1998. Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, Tauxe RV, Heennessey T, Griffin PM, DuPont H, Sack RB, Tarrp Neill M, Nachamkin I, Reller B, Osterholm MT, Bennish ML, Pickering LK. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis 32:331–351, 2001. Mead PS, Slutsker L, Dietz V. Food-related illnesses and death in the United States. Emerg Infect Dis 5:607–625, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

23 Hepatitis Jayant A. Talwalkar and Michael R. Charlton Mayo Clinic and Foundation, Rochester, Minnesota, U.S.A.

1

INTRODUCTION

Viral hepatitis is a common cause of acute and chronic liver disease in the United States, producing substantial morbidity and mortality rates. The lion’s share of the morbidity and mortality associated with viral hepatitis occurs in patients with chronic rather than acute disease. The ability to diagnose and treat viral hepatitis efficiently has importance for both the individual and public health sector. This chapter is intended to review the general concepts associated with the initial recognition and evaluation for viral hepatitis in the ambulatory care setting.

2

APPROACH TO THE PATIENT WITH ABNORMAL LIVER TEST RESULTS

A diagnosis of viral hepatitis is most commonly made during the evaluation of abnormal serum liver biochemical results. Thorough history and physical examination are cornerstones in the evaluation of most medical conditions and are particularly important in the evaluation of abnormal liver biochemical findings. Documenting a history of blood or blood product transfusion before 1992, a frequent mode of acquisition for chronic viral hepatitis, is especially important. Review of all recent and long-standing medications including nonprescription drugs such as vitamins and herbal preparations is also essential. A thorough family history determines the level of suspicion of disorders such as genetic hemochromatosis, ␣1-antitrypsin deficiency, and Wilson’s disease. Social history is important to determining the potential impact of hepatotoxins such as alcohol, illicit drugs, environmental or work exposures, and sexually transmitted diseases, e.g., hepatitis B through anal intercourse. Exposure to these risk factors is best elicited through direct questioning. Initial laboratory investigations of an individual with abnormal liver biochemical results should include a complete blood count with differential and a serum electrolyte panel, including fasting plasma glucose and serum creatinine levels. The liver profile itself should include determination of: serum aspartate (AST, formerly SGOT) and alanine (ALT, formerly SGPT) aminotransferases, total and direct bilirubin, and alkaline phosphatase. Prothrombin time (PT or international normalized ratio [INR]) and albumin are useful to characterize hepatic synthetic function. Other blood tests that are essential in the initial 455

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PATIENT WITH ABNORMAL LIVER TEST RESULTS History Blood transfusion Genetics ␣1-Antitrypsin deficiency Wilson’s disease Hemachromatosis Hepatotoxins Alcohol Illicit drugs Environmental/work Sexually transmitted diseases, human immunodeficiency virus (HIV) Medications Laboratory Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin International normalized ratio (INR), albumin Fasting iron, total iron binding capacity (TIBC), ferritin Ceruloplasmin ␣1-Antitrypsin phenotype Antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), and antimitochondrial antibody (AMA) Serum protein electrophoresis Imaging Sonography Referral as needed for Endoscopic retrograde cholangiopancreatography (ERCP) Biopsy

evaluation of persistently abnormal liver biochemical findings include fasting iron, total iron binding capacity (TIBC), and ferritin to exclude hemochromatosis; ceruloplasmin to screen for Wilson’s disease; ␣1-antitrypsin phenotype studies to exclude ␣1-antitrypsin deficiency; antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), and ␥globulin level by serum protein electrophoresis to screen for autoimmune hepatitis; antimitochondrial antibody (AMA) to screen for primary biliary cirrhosis; and hepatitis serological evaluations (discussed later). An increasingly frequent diagnosis to which persistently abnormal liver biochemical results are attributed is nonalcoholic steatohepatitis (NASH), also referred to as nonalcoholic fatty liver disease. No specific serum marker currently exists to identify NASH; however, central obesity, hyperlipidemia, and noninsulin-dependent diabetes mellitus are frequently associated with this disorder. Imaging by abdominal ultrasound is valuable to exclude biliary tree abnormalities as well as being highly sensitive for the detection of hepatic steatosis. Further characterization of biliary abnormalities by endoscopic retrograde cholangiopancreatography (ERCP) is often required to exclude diseases such as primary sclerosing cholangitis that may initially be detected through asymptomatic abnormal liver biochemical findings.

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Nodularity and/or reduced liver size as well as splenic enlargement are other features of advanced liver disease that may be detected on ultrasound examination of the abdomen. If abnormal serum liver test results have been documented for more than 2 months, referral for liver biopsy should be considered. Although a diagnosis can be strongly suggested by noninvasive testing, the performance of liver biopsy is often necessary for establishing a definitive diagnosis, staging the extent of liver disease, and estimating prognosis in the setting of persistently abnormal liver biochemical results.

3

VIRAL HEPATITIS

Despite a recent flurry of pretenders, only five major hepatotropic viruses that cause acute and chronic hepatitis have been identified. They are hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV). 3.1

Hepatitis A Virus

Hepatitis A virus (HAV) has been associated with up to 35% of cases of acute viral hepatitis in developed nations. HAV is a picornavirus (very small ribonucleic acid– [RNA]-based virus), similar in composition to the enteroviruses. The exact pathogenesis of acute liver injury in HAV is unknown. Transmission is predominantly from person to person by the fecal-oral route and from ingestion of contaminated food or water. Infected sewage may contaminate filter feeders, such as shellfish, which may then produce outbreaks at locations remote form their point of harvest. Parenteral transmission of HAV is extremely rare. The epidemiological characteristics of HAV are noted for large, nationwide outbreaks that occur every 10 years. A gradual decline in the overall incidence of HAV infection has been observed since 1989. Conversely, increasing rates of infection are seen among children less than 15 years of age and persons of Native American or Hispanic origin. In

HEPATITIS A VIRUS Transmission Fecal-oral Food-borne Clinical presentation Acute self-limited illness Incubation, 15–60 days Fatigue, nausea, myalgia Dark urine, jaundice, right upper quadrant (RUQ) pain Hepatic failure rare Diagnosis Immunoglobulin M (IgM) to hepatitis A virus (HAV) acutely IgG persistent for life Prevention Good hygiene and sanitation HAV vaccine for those at risk Passive immunity with pooled IgG for those exposed

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underdeveloped countries 90% of adults have immunity to HAV; in the United States, less than 40% of adults have natural immunity to HAV. The incidence of new HAV infections in the United States is between 125,000 and 200,000 cases per year. Of these, 84,000– 134,000 are symptomatic and up to 100 deaths result from fulminant hepatic failure. Individuals with existing chronic liver disease, such as hepatitis C virus, are at particular risk for the development of fulminant hepatitis A and should receive hepatitis A vaccination if not already immune. 3.1.1

Clinical Presentation

The incubation period after HAV infection is between 15 and 60 days. Patients are most infectious in the late incubation period. HAV can be documented in the stool up to 3 weeks before clinical disease and 1 week after the onset of jaundice. The greatest risk for transmission occurs during the asymptomatic phase of infection. The most frequent clinical manifestations include fatigue, anorexia, myalgias, and nausea, which occur 1–2 weeks before the onset of jaundice. Patients may notice darkening of the urine. Vomiting and right upper quadrant abdominal tenderness can also be observed. Diarrhea is more common in children and rare in adults; the severity of acute illness is greater in adults than in children. Physical examination findings of jaundice, tender hepatomegaly, and/or splenomegaly may be present. Jaundice is most easily detected under the tongue or in the conjunctivae with serum total bilirubin levels above 2.5 mg/dl. In only 50% of patients with acute hepatitis A does clinical jaundice develop. The presence of lymphadenopathy suggests the possibility of infection with other viruses such as Epstein-Barr virus, cytomegalovirus, or human immunodeficiency virus (HIV). The clinical presentations of acute hepatitis A, B, and C may be identical. Elevations in AST and ALT levels are the most characteristic laboratory findings. Elevations may reach 20 times the upper limit of normal in some cases and often peak with the development of jaundice. Total bilirubin level increases after a rapid decline in aminotransferase level with values as high as 20 mg/dl. Equal proportions of direct and indirect bilirubin are usually seen. A prothrombin time (PT) greater than 3 seconds above the upper limit of normal (or INR > 1.5) and/or the development of any degree of encephalopathy warrants hospitalization and monitoring for fulminant hepatic failure, preferably in a center that offers liver transplantation. Otherwise, outpatient monitoring is preferred. 3.1.2

Diagnosis

HAV infection should be suspected in the context of potential contaminated food or water ingestion, unexpected breaches in public health sanitation (such as with flooding), contacts with children in day care facilities, or subjects with a recent history of travel to endemic areas. The infection rate is particularly high among young Native Americans. Confirmation of HAV is performed by the presence of immunoglobulin M (IgM) anti-HAV titers in serum during the acute illness. Decreases in IgM with a rise and persistence of IgG antiHAV levels occur after several months. After recovery, the IgG antibodies persist for life and provide protection from future infections. An acute, self-limited infection is the usual clinical course for HAV. An estimated 99% of those infected recover without residual sequelae. A prolonged or relapsing cholestatic hepatitis may occur in up to 15% of cases. Fulminant hepatic failure that results in encephalopathy and death within 12 weeks of acute infection is rare. Cases compatible with chronic infection or carrier states for hepatitis A have only rarely been reported.

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Prevention

Prevention of HAV is based on the principles of avoidance, passive immunization, and vaccination. Hands should be washed with soap and water after bowel movements, changing of diapers, and before food preparation. Diaper changing tables in day care centers, if not cleaned properly or changed after each use, can be a source of contamination and transmission of the virus. Strict isolation in the home has no significant benefit as household members have usually been exposed before the clinical infection is observed. Hepatitis A vaccine (Havrix, SmithKline Beecham or VAQTA, Merck) is highly effective in preventing acute infection and can have a substantial impact on eliminating disease burden. The vaccine is made from inactivated HAV and stimulates persistent natural immunoglobulin production, thus conferring long-term immunity. Protection against HAV is conferred as early as 2–4 weeks after vaccination in over 95% of individuals. Immunization of children (2–18 years of age) consists of two or three doses of the vaccine at a dose of 0.5 ml each. Adults need a booster dose 6–12 months after an initial vaccine dose of 1.0 ml. The vaccine is thought to be effective for at least 15–20 years. Adverse reactions, which are rare, may include pain or tenderness at the injection site. Hypersensitivity reactions have not been described. At-risk individuals who should be vaccinated include persons engaging in anal-oral sex, users of illegal injectable drugs, children living in communities experiencing repeated HAV epidemics, certain institutional workers, workers in day-care centers, and laboratory workers who handle live HAV. Patients with chronic liver disease and clotting factor disorders should be vaccinated against HAV. Persons traveling internationally should be vaccinated 4 weeks prior to their travel. The use of immune globulin for passive immunization against HAV can provide global protection through the stable antigenic composition of the virus. Immune globulin should be used if the traveler is unable to tolerate the HAV vaccine or is traveling immediately. Protection through passive immunization (60%–70%) is not as good as that through the vaccine. Temporary immunity (less than 3 months) is provided by 0.02 ml/kg immune globulin administered intramuscularly. Screening for IgG antibodies to HAV before immunization among prospective travelers may detect preexisting immunity and is a cost-saving maneuver to prevent unnecessary immune globulin use. For those exposed to HAV, immune globulin (0.02 ml/kg) should be given as soon as possible and no later than 2 weeks after initial exposure. Transmission rates can be decreased by 90% if the immune globulin is given within this 2-week period. 3.2

Hepatitis B Virus

Hepatitis B virus (HBV) is an enveloped, double-stranded deoxyribonucleic acid (DNA) hepadnavirus that exists as a 42-nm particle in serum. Hepatocyte injury in HBV infection is thought to be secondary to host immune system response rather than a direct cytopathic effect. Major routes of transmission among adults in Western countries are intravenous drug use and sexual contact. The risk of HBV infection is notably high in homosexual men but is also transmitted among heterosexual partners. Transmission may be prevented by correct use of condoms. Health care workers and patients receiving hemodialysis are also at increased risk of infection. Mucous membrane or nonintact skin contact also poses a small theoretical increased risk for virus acquisition. The blood supply in developed countries has been screened for HBV for many years, and, at present, transmission by transfusion of blood products is extremely rare. The rate of HBV infection had been increasing through 1985. Then, through 1993, there was a 55% decline in the number of identified cases. This decrease in new infections

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HEPATITIS B VIRUS Transmission Sexual Injection drug use Clinical presentation Incubation, 45–160 days Subclinical to fulminant hepatic failure (⬃2%) Fever, fatigue, abdominal pain ⬃10% Chronic carriers Chronic infection asymptomatic or leads to cirrhosis, hepatocellular carcinoma (HCC) Diagnosis Acute HbsAg ⫹, HbeAg ⫹, immunoglobulin M (IgM) HbcAb ⫹ Transition from acute infection HBcAb ⫹ Resolution of HBsAg, IgM HBcAb HBsAb ⫹ Chronic, immune HbsAb ⫹ and HBcAb ⫹ Chronic infection Replicative HBsAg ⫹, HBeAg ⫹, HBeAb ⫺ Very infectious Higher risk of cirrhosis and HCC Nonreplicative HBsAg ⫹, HBeAg ⫺, HBeAb ⫹ Treatment For patients with active hepatitis B virus (HBV) replication and elevated liver tests (AST and/or ALT levels) Interferon, lamivudine, famciclovir in combination Prevention Nonimmune patient exposed to HBV HBV vaccine and Hepatitis B immune globulin (HBIG) (0.06 ml/kg IM) HBV vaccine for those at risk Three 1-ml injections IM at 0, 1, 6 months

is thought to be due to increased vaccination rates among adults, modification of highrisk practices, and possibly a decrease in the number of susceptible persons. Since 1993, increases in incidence are now observed among the three major risk groups: nonmonogamous sexually active men and women as well as injection drug users. Each year in the United States, an estimated 200,000 people have new HBV infections; of them, more than 11,000 are hospitalized and 20,000 remain chronically infected. Overall, an estimated 1.25 million people in the United States have chronic HBV infection; 4000 to 5000 people die each year of HBV-related chronic liver disease or liver cancer.

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Clinical Presentation

The incubation period for HBV is 45 to 160 days. Acute HBV infection can range from subclinical disease to fulminant hepatic failure. In many acutely infected individuals, clinically apparent acute hepatitis develops with loss of appetite, nausea, vomiting, fever, and abdominal pain. Fatigue, which is often worse in the evening, is the most common symptom. Jaundice can occur but is considered rare. Similar clinical findings can be observed with acute HAV or HCV infection. Fulminant hepatic failure occurs in ⬃2% of cases. More than 90% of immunocompetent adults with acute HBV infection recover uneventfully and resolve the infection. In the remaining 10% of cases, either chronic HBV infection or fulminant hepatic failure develops. In cases of fulminant hepatic failure, liver transplantation may be a lifesaving procedure. The mortality rate for acute HBV is estimated between 1% and 2%. The natural history of chronic HBV infection varies dramatically among individuals. Some have clinically insignificant liver disease and never experience complications, whereas others have progressive fibrosis leading to cirrhosis. Others become asymptomatic chronic carriers. These are patients with normal liver biochemical profiles who are nevertheless potentially infectious. Their serological testing results are positive for hepatitis B surface antigen and negative for hepatitis B surface antibody. Young age and immunosuppressed states are known risk factors associated with the development of chronic active or persistent disease. Individuals with chronic HBV (as well as HCV) in whom cirrhosis develops may also experience an asymptomatic condition with no physical abnormalities. With advanced disease, the characteristic findings associated

Figure 1 Natural history of hepatitis B virus infection during the first year after infection. ALT, alanine aminotransferase.

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with cirrhosis such as spider angiomata, muscle wasting, ascites, peripheral edema, encephalopathy, and asterixis can occur. Patients with cirrhosis are also at increased risk for the development of hepatocellular carcinoma (HCC): ⬃1%–2%/year. Semiannual screening with an ␣-fetoprotein and ultrasound examination of the liver are therefore recommended for patients with cirrhosis secondary to chronic hepatitis B infection. A smaller increased risk for HCC exists among chronic asymptomatic carriers of HBV. 3.2.2

Diagnosis

The diagnosis of HBV infection is generally made on the basis of serological results. Virtually all individuals infected with active HBV infection, either acutely or chronically, have detectable serum hepatitis B surface antigen (HBsAg). Other markers that determine the duration (acute vs. chronic) and activity (replicative vs. nonreplicative) of infection include hepatitis B surface antibody (HBsAb), core antibody (HBcAb) with IgM or IgG, nucleocapsid (e) antigen (HBeAg), and (e) antibody (HBeAb). The time course and clinical significance of these markers are described in the following and are shown in Figures 1 and 2: Serological marker • HBsAg • HBsAb

• IgG HBcAb

• IgM HBcAb • HBeAg • HBeAb

Interpretation Acute or chronic HBV infection: Persistence for 6 months after acute infection indicates progression to chronic HBV. These patients are infectious. Individual has been vaccinated, has received immune globulin, was infected but recovered, or is an infant who has received antibodies from its mother. These patients are immune, do not need vaccination, and are not infectious. Indicates past infection and lasts indefinitely. Also may be detected in someone who has received immune globulin or an infant who has received antibodies from its mother. Can be positive in the absence of HBsAg or HbsAb; patients with isolated HbcAb are not immune and should be vaccinated. Indicates recent infection with HBV within the past 4–6 months. Can be positive in the absence of HBsAg or HbsAb. Indicates active viral replication and high infectivity. Seen in association with (⫹) HbsAg. Indicates seroconversion from the active replicative state. Seen in the chronic carrier in association with (⫹) HbsAg.

Acute HBV infection is diagnosed by the presence of serum hepatitis B surface antigen (HBsAg) and IgM antibody to hepatitis B core antigen (HBcAb-IgM) in the early stages of infection, which coincide with the onset of clinical symptoms. HBeAg is also detectable in acute infection, signifying the increased rate of viral replication. Subsequently, IgG antibodies against core antigen (HBcAb) are detectable in serum once the acute infection resolves. IgM-associated HBcAb and HBsAg become undetectable once IgG antibody (HBcAb) production is sustained. In subjects who mount an immune response against HBV, antibodies to surface antigen (HBsAb) develop. Complete resolution of acute infection results in IgG-associated HBcAb for life. The gradual loss of HBsAb in select individuals may result in an increased susceptibility to future infection. Acutely infected individuals who do not clear HBV continue to have serum HBsAg. In most cases,

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Figure 2 Natural history of hepatitis B virus infection over 10 years.

the chronic infection becomes nonreplicative with the loss of serum HBeAg and development of HBeAb. In replicative chronic infection, the presence of detectable HBeAg is usually observed. Patients with chronic replicative hepatitis B infection, defined by detectable HBeAg or HBV DNA, have a greater chance of developing cirrhosis and/or hepatocellular carcinoma than those without evidence of active HBV replication. Among individuals suspected of having chronic HBV infection, the appropriate screening test is for serum HBsAg. Other clinical scenarios that may warrant screening for HBV include the following: Presence of symptoms related to chronic liver disease Abnormal laboratory test results suggesting liver disease Individuals from countries where HBV infection is endemic (e.g., China) Risk factors such as past intravenous drug use or unprotected promiscuous sex Children of HBV-infected parents or household contacts Health care workers Patients on hemodialysis Consideration of serving as a living organ donor 3.2.3

Treatment

Most cases (⬃90%) of acute HBV infection resolve spontaneously with the development of long-lasting natural immunity to subsequent infection. Although the successful treatment of fulminant hepatic failure secondary to HBV with lamivudine is known, antiviral therapy is not recommended in acute cases. Two approved treatments for chronic HBV infection are currently available: recombinant interferon alpha-2b (INF-␣) and lamivudine (3 TC). Despite the approval of these agents for the treatment of chronic HBV infection, no treatment strategy has been consistently successful. Recent data point to combination therapy with lamivudine plus INF-␣ or famciclovir as more efficacious than

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monotherapy with either lamivudine or INF-␣. Studies of triple therapy (INF-␣ ⫹ lamivudine ⫹ famciclovir) are under way. Adefovir dipivoxil is still the subject of clinical trials. Only patients with active HBV replication and elevated serum liver transaminase levels are usually considered to be candidates for antiviral therapy. Because the standard of therapy is still evolving, treatment of HBV infection should always be on an individual basis and initiated by a subspecialist with expertise in treating chronic viral hepatitis. 3.2.4

Prevention

Hepatitis B virus vaccination prevents both primary infection and those diseases related to HBV infection. HBV vaccines (Recombivax HB, Merck and Engerix B, SmithKline Beecham) currently available in the United States are made by using recombinant DNA technology and do not contain any live components. The vaccine is given as a series of three intramuscular doses of 1 ml over a 6-month period (at 0, 1, and 6 months). A missed dose should result in the administration of the second and third doses 3 to 5 months apart. It can also be given at the same time as other vaccinations. The most common side effects of vaccination are pain at the injection site and mild to moderate fever. Serious side effects are very uncommon. Adequate antibody titers develop after the three-dose series in more than 95% of children and 90% of young healthy adults. In immunocompromised hosts protective antibody titers develop in 50% to 70% of cases. Protection is conferred for a minimum of 15 years and possibly much longer. Persons who respond to hepatitis B vaccine are protected against acute hepatitis B as well as the chronic consequences of HBV infection, including cirrhosis and liver cancer. There is currently a universal child vaccination policy in the United States. Most schools require evidence of vaccination for registration. Adults at increased risk for HBV infection who should receive the vaccine include sexually active heterosexual adults with more than one sex partner in the prior 6 months, persons with a history of a sexually transmitted disease, homosexual men, illicit injectable drug users, persons at occupational risk of infection, hemodialysis patients, clients and staff of institutions for the developmentally disabled, and household and sexual contacts of persons with chronic HBV infection. Unvaccinated individuals exposed to HBV-infected persons through contact with infected blood or body fluids should receive an intramuscular injection of hepatitis B virus immune globulin (HBIG) 0.06 ml/kg within 48–72 hours of exposure. The window of efficacy for HBIG, however, may be as long as 2 weeks after exposure to HBV. Exposed nonvaccinated patients should also receive the HBV vaccine. All women should be screened for HBsAg during early pregnancy to determine whether they are infectious and capable of transmitting HBV to their infants. If not treated, 85% to 95% of infants born to HbsAg-positive mothers may become carriers. This can be prevented by giving the infants of HbsAg-positive mothers HBIG and their first dose of HBV vaccine within 12 hours of delivery. Completion of the vaccination series by 6 months is then recommended. This treatment prevents 90% of vertically transmitted chronic HBV infections. The vaccine is safe to be given during pregnancy. 3.3

Hepatitis C Virus

Hepatitis C virus (HCV) is a single-stranded RNA virus with characteristics similar to those of the Flaviviridae family (yellow fever, dengue, Japanese, St. Louis, and tick-borne encephalitis viruses). On successful molecular cloning of the hepatitis C virus, it was

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HEPATITIS C VIRUS Transmission Injection drug use, blood products Sexual transmission less common Clinical presentation Incubation period, 14–180 days Chronic infection in 85% Cirrhosis in 20%–30% Increased risk of hepatocellular carcinoma (HCC) Associated with Porphyria cutanea tarda Membranoproliferative glomerulonephritis Cryoglobulinemia Diagnosis Anti-HCV antibody: no differentiation of acute and chronic infection Active disease determined by presence of hepatitis C virus ribonucleic acid (HCV RNA) Therapy Decrease of other hepatotoxins, especially alcohol Treatment of active disease only if associated with elevated liver tests (AST and/or ALT levels) or abnormal liver biopsy result Pegylated ␣ interferon ⫹ ribavirin HCV genotype influence on response to therapy Prevention No vaccine or immunoglobulin

discovered that this was responsible for most cases of posttransfusion non-A, non-B hepatitis. The pathogenic mechanism of HCV appears to be related to lymphocyte recognition of viral antigen in hepatocytes with a subsequent inflammatory response. Transmission of HCV is primarily blood-borne via parenteral routes (transfusions, intravenous drug use) but also occurs by sexual and perinatal routes. Since the advent of blood supply testing for HCV in the early 1990s, the risk of transfusion-related HCV infection is less than 1%. Most new infections (60%) are related to illicit injection drug use. The incidence of HCV in the United States is approximately 36,000 new infections annually (1996 estimates), down from a peak of 175,000 new cases per year. However, only 25%–30% of infections present in a symptomatic fashion. HCV is estimated to have infected 3.9 million Americans (1.8% of the U.S. population), of whom 2.7 million are chronically infected. Chronic infection develops in approximately 85% of individuals who are acutely infected with HCV. Cirrhosis develops in 20% to 30% of cases. Between 8000 and 10,000 deaths occur annually secondary to chronic HCV infection. HCV-associated end-stage liver disease is now the leading indication for liver transplantation in the United States. Despite these figures, there exists a commonly held misconception that hepatitis C is a benign condition. Although it may be for a substantial proportion of chronically infected individuals, HCV infection is associated with considerable morbidity and mortality rates.

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Clinical Presentation

The incubation period of HCV varies between 14 and 180 days. The average time from transmission to seroconversion, however, is between 6 and 8 weeks. The clinical manifestations of acute HCV infection are indistinguishable from those of nonfulminant cases of HAV and HBV infection. Jaundice occurs in only 25% of acute HCV infections, making the clinical detection of recent infection difficult. Complete resolution of acute HCV infection, with clearance of HCV RNA from serum, occurs in ⬃15% of instances within 4 months of infection. Manifestations of chronic HCV infection range from the asymptomatic state to endstage liver disease. Fatigue, which may be accompanied by right upper quadrant abdominal discomfort, is the most common subjective complaint. Although fluctuating levels of serum transaminases are common, up to 25% of individuals with chronic HCV infection have normal serum liver biochemical findings. The correlation between serum transaminase levels and histological severity of chronic HCV infection is poor. Porphyria cutanea tarda, skin lesions consistent with leukocytoclastic vasculitis, membranoproliferative glomerulonephritis, osteopetrosis, and cryoglobulinemia are associated with HCV infection as well. Diabetes mellitus has also been putatively associated with chronic HCV infection. The natural history of HCV is unpredictable. The risk of progressive disease is cumulative and influenced by host and viral factors. Despite an indolent presentation, cirrhosis may develop over a 10- to 20⫹-year period after infection. Hepatocellular carcinoma is also strongly associated with chronic HCV infection, almost always in the setting of cirrhosis. The annual risk of hepatocellular carcinoma in patients with cirrhosis secondary to HCV is 1%–2%. For this reason, semiannual screening with ␣-fetoprotein and ultrasound examination of the liver are recommended. Currently, almost one-half of adult liver transplantations in the United States are performed for end-stage liver disease from HCV. One-tenth of these transplant recipients die or require retransplantation in the first 5 years postoperatively because of recurrent HCV infection. 3.3.2

Diagnosis

The array of tests available for the diagnosis of HCV infection is limited in comparison to those available for hepatitis B. Because HCV antibodies are usually not neutralizing, the detection of antibody to HCV (anti-HCV) does not distinguish between acute and chronic infection. Approximately ⬃85% of individuals with detectable anti-HCV have active infection vs. 15% who have resolved prior infection (HCV RNA no longer present). In the acute setting, anti-HCV is only detectable in ⬃60% of patients in the first 4 weeks after infection. Although up to 12 months can elapse before HCV antibodies become detectable, seroconversion generally occurs within 2 to 6 months of infection in ⬃90% of individuals. The presence of anti-HCV antibodies is detected by either enzyme-linked immunosorbent assay (ELISA) or recombinant immunoblot assay (RIBA). These tests are equivalent in terms of sensitivity and specificity. Detection of anti-HCV antibody should be followed up with a test to determine whether HCV RNA is still present in serum, i.e., whether HCV infection persists. Either qualitative or quantitative assays for HCV RNA by polymerase chain reaction (PCR) amplification may be used. The quantitative PCR assays are generally preferable as they now enjoy similar sensitivity to that of the qualitative assays. Quantitation of HCV RNA may also be performed by a branched DNA (bDNA) hybridization assay. Despite considerable promotional literature to the contrary, none of the PCR or bDNA tests has clear superiority over its competitors. It is worth bearing in mind that the assays are not interchangeable, however, as HCV RNA is reported

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in different units. Immunocompromised patients (e.g., transplantation recipients, others receiving corticosteroids, or patients with renal failure) may not generate HCV antibodies. Such patients should undergo PCR or bDNA testing to screen for HCV infection. In addition, a very small minority of immunocompetent HCV-infected individuals test negative for anti-HCV antibody but have HCV RNA detectable in serum. HCV RNA testing is indicated when the level of suspicion is high for HCV infection despite negative antiHCV antibody test findings. There are six major HCV genotypes (1a,b,c; 2a,b,c; 3a,b; 4; 5; 6). As HCV genotype influences responsiveness to therapy (the only definitive clinical implication of HCV genotype), this test is of utility when treatment is being considered. The utility of liver biopsies in patients with chronic HCV infection is increasingly equivocal. Biopsies may be helpful in determining disease activity and stage, factors that often influence patient willingness to undergo therapy. The presence of cirrhosis does not meaningfully affect likelihood of response to antiviral therapy. 3.3.3

Treatment

Only two drugs have been approved by the Food and Drug Administration for the treatment of chronic HCV infection: recombinant interferon-alpha (INF-␣) (pegylated and standard) and ribavirin. The addition of polyethylene glycol (pegylation) to INF-␣ results in more sustained bioavailability of interferon, facilitating once-weekly dosage and having superior efficacy to that of standard interferon. Combination therapy with pegylated INF-␣ and ribavirin for 48 weeks is now the standard of care for treatment of chronic hepatitis C infection in adults. The overall sustained virological response rates (undetectable levels of HCA RNA in serum for ⱖ6 months after completion of therapy) is over 50%. Ultimate response to therapy can usually be determined after 24 weeks of treatment with pegylated INF-␣ and ribavirin (only 1:400 likelihood of clearing HCV RNA after 24 weeks of treatment). Sustained virological response rates vary substantially with HCV genotype (42% genotype 1 vs. 75% non-1 genotypes). Sustained virological response rates are also greater for patients who have no or minimal fibrosis indicated on liver biopsy and who have lower (less than 2 ⫻ 106 IU/ml) viral levels at initiation of treatment. Patients with compensated cirrhosis can expect an overall likelihood of sustained virological response of 44%. Side effects of therapy are common; they include flulike symptoms, depression, cytopenias, and thyroid dysfunction secondary to INF-␣ and hemolysis secondary to ribavirin. Dosage reductions are required in ⬃40% of patients receiving combination treatment with pegylated INF-␣ and cessation of therapy in 14%. Only adult patients with active HCV infection, as determined by the detection of HCV RNA in serum, elevated serum liver transaminase levels, and abnormal histological findings on liver biopsy, are considered to be clear-cut candidates for antiviral therapy. Because the treatment of chronic HCV is evolving so rapidly, therapy for hepatitis C should be initiated by a subspecialist. Promising new agents in various stages of clinical trials include ribozyme, interleukin-2, recombinant vaccine products, and HCV-specific helicase and protease inhibitors. Studies of thymosin, interleukin-10, mycophenolate mofetil, silymarin (milk thistle), vitamin E, amantadine, extracorporeal hyperthermia, and ursodeoxycholic acid either have not shown a benefit or have been inconclusive. 3.3.4

Prevention

Currently no effective vaccine exists for HCV. As a result, continued surveillance of the donated blood supply and counseling to reduce or modify high-risk practices remain a

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mainstay. Patients with chronic HCV infection should be advised to limit or eliminate their alcohol intake to prevent the increased risk for cirrhosis in this setting. Screening for anti-HCV among uninfected individuals in monogamous long-term sexual relationships is advised if one of the partners is known to be HCV-positive. Populations at increased risk for HCV infection are similar to those for HBV and to some extent HIV. These patients include injection drug users, hemodialysis patients, surgical and emergency room health care workers, sexual contacts of infected persons, persons with multiple sex partners, recipients of blood transfusions before July 1992, recipients of clotting factors before 1987, and infants born to infected women. 3.4

Hepatitis D Virus

Hepatitis D (HDV) is a defective RNA virus that requires coinfection with HBV for replication. HBsAg production is required for HDV to produce its outer envelope and begin replication. Its pathogenesis remains uncertain as reinfection in liver transplantation recipients with HDV can occur without recurrent HBV or signs of histological damage. Transmission is similar to that of HBV but less often by sexual or perinatal transmission. The highest seroprevalence rates for HDV occur in Italy, South America, Africa, and the Middle East. Up to 50% of individuals carrying HBsAg in these areas may have antibody to HDV. Injecting drug users and patients with a history of multiple transfusions are at highest risk for HDV in the United States. 3.4.1

Clinical Presentation

The development of acute, chronic, and fulminant hepatitis is known to occur in the presence of HDV. Patients with acute HBV and HDV are described as coinfected. Superinfection with HDV occurs in those who have existing chronic HBV infections (HbsAgpositive). Among patients with chronic HBV infection in whom fulminant hepatic failure or an unexplained hepatic decompensation develops, superinfection with HDV should be suspected.

HEPATITIS D AND E VIRUSES Hepatitis D virus (HDV) Requires hepatitis B virus (HBV) coinfection (HbsAg ⫹) Transmission usually parenteral Hepatic failure potentially triggered by superinfection of HBV with HDV Diagnosis with immunogloblin M (IgM) and IgG antibodies Treatment with alpha-interferon No vaccine or immunoglobulin Hepatitis E (HEV) Fecal-oral or water-borne transmission Self-limited without chronicity Diagnosis by anti-HEV IgM No treatment, vaccine, or immunoglobulin

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Diagnosis

The diagnosis of HDV infection is most commonly made by serological methods. Elevated titers of both IgG and IgM anti-HDV antibodies are usually found in combination. Titers greater than 1:100 of anti-HDV are indicative of chronic HDV infection. Paradoxically, titers of HBV as measured by HBV DNA or HBeAg fall after HDV superinfection. 3.4.3

Treatment

The only approved treatment for chronic HDV is INF-␣. Only patients with elevated serum liver transaminase levels and appropriate histological findings on liver biopsy are considered potential treatment candidates. Formal assessment and acceptance for treatment on an individual basis should be initiated by referral to a subspecialist with expertise in treating chronic viral hepatitis. 3.4.4

Prevention

Vaccination against HBV can prevent HDV infection. There is no vaccine directed at HDV. Immunoglobulin therapy is not protective. 3.5

Hepatitis E Virus

Hepatitis E virus (HEV) is a single-stranded RNA virus that causes acute episodes of hepatitis. The pathogenic mechanism of HEV is related either to a viral cytopathic effect or to immune system–mediated damage. Its mode of transmission is by waterborne or fecal-oral routes. Epidemics of infection from HEV have occurred primarily in Southeast and Central Asia, India, Africa, and Central America. Originally described as a disease of young adults and children, it has a prevalence in developed countries that is low but measurable (1% to 2%). There have been no known epidemics of HEV infection acquired within the United States to date. 3.5.1

Clinical Presentation

The incubation period for HEV is between 15 and 60 days. In general, HEV infection is a self-limited illness with no evidence of chronicity. The clinical course of HEV resembles that seen with HAV infection. Jaundice may occur but is less often seen in children. Fulminant hepatic failure from HEV has been observed in pregnant women during their third trimester with an associated 30% mortality rate. 3.5.2

Diagnosis

A serological test for the detection of anti-HEV IgM antibody is now available. Anti-HEV IgM antibody is often undetected at presentation and usually disappears within 3 months after the onset of jaundice. IgG titers may also disappear over time, raising the concern of recurrent infection. Testing for anti-HEV is usually reserved for returning travelers from the developing world in whom hepatitis is present but other hepatitis viruses cannot be detected. 3.5.3

Treatment

Currently there is no specific medial treatment for HEV as it is self-limited. 3.5.4

Prevention

No vaccine to confer antibody protection against HEV is available. Immunoglobulin therapy is not protective.

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3.6.

Other Agents of Viral Hepatitis

Many of the herpesvirsues—varicella-zoster, herpes simplex types 1 and 2, Epstein-Barr virus, and cytomegalovirus—may also cause hepatitis. Hepatitis secondary to these agents is much less common than that to hepatitis A–E. Of these, varicella-zoster and herpes simplex may cause severe liver dysfunction in previously healthy individuals. Transaminase levels are usually greatly increased with relatively less abnormal bilirubin levels. In contrast to that in other forms of acute viral hepatitis, liver biopsy may be diagnostic in this setting because of the presence of inclusion bodies. An appropriate antiviral therapy (acyclovir, penciclovir, or famciclovir) may be lifesaving. 3.7

New Viral Agents: Hepatitis F, Hepatitis G, TT-Virus, and SEN-Virus

The advent of techniques such as polymerase chain reaction and representational difference analysis has facilitated the discovery of new viruses. Whereas some recently discovered viruses are of clear importance as agents of human disease (hepatitis C), others are not. Hepatitis F, initially described in France and thought to be a new fecal-enteric virus, seems not to exist at all. Hepatitis G (also referred to as GBV-C) is a parenterally transmitted single-stranded RNA virus originally isolated from the serum of a surgeon with non-a, non-B, non-C hepatitis. Despite the initial transmissibility of hepatitis to chimpanzees from the original serum from which hepatitis G was isolated, hepatitis G has yet to be unequivocally demonstrated to cause liver disease or to be hepatotropic. TT-virus, a highly prevalent member of the circoviridae (single-stranded circular DNA virus) family that bears the initials of the first patient from whom it was isolated, may be parenterally and enterally transmitted. TT-virus, although initially linked to posttransfusion hepatitis, appears neither to be hepatotropic nor to be associated with any form of liver disease. Most recently the SEN-virus, also named after the first patient from whom it was recovered, has been touted as an agent of parenterally transmitted hepatitis. Similarly to TT-virus, however, there is no conclusive evidence that this prevalent new virus either is hepatotropic or causes liver disease. There is no clinical setting that warrants routine testing for any of these new viruses (hepatitis G, TT-virus, and SEN-virus). 4

EVALUATION OF POTENTIAL OCCUPATIONAL EXPOSURE TO VIRAL HEPATITIS

Almost every physician practicing in the ambulatory care setting is called on to evaluate an employee or patient who has sustained a needle-stick injury or similar potential occupational exposure to viral hepatitis (also see Chapter 42). Investigation of the exposure incident should include documentation of the route(s) of exposure, the circumstance under which the exposure incident occurred, and identification and documentation of the source individual, if possible. Testing of the source individual’s blood, with permission, for hepatitis B and C viruses and HIV infection should be done as soon as possible. The great majority of source individuals are eager to assist with postexposure testing. If the source individual is already known to be infected with a viral hepatitis agent or HIV, retesting is not needed. The results of the source individual’s testing should be made available to the exposed employee. Confidentiality concerning the identity and infectious status of the source individual needs to be stressed. When the source individual refuses testing or cannot be otherwise tested, the procedure outlined for an exposure to an unknown source should

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be followed. Refusal to be tested must be documented. Exposed employees should be offered baseline viral hepatitis and HIV testing. When medically indicated, postexposure prophylaxis should be provided as soon as possible to the employee. 4.1

HBV Risk Assessment and Treatment

The risk of transmission from a HBsAg-positive/HBeAg-positive patient is 25%–30%. If the source patient is HBsAg-positive/HBeAg-negative, then the transmission risk is 5%– 10%. If an employee is exposed to a source individual found to be positive for HBsAg, the employee needs to be tested for HBsAb (see Chapter 42, Table 4). If the employee is HBsAb positive, no prophylaxis is required. If the HbsAb titer is negative, the employee should be given a single dose of HBIG (0.06 mg/kg, intramuscularly) within 48–72 hours if possible. If the employee has not previously received the HBV vaccination, the series should be initiated at this time. Employees who refuse vaccination should be given a second dose of hepatitis B immune globulin at 1 month. If the employee has previously received hepatitis B vaccine and is hepatitis B surface antibody–negative and has been previously antibody-positive, he or she should receive one dose of the hepatitis B vaccine and hepatitis B surface antibody rechecked at 1 month. If the antibody titer is negative at that time, a second complete vaccine series should be provided. If the employee has had the HBV vaccine and is not known to be HBsAb-positive (HBsAb titer > 10 mIU/ml), he or she should receive HBIG and a booster dose of the vaccine. 4.2

Hepatitis C Virus Risk Assessment

The risk of transmission of HCV to a health care worker is estimated to be about 3.5% (0%–6%) after a needle-stick injury from a HCV-positive patient. Postexposure prophylaxis with immune globulin does not appear to be effective in preventing HCV and is not recommended. A vaccine for HCV is not available. After a potential exposure to HCV infection, the employee’s anti-HCV status should be determined by ELISA or RIBA. If the status is positive, the presence of HCV RNA should be determined by PCR. If the initial screening finding is negative, repeat screening should be performed at 1 and 6 months post exposure. A negative screening finding at 6 months post exposure is generally accepted as indicative that infection has not occurred.

BIBLIOGRAPHY Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States: Need for alternative vaccination strategies. JAMA 263:1218–1222, 1990. Boyer N, Marcellin P. Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 32(suppl 1):98–112, 2000. Centers for Disease Control and Prevention. Protection against viral hepatitis: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 39:5–22, 1990. Di Bisceglie AM. Natural history of hepatitis C: Its impact on clinical management. Hepatology 31: 1014–1018, 2000. Dusheiko GM. Rolling review—the pathogenesis, diagnosis, and management of viral hepatitis. Aliment Pharmacol Ther 8:229–253, 1994. Francis DP, Hadler SC, Thompson SE, et al. Prevention of hepatitis B vaccine: Report from the Centers for Disease Control multi-center efficacy trial among homosexual men. Ann Intern Med 97:362–366, 1982.

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Hadler SC, Margolis HS. Hepatitis B Immunization: vaccine types, efficacy, and indications for immunization. In: Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Diseases. Boston: Blackwell Scientific, 1992, pp 282–308. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: Evolving epidemiology and implications for control. Semin Liver Dis 11:84–92, 1991. Noskin GA, et al. Prevention, diagnosis, and management of viral hepatitis. Arch Fam Med 4:923– 934, 1995. Szmuness W, Stevens CE, Harley EJ, et al. Hepatitis B vaccine: Demonstration of efficacy in a controlled clinical trial in a high risk population in the United States. N Engl J Med 303: 833–841, 1980.

24 Intra-Abdominal Infections Neil H. Hyman and Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Intra-abdominal infections run the gamut from relatively minor problems that respond promptly to oral antibiotics to imminently life-threatening intra-abdominal catastrophes. Such infections may be the cause of major morbidity and mortality, particularly if not diagnosed and treated promptly. Abdominal pain has been reported to be the most common reason for admission to the hospital in the United States. Although many such cases are clear-cut intra-abdominal catastrophes that are seen in the emergency department, many other intra-abdominal infections appear in a much more subtle fashion and are seen in the office of the primary care provider. In this chapter, an approach to the patient with abdominal pain is outlined. The management principles for common intra-abdominal infections, including diffuse peritonitis, cholecystitis, cholangitis, appendicitis, diverticulitis that causes localized peritonitis, and solid organ abscesses, are discussed. Current thoughts on prophylaxis for surgical infections are addressed, as are the evolving controversies regarding treatment of Heliobacter pylori infection. Other infectious causes of abdominal pain such as dysentery and food poisoning (Chapter 22), pyelonephritis (Chapter 15), gynecological infections (Chapter 16) and male genitourinary tract infections (Chapter 17) are covered in other sections of the text. 2

APPROACH TO THE PATIENT WITH ABDOMINAL PAIN

Despite major technological advances, the cornerstone of appropriate diagnosis and treatment rests on a thorough history and physical examination coupled with the practitioner’s clinical acumen, rather than any imaging studies. 2.1

History

A thorough history includes the age of the patient, onset and duration of the pain, location and character of the pain, and whether or not the pain radiates in any particular direction or fashion. An appropriate review of systems requires a search for associated gastrointestinal, gynecological, or genitourinary symptoms. The presence of fever, chills, and sweats suggests an infectious cause. Pain of sudden onset often suggests a gastrointestinal source 473

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such as perforation or obstruction. A more insidious onset suggests an inflammatory process such as appendicitis or diverticulitis. Crampy or colicky pain often signifies mechanical obstruction of a hollow viscus such as renal colic or small bowel obstruction. Bilious vomiting more strongly suggests a ‘‘surgical’’ cause of abdominal pain than nonbilious vomiting. Patients may describe ‘‘coffee ground’’ emesis, which on closer questioning is simply nonbilious in nature. Past medical and surgical history is also of considerable importance. Previous lower abdominal surgery in a patient with crampy abdominal pain suggests a diagnosis of small bowel obstruction. Patients with risk factors or known atherosclerotic vascular disease or atrial fibrillation need to be considered for the possibility of mesenteric ischemia. 2.2

Physical Examination

Simple observation of the patient may be particularly helpful. Patients with renal colic frequently writhe, searching for a comfortable position. On the other hand, patients with peritoneal irritation attempt to lie as still as possible. Vital signs are most helpful in terms of screening for a true intra-abdominal catastrophe. Although nonspecific, tachycardia should increase the level of suspicion for an intra-abdominal infection. Hypotension suggests septic shock or a ruptured abdominal aortic aneurysm. Auscultation of the abdomen can often provide important clues as to the diagnosis and management. Hyperactive high-pitched bowels sounds suggest bowel obstruction, whereas a quiet abdomen typically indicates an ileus associated with an infectious process. Bruits are a marker for vascular disease. It is usually best to avoid the area of maximal pain when starting the abdominal examination. Vigorous palpation of the area of maximal tenderness often precludes completion of the examination. If simple percussion causes pain, there is probably no reason to pursue palpation. If coughing causes severe pain in a specific area, it is likely that vigorous palpation will be intolerable. Diffuse tenderness is most often noninfectious in origin; exceptions include primary peritonitis in the cirrhotic patient and secondary peritonitis from a perforation. The psoas sign is elicited by extending the patient’s thigh. This maneuver stretches the ipsilateral psoas muscle, causing pain if the muscle is in contact with an abscess or inflamed appendix. The obturator sign is performed by flexing the knee and rotating the lower leg laterally. This causes internal rotation of the femur, stretching the obturator muscle. An inflamed appendix in this area causes pain during the maneuver. Peritoneal signs such as rebound tenderness and involuntary guarding suggest intraabdominal infection. Rebound tenderness is elicited when release of the palpating hand causes an obvious involuntary spasm of pain that is visually evident to the practitioner. Voluntary guarding implies that the muscles of the abdominal wall are contracted but the patient is capable of voluntarily relaxing them. Involuntary guarding denotes inability to relax the abdominal musculature and is a sign that raises much more concern. Patients suspected of having an intra-abdominal infection generally require a rectal examination. A rectal or bimanual exam may identify a pelvic abscess associated with diverticulitis, appendicitis, or pelvic inflammatory disease. Patients with Crohn’s disease may have fistulas and abscesses. Frank rectal blood suggests colonic bleeding from ischemia, diverticular disease, infectious colitis, inflammatory bowel disease, or tumor. Melena raises the concern for upper gastrointestinal bleeding. Occult bleeding (as detected by guaiac testing) can be seen with infectious colitis in addition to noninfectious causes.

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If the patient does not appear toxic and does not have tachycardia or show involuntary guarding, then a course of outpatient oral antibiotics is likely to be appropriate. Alternatively, for a patient with fever, tachycardia, and involuntary guarding triage for admission for intravenous antibiotics is probably best. If the patient exhibits more diffuse tenderness, surgical evaluation and possibly even urgent surgical intervention are often required. 2.3

Laboratory and Radiological Assessment

Patients should have a complete blood count (CBC) with differential performed. Although some patients with an intra-abdominal infection may have a normal white blood cell count, most have a polymorphonuclear predominance. A patient with epigastric or right upper quadrant pain usually requires evaluation of liver transaminases, alkaline phosphatase, and lipase or amylase. Young women with right lower quadrant pain usually require urinalysis and urine pregnancy test. The urinalysis may also be helpful in excluding urinary tract infection and nephrolithiasis. If a confident diagnosis cannot be made on the basis of history, physical examination, and laboratory evaluation, then radiological studies are warranted and appropriate. A simple plain film of the abdomen can be useful to look for kidney stones, or gallstones, evidence of small bowel obstruction, or an appendicolith. Upright films may reveal free intraperitoneal air, indicative of perforation. In selected circumstances, imaging studies are very useful when guided by specific clinical concerns. If the diagnosis is not clear from the history, physical examination, and laboratory studies, a computed tomographic (CT) scan with oral, intravenous, and occasionally rectal contrast media may be helpful. In many circumstances, it may not be possible to secure a diagnosis on the basis of a ‘‘snapshot’’ in time. With continuing observation, often in an outpatient setting, the signs and symptoms become more focused and allow for an accurate diagnosis. The only decisions that are required initially are whether the patient requires an urgent operation or admission to the hospital. A patient who is tachycardic and toxic with local peritoneal signs is best admitted to the hospital for observation. Alternatively, a patient who does not appear particularly ill and has a short history of right lower quadrant pain without peritoneal signs can often be followed as an outpatient with follow-up telephone contact and/or repeated physical examination. An approach to the patient with suspected intra-abdominal infection is given in Figure 1.

3

PERITONITIS

The peritoneal membrane surrounds most of the intra-abdominal organs. It extends from the diaphragm to the pelvis. The kidneys, postbulbar duodenum, pancreas, and portions of the colon are retroperitoneal. Intra-abdominal infection may therefore reside within the peritoneal cavity or the retroperitoneal space. Peritonitis is inflammation of the peritoneal membrane. Within the peritoneum, the infection may be localized or diffuse. Diffuse peritonitis can be caused by bacterial seeding of ascites fluid (primary peritonitis) or a perforation of an abdominal viscus (secondary peritonitis). Localized peritonitis can occur next to an inflamed organ such as the appendix, gallbladder, or colonic diverticula. Peritonitis complicating peritoneal dialysis is reviewed in Chapter 36.

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DIFFUSE PERITONITIS Primary or spontaneous bacterial peritonitis (SBP) Most common in patients with advanced alcoholic liver disease, cirrhosis, and ascites Abdominal pain and fever, though patients may be afebrile and less commonly may not experience abdominal pain Ascitic fluid polymorphonuclear neutrophil (PMN) > 250/mm3 Monobacterial with aerobic gram-negative rods (GNRs) and S. pneumoniae most common Empirical therapy with ceftriaxone Secondary peritonitis Due to intra-abdominal viscus perforation Sudden onset of pain, fever, nausea, and vomiting May progress rapidly to septic shock Free peritoneal air sometimes seen on acute abdominal series Urgent surgical intervention required Antibiotic therapy (Table 2)

3.1

Diffuse Primary Peritonitis

Primary or spontaneous bacterial peritonitis (SBP) is an infection predominantly seen in patients with alcohol-induced hepatic cirrhosis and ascites. Less commonly, primary peritonitis can develop in patients with ascites due to other causes of liver failure, congestive heart failure, or malignancy. Bacteria enter the peritoneal fluid either hematogenously, from the lymphatic circulation, or directly from transmigration across the intact bowel wall. The damaged reticuloendothelium of the cirrhotic liver is unable to clear bacteria from the blood as it normally should. Bacteria entering the blood from any source are therefore not cleared and have a higher rate of seeding of the ascitic fluid in the peritoneum. Since the peritoneal fluid infection is not due to a perforated viscus, the peritonitis is classically monobacterial. Gastrointestinal aerobic gram-negative rods (GNRs) such as Escherichia coli, Klebsiella spp., Proteus spp., and Enterobacter spp. account for the

< Figure 1 Approach to the patient with abdominal pain due to infection. Abdominal pain that has an infectious cause may produce localized or diffuse discomfort. Patients with diffuse abdominal pain should be admitted to the hospital for surgical evaluation and CT imaging as needed. If spontaneous bacterial peritonitis is suspected, the patient should undergo paracentesis. Patients with suspected diverticulitis or cholecystitis who are not acutely ill can be managed with oral antibiotics as long as close follow-up and surgical consultation are arranged. Patients with moderate or severe infection require hospitalization. The type of antibiotic empiricism is based on the severity of illness. Those who appear more ill should receive a broader spectrum of antibiotics. Patients with suspected parenchymal abscesses should undergo CT imaging. (1) Mild: abdominal pain controlled with oral analgesics, ability to take oral medications and maintain hydration. (2) Anaerobic agents include clindamycin or metronidazole (3) See Table 2 for dosage. (4) Moderate illness is severe enough to warrant hospitalization, but patient is not hypotensive or requiring intensive care (ICU) monitoring. (5) Severe illness requires ICU monitoring and blood pressure support. GU, genitourinary tract; LDH, lactate dehydrogenase; PMN, polymorphonuclear neutrophil; ICU, intensive care unit; CT, computed tomography. (Adapted from Grace and Ahern 2001.)

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majority of infections. Less commonly seen today are infections from Streptococcus pneumoniae, other Streptococcus spp., and Enterococcus spp. Staphylococcus aureus accounts for about 4% of infections. Anaerobic bacteria such as Bacteroides spp. are uncommon. In about a third of patients with SBP, the ascites culture finding is negative. Typically, the patient reports acute onset of diffuse abdominal pain, fever, nausea, and vomiting. Patients may be afebrile and on occasion have no abdominal tenderness. Therefore, all patients with cirrhosis-related ascites should have paracentesis to exclude SBP. Fluid obtained by paracentesis should be sent for protein analysis and cell count. An accepted definition of SBP is an ascites fluid neutrophil count >250 polymorphonuclear neutrophils/mm3. An ascites fluid lactate of ⱖ25 mg/dl and a pH <7.35 also lend evidence to the diagnosis. The fluid should be sent for Gram stain and aerobic and anaerobic cultures. The sensitivity of the Gram stain is poor (30%–40%) and generally cannot be relied on to help select antibiotic therapy. Additionally, the fluid can be placed in blood culture bottles to increase the yield of the culture. A CT scan may be considered to help exclude secondary peritonitis from a perforated viscus. Empirical treatment should be aimed at aerobic GNRs and streptococci. A thirdgeneration cephalosporin such as ceftriaxone is generally selected. If the patient is penicillin- or cephalosporin-allergic, the combination of aztreonam and vancomycin can be used until culture results are available. Initial antibiotic therapy should subsequently be tailored on the basis of results of the ascitic fluid culture. If the culture is polymicrobic or grows an anaerobic bacterium, reassessment to exclude secondary peritonitis is warranted. Prevention of SBP has been successful with oral co-trimoxazole or norfloxacin. The use of these prophylactic antibiotics must be tempered by the risks of toxicities, the selection of resistant bacteria, and knowledge that even successful prophylaxis has not improved long-term survival rate in these patients. 3.2

Diffuse Secondary Peritonitis

Diffuse secondary peritonitis is a surgical emergency resulting from spillage of gastrointestinal contents into the peritoneal cavity. There is usually sudden onset of diffuse abdominal pain, fever, nausea, and vomiting. Patients are acutely ill with a tense, rigid, and quiet abdomen. Peritoneal signs are evident. The infection may progress rapidly to septic shock. The diagnosis of the ‘‘acute abdomen’’ is generally made clinically. There is usually a markedly elevated white blood cell (WBC) count, but patients with overwhelming sepsis may have leukopenia and a marked bandemia. An acute abdominal series may show free intraperitoneal air. In less well-defined cases, a CT scan may help visualize free air or loculated abdominal fluid. Emergent surgical consultation and operative intervention are required. The bacteriological finding is typically polymicrobial, representing the bowel flora, including aerobic GNRs, anaerobic gram-negative and gram-positive organisms, and enterococci. Empirical antibiotics are outlined in the following and in Tables 1 and 2. Although yeast may be part of the normal bowel flora, empirical antifungal therapy is generally not recommended. 3.3 3.3.1

Localized Peritonitis Cholecystitis

Cholecystitis is an inflammation of the gallbladder secondary to obstruction of the cystic duct with subsequent bacterial infection. In 95% of patients, the obstruction is due to

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LOCALIZED PERITONITIS Cholecystitis and cholangitis History and physical Right upper quadrant (RUQ) pain, fever, nausea, vomiting Positive Murphy’s sign Sonography Gallstones Thickened gallbladder (GB) wall, pericholecystic fluid Sonographic Murphy’s sign Cholangitis RUQ pain, fever, jaundice Frequent bacteremia and sepsis Antibiotic management (Table 1) Appendicitis Periumbilical pain to right lower quadrant (RLQ) Fever, nausea, leukocytosis Pregnancy test for sexually active women Computed tomography (CT) scan for uncertain diagnosis Antibiotic management (Table 1) Diverticulitis Left lower quadrant (LLQ) pain, fever Leukocytosis sometimes absent CT scan for Palpable mass Failure to respond to antibiotics in 48–72 hours Diverticulitis not precluded by negative CT scan result Antibiotic management (Table 1)

gallstones. Acalculous cholecystitis can be seen in the more acutely ill patient after trauma, extensive burns, and surgery. Patients with symptomatic gallstones (biliary colic) classically describe postprandial right upper quadrant pain that radiates to the tip of the scapula. Presumably, this pain arises from transient obstruction of the cystic duct by stones that are ultimately dislodged and fall back into the gallbladder or pass through the ductal system into the duodenum. Most patients have resolution of their symptoms within hours. When a stone persistently obstructs the cystic duct, the gallbladder becomes distended, edematous, and ultimately infected. Patients have right upper quadrant and epigastric pain, nausea, vomiting, and fever. Physical examination reveals right upper quadrant tenderness. The gallbladder may be palpable in up to 30%–40% of patients. Palpation of the right upper quadrant while the patient takes a deep breath causes an arrest of inspiration (Murphy’s sign). Laboratory evaluation reveals a mild leukocytosis. Abnormalities in serum bilirubin can be seen in 50% of patients; 40% have elevations in aminotransferases, and 25% have an increased alkaline phosphatase. Differential diagnosis includes right lower lobe pneumonia, myocardial infarction, perforated duodenal ulcer, hepatitis, and right-sided pyelonephritis or nephrolithiasis.

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In most cases, the diagnosis is easily confirmed with right upper quadrant ultrasonography. In addition to the presence of gallstones, gallbladder wall thickening and pericholecystic fluid are generally present. A sonographic Murphy’s sign (tenderness when the sonographic probe is placed in proximity to the gallbladder) is typically present. In the era of open cholecystectomy, initial management often consisted of admission to the hospital for intravenous antibiotics and fluid resuscitation. Appropriate antibiotics (see Table 1) were associated with resolution of acute cholecystitis in approximately 80% of cases. The rationale of initial antibiotic therapy was to delay cholecystectomy by approximately 6 weeks to allow for a ‘‘cooling off’’ of the gallbladder in order to operate in a noninfected field. Subsequent studies have shown that this approach was neither safer nor more costeffective as compared to cholecystectomy during the initial admission of the patient with acute cholecystitis. This issue has been once again revisited in the era of laparoscopic cholecystectomy. The emerging literature is showing that the best treatment is prompt laparoscopic cholecystectomy, rather than a delay for ‘‘cooling off.’’ Although there is no doubt that conversion rates to open procedures are substantially higher for acute cholecystitis rather than elective cholecystectomy, edema and inflammation are much more easily handled through the laparoscope than fibrosis that forms as the infection resolves. When a patient has cholecystitis but has only mild tenderness and does not appear toxic, it is reasonable to initiate oral antibiotic therapy and promptly consult a surgeon. It is probably in the best interest of the patient that cholecystectomy be arranged within the next several days. For the more toxic and ill-appearing patient, hospital admission for intravenous antibiotics is appropriate along with prompt surgical consultation for cholecystectomy during that admission. In patients with multiple comorbidities such as diabetes mellitus or coronary artery disease who are considered less than optimal surgical candidates, a period of delay may be warranted to assess or stabilize the comorbid condition. Although concern of operative risk is certainly appropriate, it is this high-risk subset of patients who often tolerate a delay in surgery poorly. If a patient does not improve or worsens on appropriate antibiotic therapy, prompt surgical intervention is needed. The vast majority of these patients have a complication of cholecystitis such as a gangrenous gallbladder, pericholecystic abscess, or cholangitis. 3.3.2

Cholangitis

Acute cholangitis results from obstruction and infection of the biliary duct system, most commonly as a result of gallstone impaction in the common bile duct. Less common causes include obstruction from malignancies of the pancreas, biliary tree, or ampulla of Vater and hepatic metastases. Risk factors for cholangitis include age >60 years, recurrent cholecystitis, and history of postcholecystectomy jaundice or common bile duct exploration or instrumentation. In the periphery of the liver there are direct connections between the branches of the bile duct and the hepatic venous system, which allow direct access of infected bile to the systemic circulation. A patient with acute cholangitis typically experiences epigastric or right upper quadrant pain, nausea, fever, and jaundice. The classic Charcot’s triad of fever, jaundice, and right upper quadrant pain is seen in only 19% of patients. Liver transaminases and alkaline phosphatase are often very abnormal. Leukocytosis can be marked. Patients with cholangitis are often quite ill, tend to have positive blood culture findings, and are frequently hemodynamically unstable.

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All patients with suspected cholangitis require hospital admission for vigorous fluid resuscitation, intravenous antibiotics, and careful observation. Prompt endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy and biliary drainage allows for prompt relief of obstruction and clinical improvement in the vast majority of cases. Laparoscopic cholecystectomy may then be undertaken at a later date to prevent recurrence of cholangitis or biliary symptoms. For elderly or chronically ill patients, cholecystectomy may not be required as many such patients have no further biliary tract problems. If endoscopic decompression is not successful or available, then prompt surgical management via cholecystectomy is warranted. 3.3.3

Appendicitis

Appendicitis occurs when a fecalith or lymphatic swelling causes obstruction of the appendiceal orifice. The appendix becomes swollen, engorged, and infected. The classic presentation is vague periumbilical pain that migrates over time to the right lower quadrant as visceral inflammation progresses to parietal peritoneal inflammation. There are generally anorexia, nausea, low-grade fever, and a modest leukocytosis. When appendicitis occurs in this manner, the diagnosis is usually straightforward and an appendectomy is performed. However, many cases present atypical features that readily lead the clinician astray. Patients may have urinary symptoms or abnormalities on a urinalysis suggestive of a urinary tract infection or diarrhea suggestive of gastrointestinal infection. In women of childbearing age the differential diagnosis includes ovarian cyst, ectopic tubal pregnancy, and tubo-ovarian abscess. Acute appendicitis is the second most common cause of surgical abdominal disease in older adults. These patients may have atypical symptoms, plus the diagnosis is often not entertained early enough by the clinician. As compared to younger patients, they have a higher incidence of delayed diagnosis with subsequent perforation. A ruptured appendix can be a serious and life-threatening emergency. A patient with a ruptured appendix usually requires more prolonged hospitalization and is subject to a higher rate of postoperative abscess or wound infection. Long-term sequelae such as small bowel obstructions and infertility of women of childbearing age are real concerns. Historically, surgeons have been trained to ‘‘shoot for’’ an accuracy rate of approximately 85% when operating on a patient with presumed appendicitis. The rate of finding a normal appendix at appendectomy in women of childbearing age has commonly been in the range of 30%–40%. This is one area where radiological imaging, most notably CT scanning, has represented a major advance. When the diagnosis is not straightforward, CT scan has emerged as a very accurate modality to make the diagnosis. Another use of CT scan is to exclude appendicitis in patients that are thought to have a low likelihood of the disease, thereby preventing unnecessary surgical exploration to rule out appendicitis. A normal CT scan result may prevent admission from the primary care physician’s office. An appendiceal mass may be due to a periappendiceal abscess or phlegmon. The patient may report right lower quadrant pain that has waxed and waned for days to weeks. A right lower quadrant mass may be found on palpation of the abdomen. A CT scan usually shows a phlegmon of matted loops of intestine or a discrete collection of pus around the base of the cecum (abscess cavity). If there is an appendiceal phlegmon, intravenous antibiotics frequently suffice. A true abscess may be managed by radiographically guided percutaneous drainage coupled with appropriate antibiotics. In both of these scenarios, interval appendectomy can be performed 6 to 12 weeks later, often with laparoscopic assistance and a short hospital stay. A evaluation to exclude other causes of a

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right lower quadrant mass such as a perforated cecal neoplasm, Crohn’s disease, or cecal diverticulitis is usually warranted. This can be achieved by colonoscopy with ileal intubation or alternatively by barium enema and/or small bowel series. 3.3.4 Diverticulitis Diverticula are herniations of the mucosa and submucosa through the colonic wall where the branches of the marginal arteries penetrate the colonic tunica muscularis. Strictly speaking, these are actually pseudodiverticula since the muscle is not part of the herniated sac. Diverticula are most commonly found in the sigmoid and descending colon in persons of Western societies, although they can occur anywhere throughout the large intestine. In Asian societies, diverticula are more common in the ascending colon. Diverticula are typically small (5–10 mm) and number from very few to hundreds. Diverticulosis appears to have been relatively rare before the 20th century. However, with the advent of refineries and the marked reduction in dietary fiber, diverticulosis has become a very common condition. Although the true incidence of diverticulosis in Western societies is not clear, the condition clearly increases in frequency with age and probably occurs in at least two-thirds of adults older than 85. Patients with uncomplicated diverticular disease may experience intermittent abdominal pain and bloating that can be exacerbated by eating and relieved with defecation. There are no signs of peritoneal inflammation. Diverticulitis is probably better termed peridiverticulitis since the infection results from micro- or macroperforations of a diverticulum with an associated inflammatory response in the surrounding soft tissue. Presumably undigested food and bacteria collect in the diverticula, leading to ischemia, obstruction, and inflammation. Perforation of the fundus of the herniation can lead to limited pericolonic inflammation or more seriously to a diffuse secondary peritonitis or abscess formation. Diverticulitis occurs in up to 20% of patients with diverticulosis; the risk increases with age and the larger number of diverticula. The disease is more common in men than in women and occurs most commonly in the sigmoid colon. Patients with diverticulitis typically experience left lower quadrant pain associated with altered bowel habits, nausea, vomiting, and a low-grade fever. Urinary frequency or urgency can occur when there is a diverticular mass irritating the urinary bladder. Concommitant gastrointestinal bleeding is rare. On physical examination, there is generally left lower quadrant tenderness, although the maximal tenderness may be in the suprapubic area or even to the right of midline. Guarding and rebound may be present, and a mass is occasionally palpable. There may be tenderness in the left lower quadrant on rectal exam. It should be remembered that the sigmoid colon often deviates well to the right of midline, and the distinction between diverticulitis and appendicitis may be difficult in this setting. A WBC can be helpful in assessing severity of infection and response to treatment, but in many cases leukocytosis is absent. Patients who have classic signs and symptoms do not necessarily require any imaging studies during the acute illness. Sigmoidoscopy and colonoscopy are usually contraindicated in acute conditions because of the risk of perforation from air insufflation. Patients with localized tenderness who do not appear toxic and do not have a high fever or peritoneal signs can often be managed as outpatients with oral antibiotics. Although somewhat controversial, a low-residue diet is probably better tolerated by the patient in the acute phase. Patients should be advised to report new or worsening symptoms. Should the situation worsen or fail to resolve on oral antibiotics, surgical consultation is warranted. Hos-

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pitalization for intravenous antibiotics (Table 2) may be required. If there is no response to antibiotic therapy in 48–72 hours, a CT scan is frequently very helpful to assess for an abscess. Water-soluble contract studies can also make the diagnosis, but CT scanning is generally more accurate and provides more clinically useful information. Although these scans reliably demonstrate abscesses that occur outside the colon, they often do not reveal abscesses contained within the leaves of the mesentery or in the bowel wall itself. If the diagnosis of diverticulitis appears secure and there is no response to appropriate antibiotic therapy, surgical resection is appropriate even though an abscess is not demonstrable by CT scan. When a CT scan does show an overt abscess, it can be drained percutaneously. This approach can prevent urgent surgery, which often necessitates temporary colostomy formation. Successful drainage often relieves symptoms and allows for bowel preparation and an elective single-stage surgical procedure (resection and anastomosis). Once an episode of diverticulitis has been successfully treated with antibiotics, subsequent work-up with sigmoidoscopy and/or barium enema is appropriate to document the presence of diverticula and to exclude a colonic neoplasm. Once the acute symptoms have resolved, there is some evidence that a high-fiber diet may decrease the risk of subsequent episodes. Patients who have recurrent episodes should be evaluated for elective surgical resection. A recommendation for surgery is often made on the basis of the fear of perforation with a subsequent episode. However, this possibility, although legitimate, is probably overestimated. Most patients who experience a perforation usually do so on the initial episode of diverticulitis. It is rather uncommon for a patient who has previously been treated for diverticulitis to experience perforation. In a 10-year review at our institution, there was only one case of diverticular perforation in a patient who had previously been treated for an episode of acute diverticulitis (unpublished data). Therefore, the decision for elective surgery is probably best made on a case-by-case basis. Surgery is highly effective in preventing recurrent diverticulitis, with postsurgical recurrence rates less than 10% if the procedure is performed properly. However, the surgeon must also consider the short-term risks of colectomy and the potential longer-term problems such as ventral hernias and adhesive small bowel obstruction. Probably the most important factors are the difficulty of treating the patient’s episodes, their frequency, and their effect on the patient’s quality of life. 3.4

Antimicrobial Therapy for Localized and Secondary Peritonitis

The bacteriological characteristics of appendicitis and diverticulitis reflect the bacterial flora of the colon, whereas the pathogens of cholecystitis reflect duodenal bacteria. The stomach and upper small bowel generally contain a sparse flora (<105 bacteria/ml) of streptococci, lactobacilli, and other oropharyngeal bacteria. Hypochlorhydria can increase the types and numbers of bacteria similar to lower small intestine and colon. The lower small bowel contains GNRs such as Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., and occasionally Pseudomonas spp., in addition to streptococci, enterococci, and anaerobic bacteria including Bacteroides fragilis, Clostridia spp., and Fusobacterium spp. The colon harbors types of bacteria similar to those of the lower small intestine though in much greater quantities (>1010 bacteria/ml). Intra-abdominal infections therefore are polymicrobic, and antimicrobial therapy must be directed at this diverse flora. Although enterococci are part of the normal bowel flora and may be involved in 15%–20% of intra-abdominal abscesses, there is controversy regarding the need to treat enterococci in all patients with intra-abdominal infections.

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Empirical therapy for Candida spp. is generally not indicated. The antimicrobial activities of various agents that may be used to treat intra-abdominal sepsis are summarized in Table 1. Antimicrobial therapy should be used in addition to surgery except in mild diverticulitis. Antibiotics should be started after blood cultures have been drawn but before surgery. Most antibiotic regimens include agents active against aerobic GNRs (gentamicin, trimethoprim & sulfamethoxazole, ceftriaxone, ciprofloxacin) and anaerobes (clindamycin or metronidazole). Agents that have activity against both aerobes and anaerobes (ampicillin with clavulanic acid, cefotetan, ampicillin with sulbactam, imipenem with cilastatin, piperacillin with tazobactam) may be used with equal efficacy. Enterococcal activity can be added with ampicillin or vancomycin or as part of the spectrum of piperacillin or imipenem-cilastatin for life-threatening infections. Therapy should generally be continued for 24–48 hours, depending on improvement of clinical features such as normalization of the WBC, defervescence of fever, and resolution of the associated ileus. Longer courses may be needed if the patient is not improving. Suggested regimens for outpatient and inpatient management are outlined in Table 2. 4 4.1

INTRAPARENCHYMAL ABSCESSES Hepatic Abscess

Pyogenic liver abscess (PLA) is a focal collection of purulent material caused by bacteria or fungi and less commonly by parasitic agents such as Entamoeba histolytica. Agents

Table 1 Relative Activitiesa of Antimicrobial Agents Used to Treat Intra-Abdominal Infections

Antibiotic

Non-pseudomonas species Gram-negative gram-negative aerobes anaerobes

Aminoglycoside Ampicillin Ceftazidime Cefotetan Ceftriaxone Ciprofloxacin Clindamycin Co-trimoxazole Imipenem/meropenem Metronidazole Piperacillin

⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹ ⫹⫹⫹ ⫺ ⫹⫹

⫺ ⫺ ⫺ ⫹⫹ ⫺ ⫺ ⫹⫹⫹ ⫺ ⫹⫹⫹ ⫹⫹⫹ ⫹⫹

Piperacillin/tazobactam

⫹⫹⫹

⫹⫹⫹

Trovafloxacin Vancomycin Amoxicillin/clavulanate Cefpodoxime

⫹⫹⫹ ⫺ ⫹⫹ ⫹⫹

⫹⫹⫹ ⫺ ⫹⫹ ⫺⫺⫺

Pseudomonas aeruginosa

Enterococcus species

⫹⫹⫹ ⫺ ⫹⫹⫹ ⫺ ⫺ ⫹⫹⫹ ⫺ ⫺ ⫹⫹ ⫺ ⫹⫹ (Use w/ aminoglycoside) ⫹⫹ (Use w/ aminoglycoside) ⫹⫹⫹ ⫺ ⫺⫺⫺ ⫺⫺⫺

⫺ ⫹⫹ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫹⫹ ⫺ ⫹⫹

a ⫺, no activity; ⫹, limited activity; ⫹⫹, moderate activity; ⫹⫹⫹, high activity. Source: Adapted from Grace CJ et al. 1999.

⫹⫹⫹ ⫹ ⫹⫹⫹ ⫹⫹⫹ ⫺⫺⫺

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Table 2 Antimicrobial Therapy for Intra-Abdominal Infections Dosagea

Regimen Oral therapy for mild diverticulitis or cholecystitis Amoxacillin-clavulanic acid Co-trimoxazole or cefpodoxime proxetil or ciprofloxacin and metronidazole or clindamycin Intravenous Moderate illness (see text and Figure 1) Cefotetan Gentamicin or ceftriaxone or co-trimoxazole plus metronidazole or clindamycin Severe illness (sepsis, shock, ICU admission) Gentamicin or ceftriaxone and metronidazole as above and ampicillin Piperacillin-tazobactam and gentamicin as above Ciprofloxacin and metronidazole, ampicillin as above

875 mg bid Double-strength bid 400 mg bid 500 mg bid 500 mg tid 300 mg qid

2 g q12h 7 mg/kg/dayb 1 g/day 10 mg/kg/day In divided doses 500 mg q8h 600 mg q8h

1 g q6h 3.375 g q6h

400 g q8h

a

Assuming normal renal function. ICU, intensive care unit. See Chapter 4, Tables 3 and 4.

b

may be single or multiple. It is an uncommon but potentially life-threatening infection intra-abdominal infection. Bacteria or fungi gain access to the liver parenchyma via the portal vein from appendicitis or diverticulitis or via the hepatic artery during a systemic bacteremia. There can be contiguous spread from an infected gallbladder or obstructed biliary tree. The most common cause of PLA is biliary tract disease. Patients at increased risk include those with diabetes mellitus, cirrhosis, malignancy, inflammatory bowel disease, immune suppression, chronic granulomatous disease, and malnutrition. Patients with chronic indwelling central venous catheters and those who have had hepatobiliary instrumentation are also at higher risk. PLAs are most often polymicrobic, reflecting the frequent origin from biliary and bowel lesions. Aerobic GNRs, anaerobes, and enterococci are often

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INTRAPARENCHYMAL ABSCESS Hepatic Related to biliary or colonic disease or bacteremia Days to weeks of symptoms Right upper quadrant (RUQ) pain, fever Diagnosis by computed tomography (CT) scan or sonography Drainage and prolonged antibiotics Repair of underlying gastrointestinal source Splenic Caused by bacteremia, most often from endocarditis Acute onset of left upper quadrant (LUQ) pain radiating to shoulder and fever Diagnosis by CT scan or sonography Antibiotics and splenectomy (less commonly percutaneous drainage) Pancreatic Caused by bacterial contamination of severe pancreatitis Difficult to differentiate from sterile pseudocyst Diagnosis by CT scan Renal Perinephric Ascending genitourinary (GU) infection Increased risk with renal stones and/or obstruction Persistent flank pain and fever Urinalysis and culture results most often positive except with complete obstruction Aerobic gram-negative rods (GNRs) most often Percutaneous drainage and antibiotics Intrarenal Hematogeneous in origin S. aureus most common Concern for bacteremia and renal abscess raised by S. aureus in urine Urinalysis result possibly normal Diagnosis by CT scan Percutaneous drainage and antibiotics

involved. Monobacterial infections with Staphylococcus aureus, Yersinia spp., and Candida spp. can occur. Patients with PLA generally experience several weeks of nonspecific symptoms including fever, malaise, weight loss, and abdominal pain. The discomfort is not always localized to the right upper quadrant. Physical examination may reveal abdominal tenderness, hepatomegaly, and, less often, jaundice and right lower lung abnormalities. Laboratory assessment generally shows a leukocytosis and elevations of alkaline phosphatase and, less often, transaminases. Diagnosis is confirmed with ultrasonography or CT scan imaging. CT performed with intravenous contrast medium has a sensitivity of approximately 95% and is best for detecting multiple lesions. Treatment generally requires percutaneous drainage, antibiotics, and management of the underlying cause of the PLA. Surgery may be required if percu-

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taneous drainage is unsuccessful and/or for treatment of the causative biliary or intestinal infection. Empirical antibiotics should cover aerobic and anaerobic GNRs and enterococci (see Tables 1 and 2). If S. aureus or streptococci are suspected because of the possibility of endocarditis, nafcillin or vancomycin can be used alone or added to the current regimen (see Table 2). The initial antibiotic selection should be adjusted on the basis of blood and abscess culture results. 4.2

Splenic Abscess

Splenic abscess is a rare complication of bacteremia that commonly originates from endocarditis. Patients at increased risk include those who have sickle cell disease and those who use injection drugs. S. aureus and streptococci are the most common pathogens, though aerobic and anaerobic GNRs have also been involved. Twenty-five percent are polymicrobic. Patients have fever and left upper quadrant (LUQ) pain that may be referred to the left shoulder. Physical examination reveals tenderness in the LUQ and occasionally pulmonary rales and evidence of a left pleural effusion. Seventy percent of patients have positive blood culture results. Diagnosis is confirmed by CT scan imaging. Initial empirical antibiotics should include a combination of 1) ceftriaxone or ciprofloxacin, and 2) ampicillin or vancomycin, and 3) metronidazole or clindamycin. Single agents such as piperacillin with tazobactam or imipenem with cilastatin can also be used. The initial antibiotic selection should be based on blood and abscess culture results. Splenectomy is generally required, although percutaneous drainage may be attempted in selected circumstances. 4.3

Pancreatic Abscess

The majority of cases of pancreatitis resolve without sequelae. However, pancreatic abscesses may originate as a complication of severe pancreatitis. The necrotic pancreatic tissue becomes secondarily infected from the biliary tree, duodenum, or transverse colon. Therefore, most of these infections are polymicrobic, reflecting the regional bowel flora. Patients have fever and midabdominal pain that radiates to the back. The abscess may develop acutely during a severe episode of pancreatitis. Amylase or lipase is often elevated. Pancreatic ‘‘abscesses’’ are quite different from other intra-abdominal abscesses in regard to the nature of the problem and management. The digestive pancreatic enzymes obtain access to the peripancreatic space, causing necrosis of the retroperitoneal fat. There is essentially a retroperitoneal ‘‘burn’’ with a severe inflammatory response, potentially causing massive fluid shifts and extensive cytokine release. These patients are often hemodynamically unstable and at considerable risk for progressive multiorgan failure. Initial treatments for this necrotizing infection are hemodynamic support and intensive care. Serial CT scanning is very useful to follow the course of the inflammatory response and assess for the development of infected necrosis. Although somewhat controversial, antibiotics probably are helpful in selected cases of severe pancreatitis associated necrosis (see Tables 1 and 2). Clinical deterioration, positive blood culture findings, or the appearance of gas bubbles around the pancreas suggests the development of infection, complicating the intrinsic inflammatory nature of the pancreatitis. CT-guided fluid aspiration can confirm the presence of infection. It is at this point that drainage may be helpful. As opposed to other intra-abdominal ‘‘abscesses’’ that are confined collections of purulent material, large amounts of infected retroperitoneal soft tissue, when present, limit the efficacy of CT-

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guided percutaneous drainage. Surgical de´bridement, often done repetitively as further necrosis ensues, is often required to salvage these challenging patients. On other occasions, an episode of pancreatitis may resolve, leaving a loculated collection of pancreatic fluid (pancreatic pseudocyst). Many resolve with expectant management, but others may require radiological, endoscopic, or surgical drainage. 4.4

Renal Abscess

Renal abscesses may be perinephric or intrarenal in location. Perinephric abscesses are generally seen in patients with diabetes mellitus and/or kidney stones. There is often obstruction of the genitourinary tract. These infections are most often due to aerobic GNRs. Intrarenal abscesses originate from a bacteremia and are most often due to S. aureus. Patients report fever and unilateral flank pain. They may have originally been treated for pyelonephritis but either did not respond or quickly relapsed. The urinalysis may yield normal results, especially with intrarenal abscesses. Diagnosis is confirmed with CT or sonographic imaging. Therapy consists of percutaneous drainage and antibiotics aimed at the offending pathogen. 5

SURGICAL PROPHYLAXIS

In recent years, there has been an increasing emphasis on ‘‘tightening up’’ the indications for antibiotic usage both to prevent and to treat surgical infections. There is increasing concern about resistant bacteria, and multiple studies have shown the lack of benefit and possible detriment of prolonged courses of antibiotics. The ‘‘more must be better’’ ap-

Table 3 Categories of Surgical Procedures Type of surgery Clean Elective surgery No inflammation or break in sterile technique No entry of a contaminated cavity such as the gastrointestinal or genitourinary tract Clean-contaminated Otherwise clean surgery done emergently Controlled entrance into a colonized body cavity Contaminated Acute nonpurulent inflammation Major contamination from a colonized body cavity Dirty Overt purulence encountered Preoperative perforation of a colonized body cavity Source: Adapted from Grace and Ahern 2001.

Example

Infection risk

Hernia repair

1%

Elective colon resection

8%

Colon resection for acute diverticulitis

15%

Colon resection for perforated diverticulitis

40%

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proach is steadily being replaced by a more judicious and focused approach. One example of this is in surgical prophylaxis. The goal of perioperative antibiotics is to prevent wound infection. The probability of wound infection in any particular case can be predicted on the basis of category of procedure (Table 3). It is clear that antibiotic prophylaxis is effective in reducing the wound infection rates for clean, uncontaminated cases but should only be administered perioperatively. A more prolonged course of antibiotics should be used for contaminated or dirty cases since there are generally residual bacteria in the peritoneal cavity. Prophylactic antibiotics should be administered on induction of anesthesia to provide high tissue levels during the surgical procedure. Antibiotics with short half-lives may need redosage during the surgical procedure. Postoperative antibiotics should be limited to 24 hours if given at all. The antibiotic chosen should have a narrow spectrum specific to the expected pathogens. See Figure 2 for antibiotic suggestions based on the type of surgery being performed. Luminal antibiotics should probably be used in addition to parenteral agents for colorectal prophylaxis. A common regimen includes 1 gram of oral erythromycin base and oral neomycin given at 1 p.m., 2 p.m., and 11 p.m. the day before surgery.

6 HELICOBACTER PYLORI INFECTION Heliobacter pylori (formerly Campylobacter pylori) is a motile, urease-producing gramnegative rod that lives in the mucus layer overlying the gastric mucosa. Humans are the major and possibly the only reservoir. It is a very common pathogen, infecting most people living in third world countries and 50%–60% of persons above 60 years of age living in the United States. H. pylori has been associated with gastritis, peptic ulcer disease, atrophic gastritis, gastric carcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. H. pylori does not appear to be tissue-invasive, and the mechanism of tissue damage is not clear. The microbial urease produces ammonia that protects the organism from gastric acid and may potentiate neutrophil-induced gastric injury. The identification and eradication of H. pylori–associated duodenal ulcer disease have been a major advance. Whereas recurrent ulceration after cessation of antisecretory treatment was extremely common in the past, successful eradication of H. pylori has now dramatically reduced the rate of recurrent ulcers.

HELIOBACTER PYLORI Associated with peptic duodenal or gastric ulcer, gastric carcinoma, and lymphoma Protective for gastroesophageal reflux disease (GERD), Barrett’s esophagus, adenocarcinoma of esophagogastric junction Testing Patients with peptic ulcer disease Endoscopy, serological analysis, or urease breath test Not for asymptomatic patients Treatment (Table 3) Peptic ulcer disease in H. pylori–positive patients Mucosa-associated lymphoid tissue (MALT) lymphoma

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Figure 2 Surgical prophylaxis. Antibiotics used to prevent surgical wound infections should be given immediately before skin incision. The type of antibiotic(s) used depends on the types of bacteria expected to be encountered. Operations should be considered to be clean, clean-contaminated, contaminated, or dirty (see Table 3). Suggested antibiotics and dosages are provided in the figure. For prolonged procedures, repeat dosage may be needed. Postoperative prophylaxis is not effective. (1) Some authorities add gentamicin for head and neck surgery. (2) For penicillin allergy. (Adapted from Grace and Ahern 2001.)

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The question remains whether or not H. pylori should be routinely sought after and eradicated even when it is not producing a specific complication such as peptic ulcer disease. The argument for routine treatment is prevention of peptic ulcer disease and possibly carcinoma of the stomach. With the apparent decrease in H. pylori infections in some Western societies, there has been a parallel decrease in the incidence of distal gastric malignancies. However, despite the link between H. pylori and gastric malignancy, evidence is lacking that eradicating infection actually reduces the risk of gastric carcinoma. There are potential downsides of routine H. pylori treatment. These include the obvious risk of selecting for resistant bacteria and the development of antibiotic complications such as C. difficile colitis. Certain strains of H. pylori have been epidemiologically

Table 4 Treatment Regimens for Helicobacter pylori Infection Regimen 7–10 Days Proton pump inhibitor omeprazole 20 mg bid or lansoprazole 30 mg bid plus Clarithromycin (500 mg PO bid) plus Amoxicillin (1 g PO bid) or Metronidazole (500 mg PO bid) 7–10 Days Ranitidine 300 mg bid plus Clarithromycin 500 mg bid plus Amoxicillin 1000 mg PO bid or Metronidazole 500 mg PO bid 2 Weeks Pepto-Bismol 2 tab qid plus Tetracycline 500 mg qid plus Metronidazole 500 mg tid Combination packets Helidac qid Bismuth 262.4 mg Metronidazole 250 mg Tetracycline 500 mg Prevpac bid Lansoprazole 30 mg Amoxicillin 500 mg Clarithromycin 500 mg a

Costsa $78.00 For 10 days

$74.00 For 10 days $72.00 For 10 days $18.40 For 10 days $60.00 For 10 days $64.00 For 10 days As above As above As above Over-the-counter $5.00 For 14 days $84.00 For 14 days $80.48 For 14 days

$252.00 For 14 days

Average wholesale price, Drug Topics 2000 Red Book.

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associated with protection against gastroesophageal reflux disease (GERD), Barrett’s esophagus, and adenocarcinoma of the esophagogastric (EG) junction. Routine treatment of H. pylori may decrease the risk of distal gastric malignancies at the expense of increasing the risk of GE junction malignancy. Therefore, routine eradication of H. pylori is not recommended at this time except in the treatment of symptomatic ulcer disease. Eradication may be reasonable in selected patients such as those with a history of cigarette smoking and family history of distal gastric adenocarcinoma. The routine testing and treatment of dyspeptic patients without endoscopic or radiographic documentation of ulcer disease have been suggested, though this course remains controversial. There are no data concerning postoperative treatment for H. pylori in patients who have undergone surgery for ulcer disease. Testing for H. pylori may be performed in three ways, all of which have excellent accuracy: 1) upper endoscopy and biopsy with samples taken for culture and staining of the organism and detection of preformed urease; 2) the urease breath test, involving the ingestion of radiolabled urea13 or urea14 containing meal and breath testing for CO213 or 14; and 3) serological testing for immunoglobulin G (IgG) and less commonly IgM antibodies to H. pylori. Drug therapy involves a bismuth salt combined with a type 2 histamine (H2) blocker (ranitidine) or proton pump inhibitor (PPI) (omeprazole 20 mg bid or lansoprozole 30 mg bid), together with two antibiotics. The PPI not only reduces gastric acidity but may also inhibit the bacterial urease. Antibiotics with clinical activity include amoxicillin, tetracycline, metronidazole, and clarithromycin. Several suggested treatment regimens are outlined in Table 4. Commercially available combination packets can simplify administration and improve compliance. Eradication rates approaching 80%–90% can be achieved. The urease breath test is the simplest follow-up test to prove eradication. Serological evaluation should not be used for posttreatment test of cure. If eradication is not achieved, a second-line treatment should be instituted. If clarithromycin and ampicillin are used in the primary treatment, then the second-line regimen should include a 7-day course of a PPI, bismuth subsalicylate (PeptoBismol), tetracycline, and metronidazole. If failure persists, H. pylori antimicrobial testing is warranted. BIBLIOGRAPHY Arnbjornsson E. Management of appendiceal abscess. Curr Surg 4:4–8, 1994. De Boer WA, Tytgat NJ. Treatment of Heliobacter Pylori infection. Br Med J 320:31–43, 2000. Dellinger EP, Gross PA, Barnett TL, Krause PJ, Martone WJ, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Clin Infect Dis 18:422–427, 1994. Elsakr ER, Johnson DA, Younes Z, Oldfield EC. Antimicrobial treatment of intra-abdominal infections. Dig Dis 16;47–60, 1998. Grace C, Ahern J. Guide to Antimicrobial Therapy for Adults. Burlington, VT: Fletcher Allen Health Care, 2001. Grace CJ, Alston WK, Ramundo MB. Pyogenic liver abscess. In: Medical Management of Liver Disease. New York: Marcel Dekker, 1999. Hardin DM. Acute appendicitis: Review and update. Am Fam Physician 60:2027–2034, 1999. Johnston DE, Kaplan MM. Pathogenesis and treatment of gallstones. N Engl J Med 328:412–424, 1993. Kohler L, Sauerland S, Neugebauer E. Diagnosis and treatment of diverticular disease: Results of a consensus development conference: The Scientific Committee of the European Association for Endoscopic Surgery. Surg Endosc 13:430–436, 1999.

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Lillemore KD. Surgical treatment of biliary tract infections. Am Surg 66:138–144, 2000. Parks TG. Natural history of diverticular disease of the colon. Clin Gastroenterol 4:53–61, 1975. Stollman NH, Raskin JB. Diverticular disease of the colon. J Clin Gastroenterol 29:241–252, 1999. Westphal JF, Brogard JM. Biliary tract infections: A guide to drug treatment. Drugs 57:81–91, 1999. Williams MP, Pounder RE. Heliobacter pylori: From the benign to the malignant. Am J Gastroenterol 94(suppl):511–516, 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics, 2000.

25 The Patient with Human Immunodeficiency Virus Infection Recognition, Testing, and Initial Assessment Kenneth H. Mayer Brown University, and The Miriam Hospital, Providence, Rhode Island, U.S.A.

Daniel E. Cohen Fenway Community Health, Boston, Massachusetts, U.S.A.

1 1.1

INTRODUCTION The Epidemic of Human Immunodeficiency Virus

In the early 1980s, clinicians in San Francisco, Los Angeles, and New York began reporting the appearance of unusual malignancies and opportunistic infections among men who had sex with men (MSM) and intravenous drug use (IDU), suggesting a syndrome of acquired, not endogenous, immune deficiency possibly due to a transmissible agent. In 1984 the human immunodeficiency virus (HIV) was identified independently by laboratories in the United States and France. HIV originated on the African continent and is the cause of acquired immunodeficiency syndrome (AIDS). Tremendous strides have been made in the treatment of HIV infection since 1996, primarily related to the advent of highly active antiretroviral therapy (HAART). The AIDSrelated mortality rate and opportunistic illnesses among HIV-infected patients have decreased and patients’ quality of life has improved. However, the advent of new therapies, monitoring schema, and drug toxicities has complicated the management of HIV infection as a chronic disease. The standard of care changes almost on a monthly basis, as results from ongoing clinical trials are reported, and even optimally treated patients may not respond appropriately to therapy. HIV-positive patients are still at greater risk of illness and death than the population at large. For these reasons patients with HIV infection have better outcomes when under the care of clinicians with experience in the management of HIV disease. Although specialists may play an increasingly central role in managing patients once they are found to be HIV-infected, well-informed primary care providers are an essential part of any effective HIV treatment and prevention program. The prompt identification of HIV infection by primary care providers is vitally important, since they may be the first clinicians to have contact with at risk individuals soon after they are infected. Multiple 495

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studies have demonstrated that earlier entry into care is associated with improved outcomes for HIV-infected patients. Of the 750,000 to 900,000 Americans living with HIV infection, more than one-third are unaware of their infection and an almost equal number know they are HIV-infected are not receiving state-of-the-art care. Primary providers can play a vital role in identifying these individuals and triaging them to colleagues who can provide appropriate services. In addition to identifying HIV-infected patients who are unaware of their serostatus, primary providers can play a crucial role in HIV risk reduction and thus in slowing the spread of the epidemic. Over the past few years, the rate of new HIV infections has plateaued at 30,000–50,000 per year. The majority of men and women in ‘‘high-risk groups’’ are uninfected. Therefore, clinical encounters with primary providers provide an important opportunity to convey information about the patient’s risk of infection and ideally to impart skills and motivation to help him or her reduce that risk. 1.2

Virological Characteristics

HIV is a retrovirus, meaning that its genome is composed of ribonucleic acid (RNA) but that its life cycle includes a deoxyribonucleic acid (DNA) intermediate (the provirus) that integrates into target cells, necessitating the transcription of DNA from RNA (so-called reverse transcription). The virus has several unique steps in its life cycle that offer opportunities for effective antiretroviral therapy. HIV can be transmitted as a cell-free viral particle or through cell-to-cell contact. The highest concentrations of the virus are found in blood, semen, and cervicovaginal secretions, thus explaining its epidemiological characteristics. The virus can enter the body through parenteral exposures or binding of mucosal cells that have CD4 receptors that can bind HIV. Anal sex and traumatic vaginal sex may potentiate HIV transmission through mucosal abrasions that can allow the virus more direct access to submucosal tissues. The leukocyte subpopulations that are most readily infected by HIV include T-helper cells (also called CD4⫹ T lymphocytes) and monocyte/macrophage cells, including follicular dendritic cells in the genital tract mucosa. Once the virus has contact with a target cell, the viral envelope fuses with the cell membrane, discharging the viral core into the cell’s cytoplasm. The viral RNA immediately begins the process of reverse transcription; DNA templates are produced and are integrated into the host cell’s genome and used for subsequent protein synthesis and virion assembly. Daughter virions then bud off from the cell membrane with potential to infect new target cells. The replication process is remarkably efficient and highly inaccurate. Approximately 1010 new virions are produced each day in an HIV-infected individual, but a large proportion of this viral progeny contains genetic errors of transcription. Although many of these mutant offspring will be nonfunctional, a fraction contain mutations that confer advantages such as resistance to antiretroviral medications. The clinical implication of this finding is that even before the initiation of antiretroviral therapy, virions that are not inhibited by single or double antiretroviral drug therapy are present. However, it is unlikely that mutants that are able to resist combinations of three or more drugs will be generated at the onset of infection; hence the rationale for combination antiretroviral therapy (discussed later). Another implication of the kinetics of HIV replication is that millions of HIV-infected white blood cells are formed and destroyed every day. Thus, for the majority of individuals, HIV infection is a dynamic infection in which retrovirally induced immune destruction is compensated by the host’s ability to generate new immune effector cells. The onset of

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HUMAN IMMUNODEFICIENCY VIRUS RECOGNITION Need for prompt recognition Treatment of the patient Risk reduction education Importance of detailed history Sexual Injection drug use Blood products Indications for testing Risk behavior Others (see Table 1) Acute human immunodeficiency virus (HIV) infection (see Table 2) Differential diagnosis of acute HIV infection (see Table 3)

opportunistic infections or malignancies signals the host’s inability to compensate for the high level of cellular turnover induced by chronic HIV infection (see Chapter 26). The next sections of this chapter are designed to describe the approach to the patient at risk for HIV, the detection of acute HIV infection, and the subsequent management of infected patients. 2 2.1

COUNSELING AND DISCUSSION Recognition of Those at Risk

In the early years of the HIV epidemic in the United States, the infection was detected primarily in specific populations who were considered to be at high risk, including IDU and MSM populations and patients with hemophilia and other blood product recipients. This terminology implies that certain individuals are less susceptible than others to infection. Since HIV infection now routinely affects persons in a wide spectrum of socioeconomic and behavioral categories, it is more helpful to think in terms of ‘‘risk behavior’’ than ‘‘risk group.’’ Identifying patients at risk therefore means determining an individual patient’s risk-taking behavior. This determination depends on a thorough history of sexual practices and patterns of drug use. This history should be obtained in a detailed and nonjudgmental fashion. Since persons of any age may be newly diagnosed with HIV infection, this history should be obtained from all adult patients. Since several hundred thousand asymptomatic patients in the United States are unaware that they are HIV-infected, it is incumbent on the medical provider to recognize people who are infected or at increased risk and to provide counseling and recommend testing when appropriate. The rationale for prompt detection of HIV infection is twofold: infected people are more likely to benefit from antiretroviral therapy and opportunistic infection prophylaxis the earlier they are identified, and they will be more amenable to protecting their partners if they are aware of their HIV status. 2.2

Risk Reduction

When discussing issues relating to potential HIV transmission, it is important to convey the concept of relative risk. Often when patients are counseled about the inadvisability of ‘‘high-risk’’ behavior they perceive a message that most of the activities that they enjoy

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are dangerous and hence forbidden. This may instill a sense that nothing short of complete abstinence is of any benefit and undermine the patient’s will to avoid risk. A more profitable strategy is to discuss the fact that some kinds of behavior (such as unprotected anal intercourse) is associated with a high risk of infection, others (such as intercourse with a latex condom) are much less risky, and still others (such as fellatio) are intermediate in risk. The actual per contact rates of HIV transmission are not well established, given the ethical and logistical issues involved in determining when a person has become infected with HIV. Cohort studies suggest that the average per contact rate may vary from less than 1 per 1000 contacts to more than 1 in 10 for unprotected anal or vaginal intercourse. An infected man is four times more likely to transmit HIV to his female partner than vice versa, and a male engaging in receptive anal intercourse is far more likely to acquire HIV from his insertive partner than the converse. The reasons for the variability include the fact that different tissues are more or less susceptible to HIV infection because of the numbers and types of cells that are present that can bind or transmit HIV. Other factors may alter HIV susceptibility or infectiousness, including the presence of concomitant genital tract infection, sexual trauma, the level of HIV in the infected partner’s genital secretions, and the strain of the virus to which one is exposed. Additional factors that play a role include circumcision (the foreskin contains more cells that can bind or transmit HIV) and a woman’s prepubertal or postmenopausal status (estrogen thickens the cervicovaginal epithelium and protects against HIV). Finally, oral exposure to HIV appears to be much less risky than anal or vaginal intercourse, possibly because of endogenous anti-HIV compounds that are present in the oropharynx. However, it is important to note that there are several well-documented case reports describing HIV infection after oral exposure to ejaculate; therefore, fellatio is not as risky as unprotected anal or vaginal intercourse but is not risk-free. It is up to the well-informed patient to make his or her own decision regarding acceptance of risk with the physician serving as a nonjudgmental adviser. Attempts to assign numerical values to the risk associated with a single act are not likely to be helpful as they may be misleading or leave the patient with the impression that the physician has given leave to engage in certain types of behavior because the individual risk is low. Patients at risk for HIV infection may be in relatively stigmatized groups including IDU and MSM individuals. Accurate assessment of HIV risk and appropriate counseling for risk reduction depend on complete reporting of all potential risky behavior, including activities that may be socially unacceptable or illegal or that the clinician may find personally objectionable. In such circumstances it is essential that the clinician remain absolutely objective in his or her questioning. Such marginalized patients are not likely to be forthcoming with accurate information if they believe that their medical provider disapproves of specific behavior or is inclined to judge them on the basis of what they relate about themselves. Conversely, once a bond of trust is established between physician and patient, the patient is more likely to discuss high-risk behavior frankly and to accept the physician’s counseling regarding risk reduction. 2.3

Testing

Since a large number of HIV-infected individuals are unaware of their infection, it is critical that all clinicians assess risk for HIV and offer testing when appropriate. Obtaining a thorough history, including nonjudgmental but specific questioning about sexual activity and drug use, has become even more important in identifying patients at risk for HIV infection.

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HIV testing should be performed for any patient who requests it. Other indications for voluntary testing include sexually transmitted diseases, pregnancy, and active tuberculosis. Testing should be considered in young adults with shingles or women with refractory or recurrent vaginal candidiasis. Oral candidiasis should prompt HIV testing, especially if not explained by antibiotic use or diabetes mellitus. Although a common symptom, chronic unexplained fatigue should prompt consideration of HIV testing. Voluntary testing is also recommended for adults hospitalized in facilities where the seroprevalence exceeds 1% or where the AIDS case rate exceeds 1 per 1000 discharges. Finally, HIV testing should be considered for patients who have generalized lymphadenopathy, unexplained dementia, aseptic meningitis, peripheral neuropathy, chronic and unexplained fever, diarrhea, weight loss, generalized herpes simplex infection, or multidermatomal herpes zoster; unexplained cytopenias, including chronic disease anemia, leukopenia, and thrombocytopenia; infection with hepatitis C virus; B-cell lymphoma; or other opportunistic conditions suggestive of cell-mediated immunodeficiency (see Table 1). 2.4

Pre- and Posttest Counseling

All patients who are being tested for HIV antibodies should receive counseling before the test is performed. This should include information about what the test is actually measuring (i.e., antibodies to HIV) and the significance of positive, negative, and indeterminate results. It is important to explain that HIV infection can occur without seropositivity because

Table 1 Indications for Voluntary Human Immunodeficiency Virus Testing Patient request Sexually transmitted diseases Pregnancy Active tuberculosis Herpes zoster in young adult or multidermatomal herpes zoster Recurrent vaginal candidiasis Oral candidiasis Generalized lymphadenopathy Infection with hepatitis C virus Unexplained chronic fatigue Unexplained dementia Aseptic meningitis Peripheral neuropathy Chronic unexplained fever, diarrhea, or weight loss Generalized herpes simplex infection Unexplained cytopenias Chronic disease anemia Leukopenia Thrombocytopenia B-cell lymphoma Opportunistic illness suggesting defective cell-mediated immunity Adults hospitalized in facilities where Seroprevalence exceeds 1% or acquired immunodeficiency syndrome (AIDS) case rate exceeds 1 per 1000 discharges

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of a possible delay in the development of anti-HIV antibodies after exposure (the ‘‘window period’’), which may last for weeks or even months. All patients should give informed consent in writing before HIV testing. Posttest counseling includes providing and explaining test results and is a good opportunity to reemphasize the potential for seronegative infection during the window period. If the patient’s result is seronegative, this is often a convenient time to schedule an appointment for repeat HIV testing. Reinforcement of risk reduction behavior and further education should be provided. It is advisable to deliver all HIV test results to the patient in person, and not by telephone or correspondence. This policy minimizes miscommunication and maximizes the chance for effective risk reduction counseling. Confidentiality about the testing should be stressed. To be confident that HIV infection is not present, repeated testing should be offered approximately 6 months after the initial test if the result is negative or indeterminate. However, the patient must understand that the repeat test will be most helpful if he or she has not had any additional potential exposures during that interval. For this reason preand posttest counseling must also address risk behavior and the patient must understand exactly what behavior might cause exposure to infection. Likewise, patients may erroneously believe that sexual intercourse with penetration is only risky if ejaculation has occurred or that anal or vaginal intercourse is risky for the receptive but not for the insertive partner. Patients using injection drugs should be referred for counseling and rehabilitation. They should be educated about using sterile needles if available and techniques to clean their ‘‘works’’ (see Chapter 35, Table 3). Persons found to be HIV-positive should be referred to a clinician experienced in the management of HIV disease. This diagnosis can represent a severe psychological stress, and the patient may be at risk for depression, social withdrawal, and suicide. The provider should be alert for these symptoms and have access to social work and psychiatry support. 3 3.1

CLINICAL PRESENTATION OF HUMAN IMMUNODEFICIENCY VIRUS Acute Human Immunodeficiency Virus Infection

Acute HIV-1 infection is symptomatic in a large proportion of patients. The prevalence of symptomatic primary HIV infection, referred to as acute retroviral syndrome, varies from series to series; up to 90% of patients may manifest some symptoms. Because of a lack of awareness among susceptible patients and a low index of suspicion among health care providers, HIV-1 infection is probably still underreported. Clinical manifestations of acute retroviral illness appear within days to weeks of exposure to HIV, most commonly at 2 and 6 weeks (see Table 2). Common symptoms include fever, frequently in excess of 102⬚F; night sweats; headache; fatigue; and a nonpruritic erythematous maculopapular rash. This rash may be variable in appearance and may be evanescent; the patient may not notice it. In dark-skinned individuals it may not be readily apparent. Other common findings include lymphadenopathy and pharyngitis, occasionally with exudates. The overall syndrome may thus be indistinguishable from infectious mononucleosis. Oral or genital ulcers and oral candidiasis are occasionally seen; these findings are considered particularly suggestive of acute HIV infection by some investigators. Neurological findings may occasionally predominate, including a syndrome of aseptic meningitis. Laboratory findings are nonspecific and may include cytopenias and elevated liver enzyme levels. HIV antibody testing at this stage most often yields negative findings.

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Table 2 Signs and Symptoms Associated with Acute Retroviral Syndrome Clinical finding

Patients, %

Fever Fatigue Weight loss Pharyngitis Myalgia Night sweats Diarrhea Rash Lymphadenopathy Headache Nausea, vomiting Aseptic meningitis Oral or genital ulcers Thrombocytopenia Leukopenia Elevated liver enzyme levels

>80% >70% 70% 50%–70% 50%–70% 50% 50% 40%–80% 40%–70% 32%–70% 30%–60% 24% 10%–20% 45% 40% 21%

Source: Adapted from Schacker et al. 1996 and Kahn and Walker 1998.

Occasionally an indeterminate HIV antibody result, consisting of a reactive enzyme immunoassay and fewer than two reactive bands on the confirmatory Western blot, occurs. Because of the nonspecific nature of the syndrome, the differential diagnosis for patients with acute retroviral syndrome can be broad (see Table 3). Most often it includes infectious mononucleosis, streptococcal pharyngitis, and viral respiratory tract infections. Depending on which symptoms are predominant, acute HIV infection can be confused with secondary syphilis, acute toxoplasmosis, viral hepatitis, or viral meningitis. None of the initial clinical findings or laboratory results is pathognomonic for acute retroviral illness. Therefore, acute HIV infection should be considered for any patient who is experi-

Table 3 Differential Diagnosis of Acute Retroviral Syndrome Infectious mononucleosis (Epstein-Barr virus or cytomegalovirus) Toxoplasmosis Streptococcal pharyngitis Rubella Secondary syphilis Viral meningitis Other viral infections (e.g., influenza) Viral hepatitis Disseminated gonococcal infection Primary herpes simplex infection Drug reaction

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encing a compatible syndrome. Making the diagnosis depends on identifying a potential HIV exposure in the preceding few weeks. Therefore, patients who have such an illness should be questioned about potential risk behavior, including sexual activity or injection drug use in the previous 6–8 weeks. If high suspicion is generated by this history, but the antibody test result is negative or indeterminate, the diagnosis can be confirmed by testing plasma or serum for the presence of HIV RNA by one of the sensitive newer amplification techniques, i.e., polymerase chain reaction (PCR), branched DNA assay (bDNA), or nucleic acid sequence based analysis (NASBA). HIV RNA testing is not recommended for screening of lower-risk populations because nucleic acid amplification assays are costly, laborious, and prone to false-positive results. After the acute retroviral syndrome, HIV-infected patients often remain asymptomatic for many years before the onset of immunodeficiency. They need careful primary care to manage any common comorbidities such as sexually transmitted diseases, tuberculosis, or viral hepatitis and to monitor their immune function to determine when antiretroviral and prophylactic antimicrobial therapies are indicated. 3.2

Natural History of Human Immunodeficiency Virus

The clinical course of untreated HIV infection has by now been well established. In most cases HIV causes progressive loss of T-helper cells, which eventually renders the patient unable to mount an immune response against a variety of opportunistic pathogens. A hypothetical patient’s clinical course over time is illustrated in Figure 1. The actual time course of this decline is highly variable from one patient to another. Indeed, in a small minority of cases, no loss of immunological function is detectable even after 10 years or more of untreated infection. Antiretroviral drug therapy is generally not indicated for this population, referred to as long-term nonprogressors. In these individuals, the immune system appears able to control HIV replication. In most cases, however, T-helper cell counts eventually decline to the point that clinical illness is imminent. This fact is the rationale for the use of HAART. However, that decline may take place in as few as 1–2 years or after 8–10 years of infection. During most of this time patients generally remain asymptomatic and are usually unaware of their infection. One powerful predictor of the rate of eventual T-cell decline and subsequent risk of progression to AIDS is the baseline plasma HIV RNA level. This value tends to be relatively stable after the acute HIV infection has subsided, when an equilibrium of sorts is established between viral replication, on one hand, and T-helper cell generation, on the other. The amount of virus present in the patient’s plasma is determined by a balance between viral replication and destruction. This steady-state level of virus (viral load) varies individually from <1000 (log 103) copies/mm3 to >100,000 (log 105) copies/mm3. With time, though, the viral load steadily increases, in conjunction with progressive immune destruction and a fall in the CD4⫹ lymphocyte count. There is a fairly well-defined correlation between a patient’s T-helper cell count and the particular infections to which he or she is susceptible. In general, more virulent pathogens such as Mycobacterium tuberculosis and Streptococcus pneumoniae may cause disease at relatively high T-helper cell counts in excess of 300 cells/mm3. Other opportunistic pathogens, such as Pneumocystis carinii, seldom present a threat until counts are below 250 cells/mm3. Finally, organisms such as Toxoplasma gondii and Mycobacterium avium complex may be life-threatening when counts are below 100 cells/mm3. The advanced stage of HIV infection, acquired immunodeficiency syndrome (AIDS), is defined by the acquisition of opportunistic illnesses or a T-helper cell count below 200 cells/mm3.

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Figure 1 Natural history of infection and response. On initial infection with HIV there is rapid replication of HIV, sometimes up to 106 (1,000,000) virions/mm3 of blood. Immunological destruction begins with a fall in CD4⫹ helper lymphocytes. During this time the patient may experience the acute retroviral syndrome. A steady state is finally reached, in which the CD4 count and viral load remain relatively stable despite high levels of HIV replication and destruction. Most patients are asymptomatic during this time. With time HIV replication continues, in association with progressive immunological damage, placing the patient at risk for opportunistic infections. CD4 count, cells/cubic millimeters; viral load log 10. HIV, human immunodeficiency virus; TB, tuberculosis.

4 4.1

INITIAL MANAGEMENT OF THE HUMAN IMMUNODEFICIENCY VIRUS–POSITIVE PATIENT History

Critical portions of the initial medical history of a patient with HIV infection include the date of his or her first positive HIV result, his or her last negative HIV test result (if available), and any prior CD4⫹ lymphocyte counts and quantitative HIV RNA measurements. It is helpful to obtain documentation of the patient’s HIV status as there have been cases of factitious HIV infection in which patients seek to be wrongly identified as HIVpositive for secondary gain. It is also helpful to ascertain why the patient was tested and what the presumed mode of acquisition was. Occasionally a patient does not know how he or she became HIV-infected, and this situation can serve as an initial opportunity for education about methods of HIV transmission. Aside from a general past medical history and review of systems, the HIV-specific medical history should inquire about typical presenting symptoms of HIV, including fevers, night sweats, weight loss, generalized lymphadenopathy, diarrhea, and oral candidiasis. Questions should also address any history of opportunistic illnesses, especially including recurrent bacterial pneumonias, Pneumocystis carinii pneumonia, tuberculosis (including extrapulmonary disease), cryptococcal meningitis, herpes zoster, cytomegalovirus infec-

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INITIAL MANAGEMENT History Fever, night sweats Chronic diarrhea Weight loss Geographical exposure risk Sexually transmitted diseases Tuberculosis (TB) Medications Physical exam Lymphadenopathy Hepatosplenomegaly Oral Thrush Kaposi’s sarcoma Poor dentition Pelvic exam and Papanicolaou (Pap) smear Anorectal Laboratory (see Table 4) Immunizations (see Table 5) Prophylaxis (see Table 6) Indications for antiretroviral therapy (see Table 6) Available antiretroviral agents (see Table 7)

tion, Mycobacterium avium infection, invasive cervical cancer, and Kaposi’s sarcoma. A geographical history should be obtained since regionally prevalent illness such as histoplasmosis, blastomycosis, and coccidioidomycosis may occur as reactivation disease after a patient has left an endemic region. Because of the nature of HIV transmission, a detailed sexual history should also be included and any history of specific sexually transmitted diseases should be elicited. Included in this category are viral hepatitides, which should also be asked about specifically. 4.1.1

Tuberculosis History

A detailed tuberculosis (TB) exposure history should include: any known exposure to TB including a family history; date of the patient’s last tuberculin skin test; history of a reactive skin test result and, if present, duration of therapy for latent TB (chemoprophylaxis), if any, and date of the last chest radiograph (if any). 4.1.2

Medication and Drug History

A thorough medication history is essential, especially if antiretroviral therapy is going to be initiated. Patients should be asked about all medications they are currently taking, including over-the-counter medications, herbal preparations, and nutritional supplements. There is a tendency for many patients to consider herbal medications benign and therefore not mention their use. Patients should be reminded that any pharmacologically active substance may have unwanted side effects or interactions with other medications. Use of tobacco, alcohol, and illicit drugs should be accurately ascertained in a nonjudgmental manner.

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Physical Examination

A thorough physical examination should be done at the initial visit, focusing on organ systems likely to be affected by opportunistic illnesses. Height and weight should be measured at baseline; in particular, changes in weight can be a sensitive marker of systemic illness. With regard to the vital signs, fever may suggest infection, or hemodynamic instability may suggest hypovolemia or adrenal insufficiency. A thorough skin examination should look for lesions suggesting Kaposi’s sarcoma (purple nodules or plaques) and other opportunistic illnesses. The ocular fundi should be visualized, looking for retinal lesions. In the oropharynx, candidiasis and oral hairy leukoplakia are sensitive markers of immune suppression; Kaposi’s sarcoma is often seen first in the mouth; and dental and gingival health should be carefully noted. An assiduous search should be made for enlarged lymph nodes in all accessible chains. Hepatomegaly or splenomegaly may suggest a number of systemic infections. A detailed anogenital examination is imperative since many HIVinfected patients are also at risk for other sexually transmitted diseases. In the MSM population the anus should be closely examined for lesions of herpes simplex and human papillomavirus infection. Women should have a thorough pelvic examination with Papanicolaou (Pap) smear, and annually thereafter. Women with an abnormal Pap smear result or a history of human papillomavirus infection should have more frequent exams and should be referred for colposcopy. A careful neurological exam should also be done on all patients at baseline. 4.3

Laboratory Studies

A baseline laboratory evaluation of a new HIV-positive patient (Table 4) should include complete blood count and routine chemistry testing to assess liver and kidney function.

Table 4 Recommended Baseline Laboratory Evaluationa HIV serological tests (if not documented) CBC with differential Chemical panel including liver enzyme levels CD4⫹ cell count Quantitative HIV RNA (PCR or bDNA) Serological test for syphilis Tuberculin skin test HBsAg, HBsAb, HBcAb Hepatitis C antibody Anti-Toxoplasma gondii IgG Anti-CMV IgG G-6-PD (in appropriate populations) Papanicolaou smear (for women) a

HIV, human immunodeficiency virus; CBC, complete blood count; RNA, ribonucleic acid; PCR, polymerase chain reaction; bDNA, branched deoxyribonucleic acid assay; HBsAg, hepatitis B surface antigen; HBcAb, hepatitis B core antibody; IgG, immunoglobulin G; CMV, cytomegalovirus; G-6PD, glucose-6-phosphate dehydrogenase; CMV, cytomegalovirus.

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4.3.1 T Cells A CD4⫹ lymphocyte count is the most readily available quantitative measure of the status of the cell-mediated immune system and should be checked at baseline and periodically (discussed later). 4.3.2

Viral Load

A quantitative plasma HIV RNA assay should also be performed periodically. There is still some controversy over whether ultrasensitive assays, with lower limits of detection below 100 copies/mm3, offer any real clinical benefit over standard assays. The HIV RNA level should be measured before any planned change in antiretroviral therapy and at least every 4 weeks after a change until it has reached a stable level. Measurements every 3 months thereafter are usually adequate. Because transient states of immune activation may elevate HIV RNA levels, levels should not be measured within 4 weeks of receiving a vaccination or during an intercurrent illness unless there is concern that the illness is due to failure of antiretroviral therapy. 4.3.3

Concomitant Infections

New HIV patients should also be tested for concomitant infections that may be transmitted in a similar fashion such as hepatitis B and C virus infection and those which present particular problems for HIV-infected patients, such as tuberculosis, cytomegalovirus infection, and toxoplasmosis. At a minimum, baseline testing should include serological testing for prior and active hepatitis B infection (hepatitis B surface antigen and antibody and core antibody) and for hepatitis C antibodies. Patients who are not hepatitis B–seropositive should be given the hepatitis B vaccine series (see Chapter 43). Antibodies against Toxoplasma gondii and cytomegalovirus should be measured at baseline. These assays are performed only for evidence of prior exposure, which would indicate latent infection and risk for subsequent reactivation. Therefore, a single titer of immunoglobulin G (IgG) antibodies is adequate. This is in contrast with testing of symptomatic patients for acute toxoplasmosis, in whom acute and convalescent antibodies or IgM antibody fraction is measured. 4.3.4

Syphilis

All HIV-infected patients should be tested for syphilis and treated if a serological test is reactive. This population is at increased risk of complications from syphilis, including neurosyphilis, rapid progression of disease, and failure of treatment. For this reason, a lumbar puncture should be strongly considered for all HIV-infected patients diagnosed with syphilis of unknown duration. The use of tetracyclines for treating syphilis in HIVpositive patients is discouraged and penicillin desensitization is preferred in penicillinallergic individuals because of the predilection of the spirochete to disseminate early to the central nervous system in the setting of HIV infection. 4.3.5

Tuberculosis

Tuberculin skin testing at baseline and every year should also be routine for HIV-infected patients. Any HIV-positive patient with a reactive tuberculin skin test (at least 5-mm in diameter) result should receive antituberculous therapy for latent TB for 1 year (see Chapter 13). Declining CD4⫹ cell counts are associated with an increased rate of anergy. Therefore, in patients at particularly high risk of TB exposure (such as family members of

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infected persons) consideration should be given to antituberculous prophylaxis even in the absence of skin test reactivity. 4.4

Immunization

Although some immunizations for the HIV-infected population are still controversial, there are many that carry little risk and are likely to benefit patients (see Table 5). Current recommendations suggest that all patients with a CD4⫹ lymphocyte count of 200 cells/ mm3 or greater receive a single dose of 23-valent pneumococcal vaccine if they have not received one in the prior 5 years. In patients with fewer than 200 CD4⫹ cells/mm3, the likelihood of development of an effective humoral response to the vaccination is lower; however, the vaccination is safe and should still be considered. Yearly influenza vaccinations are warranted for all HIV-infected patients. Investigators had been concerned because plasma HIV RNA measurements obtained immediately after influenza vaccination may show a transient rise in viral load. However, there is no evidence that such transient ‘‘blips’’ lead to a sustained rise in viral load or to subsequent development of antiretroviral resistance; thus the risk associated with influenza vaccination is negligible. HIV-infected patients should receive tetanus-diphtheria booster vaccinations every 10 years in accordance with the recommendation for the general adult population. Vaccination against hepatitis B virus is recommended for all adults who do not have evidence of prior immunization or prior hepatitis B infection. Certain patient populations, such as MSM individuals and persons with chronic hepatitis C, should be immunized against hepatitis A. For young patients who are unlikely to have preexisting hepatitis A immunity,

Table 5 Adult Vaccinations in the Human Immunodeficiency Virus Populationa Vaccination

Recommended for whom

When

Influenza

All adults

Yearly

Pneumococcal (23valent)

All adults

At first visit

Diphtheria-tetanus (dT) booster Hepatitis A

All adults

Every 10 years

Comments Best response when CD4⫹ >200 cells/mm3 but vaccination of everyone No significant risk of sustained viral load increase after immunization Repeat every 5 years If first dose given when CD4⫹ <200 cells/mm3, repeat when CD4⫹ >200 cells/mm3 on HAART

MSM; chronic Months 0 and 6 liver disease Hepatitis B All non-immune Months 0, 1, 6 adults Measles-mumps-rubella Contraindicated Adverse reactions reported; avoid (MMR) use Oral polio vaccine Contraindicated Avoid use in household contacts Varicella-zoster virus Contraindicated a

MSM, men who have sex with men; HAART, highly active antiretroviral therapy.

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it is usually more cost-effective simply to vaccinate against hepatitis A virus (HAV) rather than test for HAV antibodies. Live virus vaccines should not be used for HIV-positive adults. These include oral polio vaccine, varicella-zoster vaccine, and vaccines for measles, mumps, and rubella. Furthermore, household members of an HIV-infected patient should not receive oral polio vaccine, because of the risk of infection due to fecal shedding of live poliovirus. If someone in the patient’s household has received oral polio vaccine, the patient should avoid contact with that person for the next month. 4.5

Prophylaxis for Opportunistic Infections

Prophylaxis may be primary to prevent occurrence of infection or secondary to prevent recurrence of established infection (see Table 6).

Table 6 Prophylaxis a Infection

Indications

Agents

Pneumocystis carinii CD4⫹ <200/mm3 ; TMP-SMZ pneumonia (PCP) previous PCP Dapsone

Toxoplasma gondii

Mycobacterium avium (MAI)

Candida spp.

Herpes simplex

Cryptococcus neoformans Cytomegalovirus (CMV) Histoplasmosis a

Aerosolized pentamidine Atovaquone CD4⫹ <200/mm3 ; TMP-SMZ previous toxoplasma infection CD4⫹ <100/mm3 ; Azithromycin previous MAI Clarithromycin Rifabutin Frequent and severe recurring thrush, esophagitis, vaginitis Frequent and severe recurring oral, anal, genital infections

Dose ss Daily ds tiw 100 mg/day 300 mg/mo

Comment Desensitize for severe reactions (Gluckstein and Ruskin 1995) Test for G-6-PD deficiency Nebulizer (Respirgard II)

750 mg bid ss Daily ds tiw

1200 mg/wk 500 mg bid 300 mg/day

Fluconazole

100 mg/day

Acyclovir Famciclovir Valacyclovir

400 mg bid 250 mg bid 1000 mg/day

Drug interaction with PI and NNRTI Concern for azole resistance with prolonged use

Primary prophylaxis generally not recommended

ss, single-strength; ds, double-strength; tiw, three times per week; bid, twice daily; G-6-PD, glucose-6-phosphate dehydrogenase; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor.

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4.5.1 Pneumocystis carinii Chemoprophylaxis against Pneumocystis carinii pneumonia (PCP) has demonstrated benefit in preventing mortality and should be strongly recommended in patients with fewer than 200 CD4⫹ cells/mm3 (or a CD4⫹ percentage less than 14%) or those who have oral thrush or a prior history of PCP. Trimethoprim & sulfamethoxazole (TMP-SMZ) is significantly more efficacious than other preventive therapies (dapsone, atovaquone, and inhaled pentamidine) and should be used whenever possible. Patients who experience a mild skin rash caused by sulfonamides should be advised to continue the medication and to use antihistamines as needed since frequently the rash abates. In patients with more severe reactions to sulfonamides, an oral desensitization regimen should be considered; one such regimen is outlined by Gluckstein and Ruskin (1995). Patients who have been successfully desensitized to TMP-SMZ should not interrupt therapy since restarting TMP-SMZ after an interruption can precipitate a new adverse reaction. TMP-SMZ also provides some protection against bacterial pneumonia and sinusitis as well as toxoplasmic encephalitis. 4.5.2 Mycobacterium avium Complex Use of macrolides for prophylaxis against Mycobacterium avium complex disease is recommended for patients with fewer than 100 CD4⫹ cells/mm3. Azithromycin or clarithromycin likely also provides some protection against community-acquired pneumonia and some gastrointestinal parasites such as Giardia lamblia. 4.5.3

Other Opportunistic Infections

HIV-infected patients who have severely compromised immune systems may have recurrent infections with Candida albicans (oral thrush, esophagitis, or vaginitis) and may require chronic suppressive antifungal therapy. Likewise, the patients may be predisposed to recurrent herpes simplex infections and may require acyclovir prophylaxis to decrease the frequency of recurrences. In both situations, the need for chronic suppressive therapy may be obviated by the restoration of immunocompetence through the institution of highly active antiretroviral therapy. Primary prophylaxis for cytomegalovirus infection, cryptococcosis, and histoplasmosis is generally not recommended. 5

MANAGEMENT OF ADVANCED HUMAN IMMUNODEFICIENCY VIRUS INFECTION

The care of HIV-infected individuals has become increasingly complex as newer antiretroviral therapies have become available. Natural history studies suggest that patients are likely to have clinical progression if their CD4⫹ counts are below 200 cells/mm3 but are more likely to benefit from antiretroviral therapy if it is initiated when the CD4⫹ counts are above 350 cells/mm3. Current controversy exists as to whether to start therapy even earlier, when the CD4⫹ count is between 350 and 500 cells/mm3 or to wait because of the increasing reports of antiretroviral medication–associated morbidities. The purpose of the current chapter is not to review all antiretroviral medications. Table 7 summarizes the current treatment recommendations from the International AIDS Society-USA (Yeni et al., 2002) and the Department of Health and Human Services (2002) guidelines. The latter guidelines can be obtained from the HIV/AIDS Treatment Information Services (ATIS) (1-800-448-0440) or found on the ATIS website. Table 8 summarizes the current U.S. Food and Drug Administration (FDA)-approved antiretroviral drugs.

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Table 7 Recommendations on Initiating Antiretroviral Therapy for Human Immunodeficiency Virus-1 Infectiona International AIDS Society-USA (Yeni et al., 2002) Plasma HIV RNA levels, copies/mL

T-helper cell count, cells/mm3 <350 350–500 >500

<5000

5000–30,000

Recommend therapy Consider therapy Defer therapy

Recommend therapy Recommend therapy Consider therapy

>30,000 Recommend therapy Recommend therapy Recommend therapy

Department of Health and Human Services (2002) Clinical category Acute HIV infection or <6 months since seroconversion Symptomatic (AIDS, severe symptoms) Asymptomatic, AIDS Asymptomatic

CD4⫹ cell count

Recommendations

Any

Any

Treat

Any value

Any value

Treat

CD4⫹ T cells <200/mm3 CD4⫹ T cells >200/mm3 but <350/mm3

Any value

Treat

Any value

Treatment should generally be offered though controversy exists Some experts recommend therapy while others recommend careful observation in the absence of very high viral loads Many experts defer therapy

Asymptomatic

Asymptomatic

Plasma HIV RNA

>30,000 (bDNA) or >55,000 (RT-PCR) CD4⫹ T cells >350/mm3 CD4⫹ T cells >350/mm3

<30,000 (bDNA) or <55,000 (RT-PCR)

a

HIV, human immunodeficiency virus; RNA, ribonucleic acid; AIDS, acquired immunodeficiency virus; bDNA, branched deoxyribonucleic acid; RT-PCR, reverse transcriptase polymerase chain reaction.

6

CONCLUSION

It is clear that the management of HIV infection has become increasingly complex as people with HIV are not only living longer, but also requiring more complex regimens that have associated toxicities. Thus, in the current era, it is recommended that all primary care providers familiarize themselves with the recognition of HIV infection and be comfortable with pre- and posttest counseling for persons at risk. However, it is also clear that people living with HIV tend to have better outcomes if managed by a clinician who either is trained in infectious diseases and/or AIDS medicine or has extensive experience caring for HIV-infected individuals. One of the important activities that primary providers can do in relation to HIV care is to identify those individuals in their community who can serve as referrals and/or partners in the care of HIV-infected persons. With more effective identification of infected persons at earlier stages of their infection by primary providers

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Table 8 Currently Approved Antiretroviral Medicationsa Generic name (trade name) Zidovudine (Retrovir) Didanosine (Videx)

Zalcitabine (Hivid) Stavudine (Zerit) Lamivudine (Epivir) Lamivudine; zidovudine (Combivir) Abacavir sulfate (Ziagen) Zidovudine/Lamivudine/ Abacavir (Trizivir) Tenofovir disoproxil fumarate (Viread) Nevirapine (Viramune) Delavirdine mesylate (Rescriptor) Efavirenz (Sustiva) Saquinavir (Fortovase), saquinavir mesylate (Invirase) Indinavir sulfate (Crixivan) Ritonavir (Norvir) Nelfinavir mesylate (Viracept) Amprenavir (Agenerase) Lopinavir/ritonavir (Kaletra) a

Class Nucleoside analog reverse transcriptase inhibitor Nucleoside analog reverse transcriptase inhibitor

Nucleoside analog reverse transcriptase inhibitor Nucleoside analog reverse transcriptase inhibitor Nucleoside analog reverse transcriptase inhibitor Dual nucleoside analog reverse transcriptase inhibitor Nucleoside analog reverse transcriptase inhibitor Triple nucleoside analog reverse transcriptase inhibitor Nucleotide analog reverse transcriptase inhibitor Nonnucleoside reverse transcriptase inhibitor Nonnucleoside reverse transcriptase inhibitor Nonnucleoside reverse transcriptase inhibitor Protease inhibitor

Dosage 300 mg bid 125 mg bid or 250 mg qd (<60 kg) 200 mg bid or 400 mg qd (>60 kg) 0.75 mg tid 30 mg bid (<60 kg) 40 mg bid (>60 kg) 150 mg bid 300/150 mg bid 300 mg bid 300/150/300 mg bid 300 mg qd 200 mg bid or 400 mg qd 400 mg tid 600 mg/day

Protease inhibitor

1200 mg tid (Fortovase) 400 mg bid (Invirase in combination with ritonavir) 800 mg tid

Protease inhibitor Protease inhibitor

600 mg bid 1250 mg bid

Protease inhibitor

1200 mg bid

Dual protease inhibitor

400/100 mg bid

The dosages of these medications may need to be modified when given in combination with other drugs that alter their metabolism; e.g., since the protease inhibitors and nonnucleoside reverse transcriptase inhibitors are metabolized by the hepatic cytochrome P450 system, combinations of these drugs may result in different drug dosages and/or frequencies of administration.

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and through effective triage to specialized clinicians for chronic management, the U.S. AIDS epidemic will be under better control, and the care of people living with HIV will be optimized. BIBLIOGRAPHY Carpenter CC, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: Updated recommendations of the International AIDS Society-USA Panel. JAMA 283:381–390, 2000. CDC. Guidelines for Preventing Opportunistic Infections Among HIV-infected Persons. 2002 Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep 51 (No. RR-8), 2002. Department of Health and Human Services (and Henry J. Kaiser Family Foundation). 2002 Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Available at the HIV/AIDS Treatment Information Services website: http://www.hivatis.org. Gluckstein D, Ruskin J. Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMX): Use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMX. Clin Infect Dis 20:849–853, 1995. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: Evidence of a new acquired cellular immunodeficiency. N Engl J Med 305:1425–1431, 1981. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and Henry J. Kaiser Family Foundation. Available at the HIV/ AIDS Treatment Information services Web site: http://www.hivatis.org Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 339: 33–39, 1998. Lyles RH, Munoz A, Yamashita TE, et al. Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men: Multicenter AIDS Cohort Study. J Infect Dis 181:872–880, 2000. Masur H, Michelis MA, Greene JB, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia: Initial manifestation of cellular immune dysfunction. N Engl J Med 305:1431– 1438, 1981. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection: HIV Outpatient Study Investigators. N Engl J Med 338:853–860, 1998. Schacker T, Collier AC, Hughes J, et al. Clinical and epidemiologic features of primary HIV infection (published erratum appears in Ann Intern Med 1997 Jan 15;126(2):174) (see comments). Ann Intern Med 125:257–264, 1996. Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JSG, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Volberding PA. Antiretroviral Treatment for Adult HIV Infection in 2002: Updated Recommendations of the International AIDS Society–USA Panel. JAMA 288:222–235, 2002.

26 Evaluation of the Symptomatic Human Immunodeficiency Virus–Infected Patient Janine Maenza University of Washington, Seattle, Washington, U.S.A.

1

INTRODUCTION

The introduction of highly active antiretroviral therapy (HAART) in 1995 dramatically reduced the frequency of opportunistic complications of human immunodeficiency virus (HIV) infection (see Figure 1). A remarkable improvement in the HIV-related mortality rate coincided with the fall in HIV-related opportunistic complications. Despite advancements in antiretroviral therapy and management of opportunistic complications, patients still die. Many of these deaths, however, are now of previously unlikely causes, including liver failure from hepatitis C virus (HCV) infection, alcoholism and drug toxicity, cardiovascular disease, and non-HIV-related malignancies such as lung cancer. Additionally new manifestations have become evident since the start of HAART, including lipodystrophy, lactic acidemia, and immune reconstitution syndromes. Nevertheless, opportunistic diseases continue to occur despite HAART in some patients, in the absence of therapy in others, and in relation to the initiation of such therapy in still others. Many of these diseases can be evaluated and managed in the outpatient setting. This chapter provides a review of these complications and diagnostic approaches to the more common symptom complexes in the HIV-infected patient. Expert advice and consultation are suggested when evaluating and managing these complex patients. 2

ASSESSMENT BY CD4 COUNT

The differential diagnosis of the ill HIV-infected person should be guided by knowledge of that individual’s level of immunosuppression. New symptoms in a patient with underlying HIV must be considered not only with the usual tools of history, physical exam, and laboratory testing but also with an understanding of which specific opportunistic diseases are likely with different degrees of immune suppression. Since opportunistic processes take advantage of the weakened immune system, the risk for these processes in an HIVinfected patient is defined by the total CD4 (T-helper) lymphocyte count. The type of opportunistic disease for which a given CD4 lymphocyte count puts an individual at risk is so predictable that this information is pivotal in shaping the diagnostic evaluation. Although some complications of HIV infection may be caused by newly acquired infec513

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Figure 1 Trends for opportunistic infections in HIV-infected adults and adolescents. Adult and Adolescent Spectrum of Disease (ASD) project, 1992–1998. Data are standardized to the population of AIDS cases reported nationally in the same years by age, sex, race, HIV exposure mode, country of origin, and CD4⫹ T-lymphocyte count. Since the median CD4⫹ T-lymphocyte count of reported patients with AIDS is between 100 and 100/␮L, rates indicate the incidence of OIs among persons with CD4⫹ counts in this range. Numbers of subjects included in the analysis are 10,441, 11,589, 11,276, 10,048, 9250, 8897, and 8074, respectively for years 1992–1998. HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency virus; OI, opportunistic infection. (From Kaplan et al. 2000.)

tions, many are caused by the reactivation of previously acquired asymptomatic infections, which become clinically apparent in the face of declining immunity. The hallmark of HIV infection is a progressive decline in CD4 (helper) T lymphocytes. Normal laboratory ranges for CD4 lymphocyte counts in the absence of HIV infection are usually 500–1500/mm3. After a precipitous decline in CD4 lymphocyte count at the time of initial HIV infection, most individuals have a rebound in CD4 count to normal or near-normal levels (see Chapter 25, Figure 1). The progression of untreated HIV results in a decline of approximately 30–60 CD4 cells/mm3 per year. Table 1 shows complications that are seen at varying levels of immunosuppression. In the patient with a CD4 lymphocyte cell count above 500/mm3 illnesses are rarely specifically associated with HIV infection. At moderate levels of immunosuppression (CD4 counts 200–500/mm3), complications specific to HIV must be considered. In patients with this level of immunosuppression, common HIV-associated illnesses include dermatomal herpes zoster, oral thrush, vaginal candidiasis, oral hairy leukoplakia, and Kaposi’s sarcoma. At CD4 counts below 200/mm3, the patient meets the Centers for Disease Control and Prevention (CDC) definition of acquired immunodeficiency syndrome (AIDS). It is below this level of immune function that the patient becomes at risk for the classic AIDSdefining complications (see Table 2).

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Table 1 Correlation of Complications with CD4 Cell Counts CD4 cell count

Infectious complications

>500/mm3

Acute retroviral syndrome Candida spp. vaginitis

200–500/mm3

Bacterial pneumonia Pulmonary tuberculosis Herpes zoster Thrush Cryptosporidiosis, self-limited Kaposi’s sarcoma Oral hairy leukoplakia

<200/mm3

P. carinii pneumonia Disseminated histoplasmosis Disseminated coccidioidomycosis Miliary/extrapulmonary tuberculosis Progressive multifocal leukoencephalopathy (PML)

<100/mm3

Disseminated herpes simplex Toxoplasmosis Cryptococcal meningitis Cryptosporidiosis, chronic Microsporidiosis Candida esophagitis CMV retinitis Disseminated CMV Disseminated M. avium complex

<50/mm3

Noninfectious complications Persistent generalized lymphadenopathy Guillain-Barre´ syndrome Myopathy Aseptic meningitis Cervical intraepithelial neoplasia Cervical cancer B-cell lymphoma Anemia Mononeuritis multiplex Idiopathic thrombocytopenic purpura Hodgkin’s disease Lymphocytic interstitial pneumonitis Wasting Peripheral neuropathy HIV-associated dementia Cardiomyopathy Vacuolar myopathy Progressive polyradiculopathy High-grade non-Hodgkin’s lymphoma

Central nervous system lymphoma

a

HIV, human immunodeficiency virus; CMV, cytomegalovirus. Source: Bartlett and Gallant 2000.

Frequently seen infectious complications in patients with CD4 counts less than 100– 200/mm3 include Pneumocystis carinii pneumonia (PCP), toxoplasmosis, cryptococcal meningitis, esophageal candidiasis, and progressive multifocal leukoencephalopathy (PML). Additional complications that occur with advanced HIV infection with CD4 counts less than 50/mm3 include disseminated Mycobacterium avium complex (MAC) infection, cytomegalovirus (CMV) end-organ diseases (e.g., retinitis, gastrointestinal infection, and central nervous system infection), and central nervous system lymphoma. The relative frequency with which the common opportunistic complications occur is shown in Figure 1.

3

PRESENTATION OF COMMON COMPLICATIONS OF HUMAN IMMUNODEFICIENCY VIRUS

This section reviews the more common presentations of opportunistic processes. Table 3 outlines the presentation, diagnosis, and initial therapy of the frequently encountered op-

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Table 2 Aquired Immunodeficiency Virus–Defining Infections and Malignancies in Adults Infections Pneumocystis carinii pneumonia Toxoplasma gondii of internal organs Candidiasis of esophagus, trachea, bronchi, lungs Cytomegalovirus of any organ except liver, spleen, or lymph nodes Recurrent bacterial pneumonia Cryptococcus neoformans, extrapulmonary Mycobacterium sp. infection Disseminated M. avium Pulmonary or extrapulmonary M. tuberculosis Disseminated histoplasmosis Chronic herpes simplex infection (>1 month) Progressive multifocal leukoencephalopathy Wasting syndrome Human immnodeficiency virus (HIV) encephalopathy Chronic cryptosporidiosis (>1 month) Chronic isosporiasis (>1 month) Extrapulmonary coccidioidomycosis Salmonella spp. bacteremia Extraintestinal strongyloidosis Malignancies Kaposi’s sarcoma Non-Hodgkin’s lymphoma Invasive cervical carcinoma Source: CDC 1992.

portunistic infections. Information about additional therapeutic options and specific recommendations for medication dosage may be found in a number of other sources, including Bartlett and Gallant (2000) and Dolin, Masur, and Saag (1999); suggested websites include http://www.hopkins-aids.edu, http://www.atis.org, and http://hivinsite.ucsf.edu. 3.1

Pneumocystis carinii Pneumonia

Pneumocystis carinii, now recognized as a fungus, is omnipresent in our environment. Most persons are infected asymptomatically at a young age. Reactivation may occur in a number of different immune compromised hosts (see Chapter 34), including patients with lymphoma or acute lymphoblastic leukemia (ALL), organ transplantation recipients, those receiving high-dose steroids, and persons with advanced HIV. Pneumocystis carinii pneumonia (PCP) may present in myriad ways with signs and symptoms that may be quite subtle and/or nonspecific. The classic description is fever, nonproductive cough, and progressive dyspnea over several weeks. The timing of onset is usually subacute to acute; many patients describe progressive worsening of dyspnea on exertion. Physical examination findings are usually minimal. The chest may be clear or have fine rales on auscultation. Chest radiograph findings are also variable. The most frequent abnormalities are diffuse interstitial or perihilar infiltrates. A range of other find-

Stool O&P, special stains on stool Retinal exam Colonoscopy Abdominal CT scan, ERCP

Diarrhea, weight loss

Visual loss, floaters Diarrhea Abdominal pain

Cryptosporidiosis and microsporidiosis Cytomegalovirus

a

Comment

Ganciclovir 5 mg/kg bid IV for 2–3 wk

Serological testing not helpful

TMP-SMZ 15 mg/kg/day PO/IV Switch to oral when stable If PaO2 < 70 mm Hg, prednisone in divided doses for 21 days Pentamidine 4 mg/kg/day IV for 40 mg bid for 5 days, then 20 21 days mg bid for 5 days, then 20 mg/day for 11 days Fluconazole 200 mg/day PO for Increasing incidence of azole14 days resistant Candida spp. Amphotericin B 0.7 mg/kg/day Head CT/MRI scan to rule out IV for 14 days; switch to oral mass before LP fluconazole Clarithromycin 500 mg bid PO Numerous drug interactions with ⫹ ethambutol 15 mg/kg/day rifabutin (see Chapter 4, ⫾ rifabutin 300 mg/day Table 4) Sulfadiazine 4–8 g/day PO plus Serological testing not helpful; lack of response to empirical pyrimethamine 100–200 mg therapy suggestive of lymonce, then 50–100 mg/day phoma PO plus folinic acid 10 mg/ day for 6–8 wk Limited; albendazole 400–800 Microbiology laboratory alerted mg/day bid for E. bieneusi for need of special stains

First line therapy

SOB, shortness of breath; DOE, dyspnea on exertion; LDH, lactate dehydrogenase; LP, lumbar puncture; Ag, antigen; BC, blood culture; EGD, esophagogastroduodenoscopy; CT, computed tomography; MRI, magnetic resonance imaging; O&P, ova and parasites; ERCP, endoscopic retrograde cholangiopancreatography; BAL, bronchoalveolar lavage; TMP-SMZ, trimethoprim & sulfamethoxazole.

Toxoplasmosis

Fever, sweats, weight loss, abdominal pain, elevated alkaline phosphatase level Headache, focal neurological deficit

Mycobacterium avium

Headache, fever, altered mental status

Response to empiric fluconazole, EGD Serum cryptococcal Ag (⫹) LP: lymphocytic pleocytosis and cryptococcal Ag (⫹) Lysis centrifigation BC, biopsy of bone marrow or liver Head CT/MRI scan, response to therapy

Dysphagia, odynophagia

Esophageal candidiasis Cryptococcal meningitis

Diagnosis

Fever, dry cough, progressive Induced sputum or BAL specimen for PCP stain SOB, DOE, bilateral pneumonia, elevated LDH level, hypoxia

Presentation

Pneumocystis carinii pneumonia (PCP)

Infection

Table 3 Presentation, Diagnosis and Initial Management of Common Opportunistic Infectionsa

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PRESENTATIONS OF OPPORTUNISTIC COMPLICATIONS: 1 Assessment of disease risk by CD4 count (see Table 1) CD4 > 500: no risk of opportunistic complications CD4 = 200–500: thrush, bacterial pneumonia, zoster CD4 < 200: opportunistic infections Pneumocystis carinii pneumonia Progressive dyspnea on exertion, fever, cough Bilateral interstitial infiltrates Hypoxemia, elevated lactate dehydrogenase (LDH) level Esophageal Candida spp. infection Dysphagia and odynophagia Oral Candida spp. sometimes present Cryptococcal meningitis Headache, fever, mental status deterioration Serum cryptococcal antigen Lumbar puncture after computed tomography/magnetic resonance imaging (CT/MRI) Mycobacterium spp. Disseminated M. avium Fever, weight loss, elevated alkaline phosphatase level M. tuberculosis CD4 count > 200: more likely chronic pneumonia with upper lobe infiltrates CD4 < 200: more likely disseminated or miliary Toxoplasmosis Most common human immunodeficiency virus (HIV)-related brain mass Serological result negative in 5%–10% Diagnosis by therapeutic trial

ings are common, including pneumothoraces and even a normal radiograph result. The diagnosis is often suggested by oxygen desaturation with exertion, easily measured in the outpatient evaluation with a pulse oximeter. Lactate dehydrogenase (LDH) level is generally elevated. Pulmonary function test results showing decreased carbon monoxide (CO) diffusing capacity are characteristic but nonspecific findings and should not be considered diagnostic. Use of trimethoprim & sulfamethoxazole (TMP-SMZ) as prophylaxis against PCP argues against the diagnosis since breakthrough infection is exceedingly rare. PCP breakthrough is associated more frequently with second-line medications such as aerosolized pentamidine, dapsone, or atovaquone. The diagnosis of PCP may be made by concentration and staining of an induced sputum sample or may require bronchoscopy with bronchial alveolar lavage. A definitive diagnosis is important since empirical treatment for PCP can be toxic and misdirected. Other pulmonary processes may have characteristics similar to those of PCP, including bacterial pneumonia, influenza, tuberculosis or other mycobacterial infections, histoplasmosis, Kaposi’s sarcoma, and pulmonary emboli. In 10%–15% of patients more than one opportunistic process may occur simultaneously. Standard therapy for PCP is a 21-day course of TMP-SMZ, either orally or intravenously, depending on the severity of illness. For patients with sulfa allergy there are a number of alternative agents including intravenous pentamidine, atovaquone, and clinda-

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mycin plus primaquine. Significant hypoxemia (PaO2 < 70 mm Hg or A-a gradient > 35) should be managed with adjunctive steroids along with specific antimicrobial therapy. All patients who have had PCP should then receive prophylaxis at completion of acute therapy (see Chapter 25, Table 6). 3.2

Esophageal Candidiasis

Esophageal candidiasis typically causes odynophagia with pain centered in the substernal area. Patients may also report that food and pills become stuck when swallowed. This dysphagia may progress to difficulty in swallowing liquids. Although the diagnosis may be suggested by the presence of oropharyngeal thrush, a substantial number of patients with esophageal infection have no findings on oral exam. Treatment may be given empirically with fluconazole 200 mg daily for 14 days. Topical agents are not absorbed and therefore should be used only for infection limited to the oropharynx. Diagnostic uncertainty or lack of a response to empirical therapy should lead to further evaluation by endoscopy. The diagnosis may then be made by direct visualization of the fungal plaques and confirmed by biopsy. This procedure also allows differentiation of esophageal candidiasis from other causes of odynophagia (e.g., cytomegalovirus [CMV], herpes simplex virus [HSV], aphthous ulcers) and detection of drug (azole-) resistant fungal infection. Azole-resistant infection necessitates the use of amphotericin B. 3.3

Cryptococcal Meningitis

Cryptococcus neoformans is ubiquitous encapsulated yeast that may cause infection in the lung, skin, bone, or genitourinary tract but is manifested most commonly in the central nervous system as meningitis. Cryptococcal meningitis commonly causes subacute to acute (<2 weeks) headache and fever. As the infection progresses, the patient’s mental status deteriorates with lethargy and confusion and finally leads to coma. Nausea, vomiting, and malaise may also be present. Less common findings are meningismus, cranial nerve deficits, and seizures. When considering the diagnosis, a serum test for the presence of cryptococcal antigen is extremely useful with a sensitivity of >95%. Definitive diagnosis requires lumbar puncture (LP) for testing for cerebrospinal fluid (CSF) cryptococcal antigen. The LP classically shows a lymphocytic pleocytosis with an elevated protein level and a depressed glucose level. The CSF result must be interpreted with care since the protein and glucose may be normal and white blood cells (WBCs) absent or present in low numbers. Results of CSF cultures are almost invariably positive. India ink staining of CSF may be useful for initial diagnosis but should not supplant the use of antigen testing since the sensitivity is only 60%–80%. Markers of poor prognosis include age <35 years, altered mental status at presentation, positive blood culture results, CSF WBC count <20 cells/ mm3, and CSF cryptococcal antigen titer >1:32. Determination of CSF opening pressure with the initial lumbar puncture is also crucial since management of increased intracranial pressure is an important component of effective therapy. Specific antifungal treatment initially employs intravenous amphotericin B for 2 weeks followed by oral fluconazole. Suppressive therapy is required after treatment. 3.4

Mycobacterial Infections

3.4.1 Mycobacterium avium Complex Infection Mycobacterium avium complex (MAC) infection is characterized by the development of high fever, weight loss, and diarrhea in patients with advanced HIV, in whom CD4 counts

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are usually <50/mm3. Abdominal pain due to intra-abdominal lymphadenopathy may also be present. Routine laboratory evaluations commonly show anemia and elevation of the alkaline phosphatase level. Stool cultures done to evaluate diarrhea may yield positive findings for M. avium, but the definitive diagnosis of disseminated disease should be made with mycobacterial blood culture by lysis centrifugation (Isolator tubes, Wampole Laboratories, Cranbury, NJ). Results of sputum cultures must also be interpreted cautiously, since sputum colonization without invasive disease may occur. Two or three drugs are used in the treatment of MAC. The usual therapy is clarithromycin and ethambutol (with or without rifabutin). Azithromycin may substitute for clarithromycin. Ciprofloxacin and amikacin are alternative agents. Despite susceptibility of M. avium to clofazimine, this agent has been associated with lower survival rates and should not be used. 3.4.2

Tuberculosis

Infection with Mycobacterium tuberculosis may be seen at any stage of HIV infection. Patients with a relatively intact immune system tend to have pulmonary tuberculosis. Symptoms may include fever, weight loss, productive cough, and hemoptysis, similar to those of the non-HIV-infected patient. Although chest radiograph result abnormalities are variable, findings are also usually similar to those in HIV-seronegative patients with upperlobe infiltrates and cavitary lesions. With more advanced HIV infection, tuberculosis can become more widespread and present atypical patterns. Miliary disease and tuberculous meningitis are more common. Diagnosis is made by staining and culture of samples from appropriate body sites. Treatment is with standard multidrug therapy tailored to individual susceptibilities (see Chapter 13, Table 6). 3.5

Toxoplasmosis

A brain mass is the most common manifestation of Toxoplasma gondii. The disease is due to reactivation of dormant asymptomatic infection. The development of symptoms is usually subacute; fever, headache, decreased alertness, and focal neurological deficits are the most common manifestations. Diagnosis is suggested by the classic radiographic appearance of ring-enhancing brain lesions seen on computed tomography (CT) or magnetic resonance imaging (MRI) scan. Other processes, especially central nervous system (CNS) lymphoma, may cause similar findings. Brain biopsy can be used for definitive diagnosis, but the more common approach is a diagnostic trial of empirical antitoxoplasma therapy of sulfadiazine and pyrimethamine. Improvement in symptoms and radiographic findings should occur within 1 to 2 weeks. Toxoplasma serological evaluation is not necessarily useful since the immunoglobulin G (IgG) finding is falsely negative in 5%–10% of patients with CNS toxoplasmosis. Thus, even toxoplasma-seronegative patients should receive a trial of therapy if the clinical and radiographic findings are consistent with the diagnosis. Less commonly, toxoplasmosis may cause pneumonia, retinitis, and unexplained fever. 3.6

Cryptosporidiosis and Microsporidiosis

Cryptosporidia and microsporidia (Enterocytozoon bieneusi and Septata intestinalis) are protozoa that can cause watery diarrhea in patients with moderate to advanced immunosuppression. They can also cause biliary tract disease and microsporidia keratitis. Fever is uncommon with microsporidia infection but is sometimes seen with cryptosporidiosis. Symptoms are more severe in patients with advanced HIV infection and can lead to significant malabsorption and weight loss. Stool studies are used for diagnosis. Cryptosporidium spp. can be detected by modified acid-fast or Giemsa stains. In addition, enzyme

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PRESENTATIONS OF OPPORTUNISTIC COMPLICATIONS: 2 Cryptosporidiosis and microsporidiosis Chronic diarrhea Laboratory informed of need for special stains Cytomegalovirus Retinitis: blurring, floaters → emergent ophthalmological evaluation required Cholangitis Colitis Progressive multifocal leukoencephalopathy Progressive impairment of motor and cognitive function Magnetic resonance imaging (MRI) with white matter changes Human immunodeficiency virus (HIV)-associated dementia Progressive impairment of motor and cognitive function Computed tomography/magnetic resonance imaging (CT/MRI) with cerebral atrophy

immunoassay (EIA) for detection of Cryptosporidium sp. antigen in the stool is available. The Weber chromotrope-based stain is best for identifying microsporidia. Fecal white blood cells are absent in both infections. Specific therapy for either infection is limited. Albendazole is effective treatment of E. bieneusi, but not for other Microsporidia or Cryptosporidia. Supportive care via rehydration and antidiarrheal agents is the mainstay of therapy. Potent antiretroviral therapy has been shown to lead to clinical resolution of both infections and should be optimized in affected patients. 3.7

Cytomegalovirus

Cytomegalovirus (CMV) is a member of the Herpes family. Infection with these viruses leads to chronic asymptomatic latent infection with the potential for reactivation. When CMV does reactivate, retinitis is the most common site of end-organ disease in patients with advanced HIV (CD4 count <50 cells/mm3). Gastrointestinal infection is less frequent, and encephalitis and pneumonitis are quite uncommon. The symptoms of retinitis vary with the location of the lesions relative to the macula and optic nerve. Some patients with small peripheral lesions may be asymptomatic, whereas others may note ‘‘floaters.’’ More central lesions lead to decreased visual acuity and visual field deficits. Any patient with advanced HIV infection who notes visual changes should be evaluated immediately for CMV infection with a dilated retinal exam by an ophthalmologist. Classic CMV lesions, including retinal hemorrhage and exudate, can generally be distinguished from other retinal diseases. Treatment should be started immediately, especially for those who have sight-threatening infection. Therapy usually halts disease progression and potentially reverses early damage in those edematous areas that have not had progression to necrosis. Areas that already have necrosis do not improve and permanent visual loss is the consequence. Without therapy infection leads to blindness. Treatment can be initiated with intravenous ganciclovir (GCV). Alternatives include intraocular GCV implantations, intraocular injections of GCV, or intravenous foscarnet or cidofovir. The current formulation of oral GCV is not well absorbed and not efficacious for treatment. The oral prodrug of GCV, valganciclovir hydrochloride, is better absorbed and holds promise for both prophylaxis and therapy. Gastrointestinal (GI) disease may occur

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anywhere within the GI tract with subsequent esophagitis, gastritis, cholangitis, enteritis, or colitis. Symptoms are specific to the affected area: esophageal disease notable for odynophagia, gastritis or cholangitis suggested by abdominal pain, and enteritis and colitis characterized by bloody diarrhea and fever. 3.8

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is caused by the human polyoma virus, JC virus. The virus causes a progressive multifocal demyelinating disorder of the cerebral white matter in patients with advanced immunosuppression. Over weeks to months patients experience focal neurological deficits that can include impairment of motor function, speech, or vision. Cognition remains intact in the early stage of disease. With its advance patients can become progressively demented. Headache and fever are absent. Finding characteristic white-matter changes on MRI scan usually indicates the diagnosis. Additionally the diagnosis can be made by detection of JC virus DNA by PCR in CSF or by brain biopsy. No specific therapy has proved to be effective. Highly active antiretroviral therapy controlling HIV infection, with subsequent improved immunological function, may help to improve outcome. 3.9

Human Immunodeficiency Virus–Associated Dementia

HIV-associated dementia may initially produce subtle memory or behavioral changes. Patients may withdraw socially and become apathetic and irritable. A characteristic slowing of responses may be seen with a lag between question and patient response. In later stages, cognitive function deteriorates further with progressive dementia and motor abnormalities. Gait disturbance and incoordination become evident. Occasionally patients may exhibit psychotic behavior. Standard mini–mental status exams may not reveal any abnormalities with the early changes, but specific neuropsychological and timed tests can be used. CNS imaging with CT or MRI scans reveals atrophy. Spinal fluid may be normal or show nonspecific abnormalities such as a lymphocytic pleocytosis and increased protein. There is no specific therapy. Potent antiviral therapy, especially using medications that reach the CNS, may improve cognitive function in some patients. 3.10 3.10.1

Malignancies Kaposi’s Sarcoma

Kaposi’s sarcoma (KS) is a neoplastic disorder of the vasculature caused by human herpesvirus 8 (HHV-8). Historically considered a complication specific to homosexual men, KS can occur in other populations of HIV-infected patients. The characteristic lesion is a purple painless nodule, which may also be flat or associated with surrounding ecchymosis. The hard palate, gingiva, and lower extremities are often involved. Large plaguelike lesions can evolve in association with lymphatic involvement leading to brawny edema. Visceral disease can occur even in the absence of cutaneous disease. Visceral disease most often involves the gastrointestinal tract, causing chronic blood loss, or the lungs, causing cough, dyspnea, and bloody pleural effusions. Diagnosis is generally made by the clinical appearance of the lesion. KS lesions need to be differentiated from bacillary angiomatosis, a neovascular disorder caused by Bartonella henselae or B. quintana. Biopsy is occasionally needed for non-classic-appearing lesions. Caution must be used with endoscopic biopsies since these lesions can bleed profusely. Although KS is caused by a virus, palliative

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PRESENTATIONS OF OPPORTUNISTIC COMPLICATIONS: 3 Kaposi’s sarcoma Cutaneous purple papules Gastrointestinal (GI) involvement with bleeding Pulmonary involvement with cough, hemoptysis Lymphoma Extranodal presentations Fever, weight loss, lymphadenopathy Primary central nervous system (CNS) lymphoma that resembles toxoplasmosis Lipodystrophy Associated with (HAART) Abdominal fat accumulation Fat wasting of extremities, face, buttocks Hyperlipidemia Insulin resistance and hyperglycemia Immune reconstitution syndrome Flaring of occult opportunistic infection on initiation of HAART with improved CD4 count and human immunodeficiency virus (HIV) suppresion Hepatitis C virus Coinfection very prevalent (30%–80%), especially in injection drug user (IDU) population Increased progression to cirrhosis and hepatocellular carcinoma Increased risk of worsening hepatitis with HAART agents

treatment of systemic KS requires chemotherapy or interferon alfa. Radiation therapy is effective for localized disease. 3.10.2

Non-Hodgkin’s Lymphoma

Non-Hodgkins’s lymphoma (NHL) is the most common systemic malignancy in HIVinfected patients. Most are B cell in origin and of intermediate- or high-grade large cell type. Patients with AIDS classically have extranodal disease involving the bone marrow, gastrointestinal tract, central nervous system, and liver. Fever, lymphadenopathy, fatigue, and weight loss may also be present. Diagnosis is made by biopsy of bone marrow, lymph node, or mass. Poor prognosis has been associated with stage III or IV disease, CD4 counts <100 cells/mm3, and age >35 years. Combined HAART and systemic chemotherapy have contributed to improved prognosis in these patients. Primary central nervous system (CNS) lymphoma is a late-stage complication of HIV infection that usually causes focal neurological deficits along with headache, confusion, and personality changes. The diagnosis is usually presumptive in the patient with a CNS mass lesion(s) who does not respond to a trial of antitoxoplasma therapy. Prognosis is extremely poor. Treatment, via cranial radiotherapy, is palliative. 3.11

Human Immunodeficiency Virus–Associated Wasting

Involuntary weight loss of more than 10% of baseline weight, in association with otherwise unexplained fever and fatigue or chronic diarrhea, constitutes HIV-associated wasting. Evaluation should exclude other treatable causes of diarrhea and fever. Appetite stimulants

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(megestrol acetate [Megace], 400–800 mg/day) and anabolic steroids (oxandrolone 2.5– 5.0 mg tid) are the most common therapeutic approaches. 3.12

Lipodystrophy

Lipodystrophy is a complex of symptoms, signs, and laboratory abnormalities involving body fat redistribution, hyperlipidemia, insulin resistance, and hyperglycemia. The cause is unknown, the syndrome has been linked to the use of HAART. It is not associated with progressive immune impairment, as is the wasting syndrome. Truncal obesity (most commonly associated with protease inhibitors) and/or peripheral wasting (most commonly linked to stavudine) is the most common pattern. It appears that the duration of HAART therapy is a stronger predictor of lipodystrophy than any specific agent. Loss of temporal, extremity, and buttock fat gives the appearance of wasting though these patients actually are not losing weight and do not have the AIDS wasting syndrome mentioned earlier. Elevated serum cholesterol and/or triglyceride level along with hyperglycemia may accompany these physical findings or occur without any physical changes. There is no proven therapy for the body fat changes. Recombinant human growth hormone has had modest success but is very expensive, requires daily injections, and produces improvements that reverse after cessation of the drug. Hypercholesterolemia and hypertriglyceridemia may improve with changes in antiretroviral therapy from protease inhibitor based regimens to those using nucleoside analog and nonnucleoside analog drugs (see Chapter 25, Table 8). In addition to diet and exercise, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors such as pravastatin or atorvastatin can be used to treat hypercholesterolemia. Hypertriglyceridemia can be treated with gemfibrozil. 3.13

Immune Reconstitution Syndromes

A number of opportunistic infections may appear clinically soon after the initiation of HAART. In the usual scenario a patient has had a sudden marked drop in viral load and increase in CD4 count after beginning HAART. The clinical presentation may be atypical for the specific causative pathogen. M. avium immune reconstitution syndrome usually causes fever and focal adenitis rather than bacteremia. CMV reactivation may lead to immune reconstitution vitritis. Other complications that have constituted immune reconstitution syndromes include tuberculosis and cryptococcal meningitis. Usual treatment involves the specific antimicrobial therapy that would be used for any instance of the infection, continuation of HAART, and use of anti-inflammatory agents (nonsteroidal agents or steroids). Long-term secondary prophylaxis or suppression, as would usually be indicated for M. avium infection, cryptococcal meningitis, or CMV retinitis, is generally not necessary for immune reconstitution syndromes. 3.14

Hepatitis C Virus

Although not an opportunistic infection in the true sense of the word, hepatitis C virus (HCV) infection is a growing problem in the HIV-infected population and is responsible for increasing morbidity and mortality rates. HCV is transmitted predominantly by the intravenous route. Overall it is estimated that 30% of the HIV-infected population is coinfected with HCV with rates up to 70%–80% in IDUs and close to 100% in patients with hemophilia. With improved life expectancy from HAART, patients with HCV are now beginning to experience long-term morbidity and mortality from cirrhosis and hepatocellular carcinoma. HIV-HCV coinfection causes a more rapid progression of HCV to end-

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stage liver disease. In addition, several of the HAART drugs, including protease inhibitors and nonnucleoside reverse transcriptase inhibitors (especially nevirapine), can cause hepatitis and contribute to liver damage in the HIV-HCV coinfected patient. The evaluation of the patient with HCV is reviewed in Chapter 23. The role of interferon alfa and ribavirin in the coinfected patient is not clear.

4

EVALUATION OF SYMPTOMS

The differential diagnosis of the symptomatic HIV-infected person includes HIV itself, associated opportunistic conditions, complications of medications being used for therapy, and diagnoses unrelated to HIV. In addition to eliciting a complete history and performing a physical examination the clinician should address the following questions: What is the patient’s most recent CD4 lymphocyte count? What was the nadir CD4 count? Is the patient on appropriate prophylaxis for the CD4 count? Is the patient on antiretroviral therapy or other HIV- or HCV-related medications?

APPROACH TO THE SYMPTOMATIC PATIENT Presentation and diagnosis of common opportunistic infections (see Table 3) Common drug toxicities (see Table 4) Headache (see Figure 2) Cough, dyspnea (see Figure 3) Diarrhea Acute Medications (see Table 4), dietary changes Bacterial, including C. difficile Giardia, Cryptosporidia, Entamoeba spp. Chronic Giardia, Cryptosporidia, Entamoeba, Isospora, Cyclospora spp, Check for fecal leukocytes Lower extremity pain and/or weakness Peripheral neuropathy Numbness, pain without weakness Idiopathic vs. dideoxyinosine (ddI), stavudine (d4T), dideoxycytidine (ddC) Radiculopathy Weakness without spasticity Decreased reflexes Myelopathy Weakness with spasticity Hyperactive reflexes, positive Babinski sign finding Lactic acidosis Associated with nucleoside analog reverse transcriptase inhibitors (NRTIs) especially stavudine Lactate level < 5 mmol/L common and generally asymptomatic Lactic acidosis Fatigue, dyspnea, nausea, abdominal pain

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Is the presenting complaint a possible medication side effect or toxicity? Have there been any geographical exposures (e.g., for endemic fungal infections, parasitic infections)? Does the patient have other underlying illnesses that may be associated with HIV (e.g., HCV)? Does the patient have any underlying illnesses not related to HIV? Has the patient been exposed to contaminated water or food? Summarized in the following are the most common symptoms (headache, cough, shortness of breath, odynophagia, abdominal pain, diarrhea, and leg pain) and laboratory abnormalities requiring assessment. It is important to recognize that many symptoms of the HIVinfected patient are not due opportunistic complications but are more benign (tension headache) and less life-threatening (viral bronchitis) than may be presumed. Reference should be made to Table 1 when assessing symptomatic HIV-infected patients to prevent over- or underreaction and initiation of unnecessary work-ups and therapies. It is unusual for patients to have opportunistic complications when the CD4 count is >200 cells/mm3 or when viral load is fully suppressed. This is especially true if the patient is taking HAART. Side effects of HAART are common and probably account for the majority of symptoms in patients taking these medications (see Table 4). 4.1

Headache

The factors most useful in guiding evaluation of headache are knowledge of CD4 lymphocyte count and presence or absence of fever, mental status changes, and focal neurological signs (see Figure 2). If there are no findings suggesting meningitis, encephalitis, or a mass lesion, the patient should be evaluated for sinusitis. Often the clinical diagnosis can be based on nasal symptoms and facial pain. If the diagnosis is unclear, CT imaging, rather than plain films, is useful for clarification. More common causes of headache including tension, cluster, and migraine headaches should be considered. Antiretroviral medications, especially zidovudine, can also commonly cause headaches. Any patient with mental status changes, new seizures, or focal neurological findings should have brain imaging to assess for the presence of a mass lesion. MRI with gadolinium provides more diagnostic sensitivity, but CT scanning with and without contrast often provides useful information and may be easier to obtain without delay. Patients with ringenhancing lesions should be treated empirically for toxoplasmosis. Lack of a clinical and radiographic response in 1 to 2 weeks suggests CNS lymphoma. Periventricular lesions are more consistent with CMV, which may be diagnosed by CSF culture. PML may be diagnosed by MRI scan. HIV-related dementia is generally a diagnosis of exclusion. Fever that is not explained by sinusitis should prompt consideration of CSF evaluation. If the CD4 lymphocyte count is greater than 200/mm3, lumbar puncture may be done in the alert patient with no focal findings or papilledema. If the CD4 count is less than 200/mm3 or there are any indications of a mass lesion or increased intracranial pressure, CNS imaging should precede lumbar puncture. The patient who has advanced immunosuppression, headache, and fever should always be evaluated with a serum cryptococcal antigen. Whenever CSF is sampled, opening pressure should be obtained and specimens sent for glucose, protein, cell count, cryptococcal antigen, Gram stain, and culture evaluation. Additional studies may include cultures for fungus and mycobacteria and Venereal Disease Research Laboratories (VDRL), and cytological testing.

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Table 4 Toxicities of Antiretroviral Agents Class and drug Nucleoside analogs Zidovudine (ZDV) Didanosine (ddI) Stavudine (d4T) Zalcitibine (ddC) Abacavir (ABC)

Nonnucleoside analogs Nevirapine Efavirenz Delavirdine Protease inhibitors Indinavir Ritonavir

Saquinavir Nelfinavir mesylate Amprenavir Lopinavir/ritonavir

4.2

Common

Uncommon

Headache, nausea, asthenia, myalgia, macrocytosis Nausea, diarrhea, peripheral neuropathy Peripheral neuropathy

Anemia, myopathy, hepatitis, lactic acidosis Pancreatitis, hepatitis, rash, lactic acidosis Headache, diarrhea, hepatitis, lactic acidosis Peripheral neuropathy, rash Pancreatitis, oral ulcerations, lactic acidosis Hypersensitivity uncommon but potentially lethal; fever, hepatitis, rash, nausea, arthralgia, elevated creatine kinase (CPK) and liver biochemical levels Do not rechallenge patient on recovery

Rash, hepatitis Rash, central nervous system (CNS) symptoms with altered dreams, depression, impaired concentration, confusion Rash, fever Headache, hepatitis Nephrolithiasis, elevated indirect bilirubin level Nausea, vomiting, diarrhea, circumoral parethesia, asthenia, hepatitis Nausea, vomiting, diarrhea Diarrhea Nausea, vomiting, diarrhea, rash, oral paresthesia Diarrhea, hepatitis

Hepatitis

Hepatitis Hepatitis, headache

Pulmonary Symptoms

The assessment of cough and dyspnea should be based on severity of presenting illness, CD4 count, season, presence and pattern of chest radiographic abnormalities, and level of hypoxemia (see Figure 3). 4.2.1

CD4 Count >200 Cells/mm3

In the patient who has mild to moderate HIV infection, routine community-acquired infections are the usual cause and should be diagnosed and managed as for the non-HIVinfected patient (see Chapter 12). Viral and atypical pulmonary pathogens (Chlamydia pneumoniae, Mycoplasma spp., and Bordetella pertussis) are common. Bacteria such as Streptococcus pneumoniae and Haemophilus influenzae can cause acute pneumonia; M. tuberculosis may cause a more chronic infection (see Chapter 13). Noninfectious causes, including bronchospasm, pulmonary emboli, congestive heart failure, and malignancy, must also be considered.

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Figure 2 Approach to the HIV-infected patient with a headache. CNS, central nervous system, PML, progressive multifocal leukoencephalopathy; CT, computed tomography; MRI, magnetic resonance image; HIV, human immunodeficiency virus.

4.2.2

CD4 Count <200 Cells/mm3

In the patient with more advanced disease, there are numerous diagnostic possibilities. Evaluation for pneumonia should include a chest radiograph and sputum sample for Gram stain and culture. Purulent sputum suggests a bacterial cause. S. aureus isolated in respiratory secretions may be seen in injection drug users and should suggest the possibility of tricuspid valve endocarditis. Pseudomonas aeruginosa, usually considered a nosocomial pathogen, may also cause community-acquired infections in patients with HIV infection. Legionella and Nocardia spp. may also cause purulent sputum production. Legionella spp. can be diagnosed by culture or direct fluorescent antibody staining of the sputum or urinary antigen detection (Legionella pneumophila type 1). Nocardia can be diagnosed by culture or modified acid-fast staining. Mycobacterial infection (including tuberculosis) may also cause purulent sputum and may be diagnosed by acid-fast staining and/or culture of expectorated or induced sputum. Nonproductive cough tends to be more commonly associated with endemic fungal infections (i.e., histoplasmosis, coccidioidomycosis), viral infections, or PCP. A normal chest radiograph result may indicate bronchitis, rather than pneumonia, but may also indicate PCP. Pulse oximetry should be used to help distinguish between these possibilities since exercise desaturation is a frequent finding in the patient with PCP. A dry cough associated with interstitial infiltrates suggests PCP but may also be seen with fungal or mycobacterial infection. The LDH level is frequently elevated. Induced sputum examination may yield the diagnosis. If this is unrevealing, bronchoscopy with

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Figure 3 Approach to the HIV-infected patient with pulmonary symptoms. PCP, Pneumocystis carinii pneumonia; BAL, bronchoalveolar lavage; HIV, human immunodeficiency virus.

bronchoalveolar lavage (BAL) may be necessary. In patients with progressive symptoms and negative results from induced sputum and BAL consideration should be given to chest CT scanning and to lung biopsy, either transbronchially or surgically. A focal infiltrate that has developed acutely should first suggest a bacterial process. A diagnostic work-up should include sputum Gram stain and culture. Cultures of blood and sputum direct fluorescent antibody (DFA) staining (or urinary antigen) for Legionella spp. may also be helpful. Detection of a specific organism should tailor antibiotic choice. While this information is pending, broad-spectrum antibacterial coverage (e.g., a secondor third-generation cephalosporin in combination with a macrolide or a fluoroquinolone such as levofloxacin) is indicated. Chronic focal infiltrates are more indicative of mycobacteria, fungi, or Nocardia spp. If sputum staining does not reveal the diagnosis, bronchoscopy with transbronchial biopsy should be performed. Nodular infiltrates or pulmonary cavities should be interpreted in light of a history of injection drug use as they may indicate septic emboli from right-sided (tricuspid valve) endocarditis in this setting. Blood cultures should be performed as the first step in diagnosis. As for focal infiltrates, other evaluation would include sputum culture and staining followed by bronchoscopy with transbronchial biopsy for culture and cytological testing if results of sputum studies are not diagnostic. A pleural effusion should lead to an evaluation for bacterial infection, tuberculosis, and malignancy. Thoracentesis should be done to obtain pleural fluid for standard studies (pH, cell count, protein, LDH level, Gram and acid-fast bacillus [AFB] staining/cultures, and cytological evaluation). Further diagnostic steps may need to include pleural biopsy (if the effusion is exudative) and/or CT scanning (to assess for parenchymal disease).

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The presence of a pneumothorax is strongly suggestive of PCP. In addition to placement of a chest tube, empirical therapy for P. carinii may be started, pending definitive diagnosis. 4.3

Odynophagia

Esophageal pain that is due to ‘‘pill esophagitis’’ or gastroesophageal reflux can usually be diagnosed by history alone. In the patient with CD4 count less than 200/mm3, infectious causes of esophagitis must also be considered. By far the most common opportunistic cause of odynophagia is Candida spp. esophagitis. Lack of response to empirical fluconazole should lead to endoscopy to assess for alternate causation. Biopsy and culture allow for the diagnosis of HSV, CMV, and aphthous ulcerations causing esophagitis. Mass lesions caused by Kaposi’s sarcoma or lymphoma occasionally produce odynophagia but are more commonly associated with dysphagia. 4.4

Abdominal Pain

The causes of abdominal pain in HIV-infected patients are similar to those in HIV-seronegative individuals, and just as in the assessment of the non-HIV-infected patient, the initial goal is to rule out an acute abdominal process or other life-threatening condition (see Chapter 24). In addition to appendicitis, perforated peptic ulcers, and diverticular disease, common causes of an acute abdominal disorder that are more specific to HIV infection include perforation caused by CMV infection and toxic megacolon from C. difficile infection. The location of pain may be helpful in determining the cause. Pancreatitis occurs as it does routinely with periumbilical or epigastric pain that radiates to the back. HIV-related causes of pancreatitis include medications (didanosine, stavudine, zalcitabine, pentamidine) and CMV infection. Epigastric pain may also be due to gastric or duodenal ulcer disease or gastritis. Right upper quadrant (RUQ) pain should suggest cholecystitis or hepatitis. Specific to HIV is the frequency of acalculous cholecystitis caused by Cryptosporidia, Microsporidia, or CMV. An entity known as AIDS cholangiopathy also causes RUQ pain and is characterized by a marked elevation in alkaline phosphatase level. Causative agents include CMV, Cryptosporidia, Microsporidia, Salmonella spp., and M. avium. Left upper quadrant pain may be due to splenomegaly or splenic abscess. Lower abdominal pain may indicate appendicitis, diverticulitis, incarcerated hernia, or inflammatory bowel disease. The differential diagnosis should also include such HIV-associated complications as CMV colitis and obstruction due to malignancy (lymphoma, Kaposi’s sarcoma). Back pain should suggest pyelonephritis or nephrolithiasis (particularly in patients taking indinavir). Evaluation of acute abdominal pain should include radiographic imaging with plain films to assess for perforation or obstruction. Abdominal CT scanning can detect many causes of abdominal pain, including pancreatitis, colitis, lymphadenopathy, and intra-abdominal abscess. 4.5

Diarrhea

In addition to noting CD4 lymphocyte count, a key component of a work-up of diarrhea is the determination of exposures and disease chronicity (see Chapter 22). 4.5.1

Acute Diarrhea

Acute diarrhea may be caused by new medications (especially nelfinavir, amprenavir, ritonavir, and dideoxyinosine [ddI]), dietary changes, or recent antibiotic use. If there has

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been recent antibiotic use, Clostridium difficile should be suspected and stool tested for C. difficile toxin. Stool culture for bacterial pathogens and staining for ova and parasites may reveal other causes of acute diarrhea, including Salmonella spp., Shigella spp., Campylobacter jejuni, Yersinia enterocoliticus, Vibrio hemolyticus, Giardia lamblia, Cryptosporidia parvum, and Entamoeba histolytica. If results of stool studies are unrevealing, diagnostic evaluation should proceed with flexible sigmoidoscopy. 4.5.2

Chronic Diarrhea

The initial evaluation of chronic diarrhea is similar, with medications and dietary causes assessed first. Bacterial causes including infection with C. difficile are less likely. Protozoan infections due to Cryptosporidium spp., Isospora belli, and Cyclospora cayetanensis are more frequent. The microbiology laboratory should be alerted if one of these organisms is suspected since special staining is required for their detection. If the initial work-up result is negative and white cells are present in the stool, sigmoidoscopy or colonoscopy should be performed. The absence of white cells is more suggestive of a small bowel source that can be investigated with esophagoduodenoscopy (EGD). If any of these procedures is performed, samples should be submitted for tissue stains as well as culture. 4.6

Lower Extremity Symptoms

The patient who reports foot pain and numbness may have tarsal tunnel syndrome or peripheral neuropathy. Tarsal tunnel syndrome is characterized by pain localized to the soles of the feet and a positive Tinel’s sign finding. Peripheral neuropathy is characterized by pain beginning at the toes, decreased reflexes at the ankles, and decreased vibratory sensation in the distal feet. Patients with peripheral neuropathy who are taking didanosine (ddI), zalcitabine (ddC), or stavudine (d4T) should be considered to have a toxic neuropathy. The best treatment is discontinuation of the neurotoxic drug, which may result in slow improvement in symptoms. Other causes to consider include vitamin B12 deficiency, diabetes mellitus, and alcoholism. The pain caused by peripheral neuropathy may be treated with nonsteroidal anti-inflammatory agents or tricyclic antidepressants. If these do not control symptoms, other possible options include carbamazepine (Tegretol), phenytoin, mexiletine, gabapentin, and narcotic analgesics. Weakness in association with numbness suggests polyradiculopathy or myelopathy. The patient with myelopathy has hyperactive deep tendon reflexes in the lower extremities and a positive Babinski reflex finding. Polyradiculopathy is characterized by weakness without spasticity and decreased lower extremity deep tendon reflexes. CMV is the most common cause of polyradiculopathy and is notable for an acute onset, rapid progression if untreated, and CSF showing pleocytosis with a notable neutrophil predominance. Patients who have pain alone may have any of a variety of routine musculoskeletal diagnoses but should also be evaluated for myopathy. This condition is characterized by muscle tenderness and proximal muscle weakness. Serum creatine kinase (CPK) level is elevated and electromyelography (EMG) findings are abnormal. Zidovudine (AZT) may cause myopathy and should be discontinued in patients with this diagnosis. Most inflammatory myositis is idiopathic and responds to steroid treatment. 5 5.1

EVALUATION OF LABORATORY ABNORMALITIES Anemia

The differential diagnosis of anemia in the patient with HIV is lengthy and includes many possible causes of decreased red blood cell production, increased peripheral destruction,

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and gastrointestinal blood loss. Although anemia may relate nonspecifically to chronic disease or HIV infection itself, treatable causes should always be excluded. Common causes of decreased red cell production include bone marrow suppression by antiretroviral agents (especially AZT) or other medications, marrow infiltration by tumor (e.g., lymphoma) or infection (most commonly tuberculosis or other mycobacteria or histoplasmosis), suppression from CMV or parvovirus B19, and nutrient deficiencies (iron, folic acid, and vitamin B12). Causes of hemolysis include medication toxicity (especially from sulfa drugs) and thrombotic thrombocytopenic purpura (TTP). Gastrointestinal blood loss due to malignancy, CMV colitis, or other infection must also be excluded. Initial evaluation of anemia should include review of peripheral blood smear, laboratory studies to detect nutrient deficiencies, and assessment for gastrointestinal bleeding or excess uterine bleeding. The presence of abnormalities in other cell lines and/or fever should also prompt bone marrow aspiration and biopsy. If no treatable cause is identified, therapy with erythropoietin and concomitant iron supplementation should be considered. 5.2

Hepatic and Renal Disease

Most patients who have hepatic or renal dysfunction related to HIV infection are asymptomatic; abnormalities initially appear only on routine laboratory testing. The most common situation involving hepatic abnormalities is the development of abnormal liver biochemical test results in the absence of symptoms. Elevated transaminase levels should suggest medication toxicity, viral hepatitis, or alcohol use (see Chapter 23). Hepatitis virus serological tests (A, B, and C) and/or drug holidays (i.e. temporary discontinuation of medications) can be used to clarify the cause. A markedly elevated alkaline phosphatase level may be indicative of M. avium infection but may also suggest biliary obstruction that should be evaluated radiographically to look for mass lesions and/or dilated biliary ducts. Renal dysfunction, as evidenced by elevated blood urea nitrogen (BUN) and creatinine levels, should be evaluated to determine whether the cause is prerenal, intrarenal, or postrenal, similarly to evaluation of the HIV-uninfected patient. The most common cause of renal insufficiency specific to HIV is HIV-associated nephropathy characterized by the presence of proteinuria and visualization of large kidneys by ultrasound. There is no definitive therapy, although antiretroviral agents, steroids, and angiotensin-converting enzyme inhibitors have all been utilized. 5.3

Lactic Acidemia

Lactic acidosis is a relatively new and uncommon but potentially fatal complication of nucleoside analog reverse transcriptase inhibitors (NRTIs). Although all NRTIs have been implicated, d4T appears more prone to cause the syndrome. Asymptomatic elevated lactate levels may occur in up to 5%–10% of patients on NRTI. Far fewer patients experience associated symptomatic lactic acidosis. These latter patients may report fatigue, nausea, vomiting, abdominal pain, and dyspnea. Laboratory evaluation shows an elevated lactate level, metabolic acidosis, and elevations of hepatic transaminase and creatinine phosphokinase levels. There may be associated hepatomegaly and steatosis. The syndrome is hypothesized to be due to mitochondrial damage from NRTIs. Patients with asymptomatic mild (<5 mmol/L) elevations of lactate level can be observed carefully. Symptomatic patients and those with higher lactic levels should have NRTIs stopped and be given symptomatic support.

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BIBLIOGRAPHY Anderson J. A Guide to the Clinical Care of Women with HIV. Rockville, MD: Health Resources and Services Administration, 2000. Bartlett JG, Gallant JE. 2000–2001 Medical Management of HIV Infection. Baltimore: Port City Press, 2000. CDC. 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults. MMWR 1992; 41 (no. RR-17). Currier JS. Discontinuing prophylaxis for opportunistic infection: Guiding principles. Clin Infect Dis 30:S66–S71, 2000. Dolin R, Masur H, Saag MS. AIDS Therapy. Philadelphia: Churchill Livingstone, 1999. Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW, and the Adult/Adolescent Spectrum of HIV Disease Project. Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4⫹ T lymphocyte counts above prophylaxis thresholds. J Infect Dis 182:611–615, 2000. Kaplan JE, Hanson D, Dworkin MS, Frederick T, Bertolli J, Lindegren ML, Holmberg S, Jones JL. Epidemiology of human immunodeficiency virus–associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis30:S5–S14, 2000. USPHS/IDSA Prevention of Opportunistic Infections Working Group. 1999 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. Clin Infect Dis 30:S29–S65, 2000.

27 Septic Arthritis and Bursitis Ellis H. Tobin Upstate Infectious Disease Associates, and Albany Medical College, Albany, New York, U.S.A.

Eric S. Brecher Pennsylvania Hospital, Philadelphia, Pennsylvania, U.S.A.

1

SEPTIC ARTHRITIS

With over 200 joints and well over 1000 different species of microorganisms capable of infecting any joint at a given time, the possible combinations and complications of septic arthritis could theoretically overwhelm both patient and clinician. Fortunately this daunting scenario is unfounded since the great majority of joint infections are limited to a small number of anatomical sites and only a few varieties of microorganisms. Nonetheless, distinguishing septic arthritis (pyarthrosis) from other causes of joint pain and promptly managing the infected joint before the development of irreversible damage are notable challenges. 1.1

Epidemiological Characteristics

The yearly incidence rates in the adult population range from 2 to 10 per 100,000 in the general population and 30 to 70 per 100,000 in patients with rheumatoid arthritis (RA). In populations above the age of 50, the incidence of pyarthrosis increases proportionately with age. Monoarticular infection occurs in 80% of cases. Patients with underlying illness, particularly preexisting joint disease, and immunosuppression, are predisposed to polyarticular infection. The knee is the most commonly infected joint, followed by the hip. Pyarthrosis of other joints is significantly less common (see Table 1). Any microorganism is capable of causing pyarthrosis. However, the majority of joint infections are due to a few types of pathogens (see Table 2). In general, Staphylococcus aureus is the most frequent etiological agent except in sexually active adults below the age of 30, among whom Neisseria gonorrhoeae plays a predominant role. Important epidemiological associations often exist between the type of pathogen causing septic arthritis and the age, geographical location, and immune function of the host (see Table 3). This point is best illustrated by pyarthrosis due to N. gonorrhoeae, B. burgdorferi, M. tuberculosis, viruses, and fungi. 535

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SEPTIC ARTHRITIS: 1 Hematogeneous source generally Monoarticular in 80% (see Table 1) Increased risk: rheumatoid arthritis (RA), injection drug use (IDU), crystal joint disease, degenerative joint disease Gonococcal vs. nongonococcal risks (see Table 3) Nongonococcal S. aureus > Streptococcus spp. >> gram-negative rod (GNR) Diagnosis Painful swollen joint Decreased passive and active range of motion (ROM) Arthrocentesis White blood cell (WBC) count generally >50,000 cells/m3 Gram stain and culture Suspected gonococcal: Thayer-Martin agar Analysis for birefringent crystals Computed tomography/magnetic resonance imaging (CT/MRI) scan to assess for abscess, osteomyelitis, or fistula as needed Therapy (see Table 3) Repeated arthrocentesis vs. open drainage Gonococcal IV for 24–48 hr after improvement then PO for a total of 3–4 wk Nongonococcal IV for 2 wk then PO for total of 4–6 wk

1.2

Routes of Joint Infection

Hematogenous seeding of the highly vascularized synovium and epiphyseal bone is the most common route to pyarthrosis. Sources leading to hematogenous spread of bacteria often include skin sites, intravenous catheters, and injection drug use (IDU). However, Table 1 Affected Joint Distribution in Adults with Nongonococcal Bacterial Arthritis Joint Knee Hip Ankle Shoulder Wrist Elbow Others Multiple joints

Cases, % 55 11 8 8 7 6 5 12

Source: Adapted from Goldenberg 1997.

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Table 2 Principal Microorganisms Causing Nongonococcal Bacterial Arthritis Microorganisms

Percentage

Staphylococcus aureus Streptococcus spp. Gram-negative bacilli Miscellaneous

55 27 14 4

Source: Adapted from Smith 1990.

infection of any organ system, most notably the genitourinary, gastrointestinal, or cardiovascular, could lead to bacteremia and joint seeding. Thus, the evaluation of patients with pyarthrosis must include a detailed history and physical examination directed at identifying a potential extra-articular source of infection. Pyarthrosis can also result from contiguous spread from an adjacent soft tissue infection or a juxta-articular osteomyelitis. Contamination of a joint can also occur by direct inoculation via joint aspiration, injection of a joint space, arthrography, or penetrating wound. Postoperative infections can result from arthroscopy and prosthetic joint replacement (see Sec. 1.9.1). 1.3

Pathogenesis

Within minutes of gaining entry into a joint, virulent bacteria such as S. aureus and Streptococcus spp. provoke a proliferation of synovial cells, macrophages, and polymorphonuclear leukocytes. Over the course of several hours, synovial hypertrophy and elaboration of synovial fluid result in joint swelling, effusion, and pain. At this stage, physical examination and conventional radiological imaging may demonstrate the presence of interosseous distension and signs of effusion (see Figure 1[2] and Figure 2). Over the course of 3 to 4 days, leukocyte production of cytokines and proteolytic enzymes leads to hydrolysis of cartilage. Additionally, the development of a growing synovial pannus further erodes and undermines the cartilage. Destruction of cartilage and erosion of bone can be seen radiologically as joint space narrowing and a poorly defined rim of juxta-articular bone, respectively (see Figure 1[3,4] and Figure 3a and 3b[1,2]). If the inflammatory process is allowed to proceed, bony bridging (ankylosis) ensues (see Figure 1[5] and Figure 4). Infection can spread into juxta-articular soft tissue, causing abscesses, sinus tracts, pyomyositis, fasciitis, and rupture of adjacent tendons and ligaments. Joint distension caused by an enlarging effusion can impair local blood flow, leading to avascular necrosis. The suppurative inflammatory model of septic arthritis described previously does not appear to explain the pathophysiological mechanisms of joint inflammation associated with all microorganisms. Viruses, chlamydia, mycobacteria, fungi, Borrelia spp., and other bacteria cause associated joint inflammation in ways that are not well understood. The term reactive arthritis, categorized as one of several seronegative spondyloarthropathies, has been applied to a number of infection-associated inflammatory processes. As the name implies, it reflects a poorly understood interplay between the inciting pathogen and host immune reaction. In many instances of reactive arthritis, infection appears to occur at a site distant from the joint and viable microorganisms are absent from the inflammatory joint tissues. Some of these pathophysiological mechanisms appear to be

Amoxicillin/clavulanate 500 mg tid

Ampicillin/sulbactam 1.5 g q6h or cefotaxime 1.0 g q8h or ceftriaxone 1.0 g q12h As in anti–S. aureus regimen; P. aeruginosa, ceftazidime or piperacillin or ticarcillin Ceftriaxone 2.0 g qd or penicillin G 20 million units qd, 14 to 30 days

IVDA, MRSA, INH, RIF, PZA, ETH, Source: Adapted from Smith and Shabaz 2000.

a

Foreign or domestic exposure: Mycobacterium tuberculosis

Ingestion of unpasteurized dairy products: Brucella spp.

Tick exposure: Borrelia burgdorferi

IVDA: S. aureus, Pseudomonas aeruginosa

Amoxicillin/clavulanate 500 mg tid

Ampicillin/sulbactam 1.5 g q6h

Human bite: mixed flora, including Streptococcus spp., S. aureus, Eikenella corrodens, Fusobacterium nucleatum Dog and cat bite: mixed flora, including Pasteurella multocida

Doxycycline 200 mg qd for 6 wk, plus either streptomycin 1.0 g IM qd for 3 wk or gentamicin 5 mg/kg IV or IM qd for 10 days INH and RIF for 9 to 12 mo, plus either PZA or ETH for 2 mo

Doxycycline 100 mg bid or amoxicillin 500 mg qid, 30 to 60 days

As in anti–S. aureus regimen; P. aeruginosa, ciprofloxacin 500 mg bid

Oral therapy easier to administer and less expensive; if symptoms of neuroborreliosis present, IV regimen preferred No comparative efficacy data for streptomycin and gentamicin regimens; may add rifampin 300 mg PO tid after completion of aminoglycoside course If drug resistance suspected or documented additional agents possibly required

If monobacterial infection caused by P. multocida switch to penicillin G IV or penicillin VK PO If MRSA suspected, vancomycin

Doxycycline 100 mg bid or clindamycin plus either a fluoroquinolone or trimethoprim & sulfamethoxazole No firmly established regimen. Consideration of clindamycin plus fluoroquinolone If S. aureus, vancomycin

Ciprofloxacin 500 mg bid or spectinomycin 2.0 g IM q12h

IV antibiotic continued 24– 48 hr after clinical improvement begins, then oral regimen E. corrodens resistant to oxacillin, nafcillin, and clindamycin

Penicillin allergic Vancomycin

Comments If MRSA suspected, vancomycin 1.0 g q12h

Antimicrobial

Dicloxacillin 500 mg qid, or first-generation cephalosporin Cefixime 400 mg bid or ciprofloxacin 500 mg bid

Oxacillin (or nafcillin) 2.0 g q4h or cefazolin 2.0 g q8h Ceftriaxone 1.0 g qd or cefotaxime 1.0 g q8h or ceftizoxime 1.0 g q8h

Cutaneous source: Staphylococcus aureus or Streptococcus spp. Sexually active young adult: Neisseria gonorrhoeae

Oral

Intravenous

Epidemiological features and microorganism

Table 3 Epidemiologic Associations and Antimicrobial Regimens in Septic Arthritisa

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Figure 1 Septic arthritis: Pathological abnormalities: 1, Normal synovial joint; 2, an edematous swollen and hypertrophic synovial membrane becomes evident; 3, 4, accumulating inflammatory pannus leads to chondral destruction and to marginal and central osseous erosions; 5, bony ankylosis eventually can result. (Adapted from Resnick and Niwayama 1995.)

due to a sharing of antigenic determinants between microorganism and host that leads to an autoimmune inflammatory reaction. 1.4

Risk Factors

Individuals who have preexisting joint disease (e.g., RA, crystal-induced arthritis, and degenerative arthritis) or joint trauma are at significantly higher risk for hematogenously acquired suppurative arthritis. Increased rates of pyarthrosis also occur in immunosuppressed patients, diabetics, and patients with chronic renal failure. Individuals with sickle cell anemia are at higher risk for development of pyarthrosis due to Salmonella spp. Bacterial inoculation of the blood stream by IDU increases the risk of septic arthritis. For reasons that are not understood, menstruating or pregnant women with gonorrhea are predisposed to acquisition of gonococcal arthritis.

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Figure 2 Conventional radiograph of the knee obtained in the lateral projection demonstrating a large joint effusion (arrows).

Figure 3 Pyarthrosis of first metatarsophalangeal joint: Conventional radiographs of the first metatarsophalangeal joint performed in the anteroposterior projection obtained 15 days apart. a, The initial radiograph demonstrates subtle subchondral sclerosis (arrow); b, the follow-up radiograph reveals rapid destruction of the joint manifested by joint space narrowing and marginal erosive changes.

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Figure 4 Pyarthrosis of interphalangeal joint with ankylosis: Anteroposterior conventional radiograph demonstrates bony fusion of the interphalangeal joint (arrow), a late radiographic feature of pyarthrosis, signifying end-stage joint destruction.

The presence of particular histocompatibility antigens significantly increases the risk of certain types of infection-associated arthritis. Individuals with human leukocyte antigen B27 (HLA-B27) are at increased risk of development of reactive arthritis after sexually transmitted chlamydia infection and after gastrointestinal infections due to Salmonella, Campylobacter, Shigella, and Yersinia spp. Chronic Lyme arthritis is significantly more likely to occur in individuals who have the HLA-DRB1*0401 gene. Any activity that results in direct inoculation of the joint, such as bites, punctures, injections, aspiration, and surgery, may cause pyarthrosis. Risk factors for the development of prosthetic joint infection include the development of superficial infection at the surgical site, a high surgical risk index score, and a history of malignant disease. 1.5

Clinical Manifestations, History, and Physical Examination

The acuity and severity of symptoms and signs depend on the virulence of the infecting microorganism, the underlying health and immune function of the host, and the anatomical location of the infected joint. History should be directed to identification of risk factors and possible sources of infection as well as recognition of conditions that can mimic septic arthritis (see Table 3 and Figure 5). On the basis of clinical manifestations and the natural history of disease, bacterial septic arthritis has historically been subdivided into nongonococcal and gonococcal forms. 1.5.1

Nongonococcal Septic Arthritis

Suppurative arthritis due to staphylococci and streptococci occurs abruptly with pain and swelling of the joint. Monoarticular arthritis is significantly more common than involve-

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Figure 5 Algorithm for the differential diagnosis of the painful swollen joint.

ment of multiple joints. Fever occurs commonly but is usually low-grade. Peripheral joints that can be easily examined demonstrate an effusion and are often erythematous, warm, and exquisitely tender. In deep joints (e.g., hip, shoulder) clinical signs of effusion are not usually apparent but can often be evaluated by various diagnostic imaging modalities. Pain due to pyarthrosis causes a marked limitation in both passive and active range of motion. This is in contrast to tenosynovitis, in which pain and limitation are worse with active range of motion. Similarly, whereas juxta-articular pain, erythema, and swelling can occur with osteomyelitis, septic bursitis, and cellulitis, there is minimal limitation in passive range of joint motion. When infection involves the hip or sacroiliac joint (SIJ), pain is frequently referred to the buttock, lower back, groin, or leg, often resulting in a delayed diagnosis. Clinical signs of SIJ infection include tenderness over the joint; pain with the combined maneuver of flexion, abduction, external rotation, and extension (FABERE maneuver) of the ipsilateral leg; and pain with pelvic compression. Physical findings that

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help localize hip joint infection include pain with weight bearing and movement of the joint. Sternoclavicular joint infection causes anterior chest pain that frequently radiates to the neck and ipsilateral shoulder. Physical findings demonstrate swelling and tenderness over the involved sternoclavicular joint. Joint infection due to aerobic gram-negative bacilli can result from gastrointestinal and genitourinary tract sources as well as IDU. Anaerobic and polymicrobial bacterial pyarthrosis can result from open trauma and bite wounds. Brucella arthritis occurs more frequently in parts of the world where nonpasteurized dairy products are consumed. Joint infections due to Borrelia spp. and mycobacteria should be considered when epidemiological associations are identified (Table 3). 1.5.2

Gonococcal Arthritis

Gonococcal infection occurs most often in healthy, sexually active young adults. Indeed, it is this feature that should prompt awareness and consideration of this microorganism in the appropriate clinical and epidemiological setting. In a minority of individuals with gonorrhea, bacteremia and disseminated gonococcal infection (DGI) develop. Dissemination typically results in a syndrome characterized by fever, rash, tenosynovitis, and migratory polyarthritis, often involving knee, ankle, wrist, and metacarpophalangeal joints. After 1 to 4 days, systemic manifestations wane and tenosynovitis and arthritis involving one to several joints become the predominant features. Occasionally, gonococcal arthritis occurs in individuals without an obvious history of full-blown DGI. In this form, gonococcal arthritis is clinically indistinguishable from other types of pyogenic arthritis. In most cases of DGI and arthritis, symptoms associated with infection at the primary mucosal site (e.g., cervix, urethra, rectum, pharynx) are absent, although cultures of these sites frequently yield positive results.

1.6

Differential Diagnosis

Because of the potential for rapid joint destruction, any painful swollen joint should be considered infected until proved otherwise. However, it is important to appreciate that a variety of disease entities can cause clinical manifestations that mimic pyarthrosis. The epidemiological setting, clinical history, physical findings, and synovial fluid analysis can establish a diagnosis of septic arthritis in the majority of cases. An algorithm (see Figure 5) provides an approach to considering the differential diagnosis. It is important to remember that periarticular infection and inflammation can cause symptoms that may suggest pyarthrosis; a thorough physical examination should help to distinguish one from the other. Crystal-induced arthropathy (gout and pseudogout) is relatively common, and its clinical features are indistinguishable from those of pyarthrosis. Diagnosis depends on the presence of birefringent crystals (monosodium urate monohydrate or calcium pyrophosphate dihydrate) in synovial fluid. However, joint infection and crystal-induced arthropathy may coexist. Thus synovial fluid analysis for the presence of crystals should always include Gram’s stain and cultures. Patients with RA are at increased risk of both monoarticular and polyarticular infection. Pyarthrosis should be considered when RA patients experience a flare in joint symptoms, particularly single-joint or multiple-asymmetrical-joint inflammation. The epidemiological and clinical presentations of gonococcal arthritis and reactive arthritis due to Chlamydia trachomatis can be identical.

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Approach to Establishing the Diagnosis Synovial Fluid Analysis

The diagnosis of septic arthritis is established when microorgansisms are identified in synovial fluid. However, not all joints are easily accessible for fluid aspiration, and not all microorganisms causing arthritis are readily cultured or present in the joint at the time patients reach clinical attention. Culture of blood and extra-articular sites of primary infection may provide presumptive microbiological diagnosis. When septic arthritis is being considered, joint aspiration should be performed before antibiotic therapy. If antibiotics have been administered before joint aspiration, the yield of positive cultures can decrease significantly. Since joint destruction can occur within a few days of infection, there should be no delay in performing an arthrocentesis. The ease of aspiration depends on the joint involved; the knee is the most accessible. Arthrocentesis of other joints often requires the expertise of rheumatologists or orthopedic surgeons or guidance by radiological imaging (Figure 6). Gram stains have positive results in only 30% of nongonococcally infected joints and very rarely in gonococcal arthritis. Cultures yield positive findings in 90% of joints with nongonococcal pyarthrosis and 50% with gonococcal arthritis. Blood cultures yield positive results in 10% to 60% of patients with nongonococcal arthritis but less than 10% of patients with gonococcal infection. When gonococcal arthritis is being considered, cultures of mucosal sites (urethra, cervix, rectum, and pharynx) should also be obtained, immediately inoculated onto selective growth medium (Thayer-Martin agar), and placed in an enriched CO2 environment. The yield from these mucosal sites is approximately 85%. Polymerase chain reaction (PCR) can measure N. gonorrhoeae deoxyribonucleic acid (DNA) in synovial fluid and may prove to be a rapid, sensitive, and readily available technique.

Figure 6 Needle aspiration of infected left sternoclavicular joint: A nonenhanced axial computerized tomography (CT) scan displayed with soft tissue window of the thorax demonstrates the tip of an aspiration needle within the left sternoclavicular joint (solid arrow). Subtle asymmetrical enlargement of the left pectoralis major muscle is seen (open arrow). Gram’s stain and culture of synovial fluid yielded gram-positive cocci and Staphylococcus aureus, respectively.

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The total white blood cell count in synovial fluid can be determined rapidly, but its ability to distinguish among pyogenic, reactive, and noninfectious inflammatory processes is limited. Pyogenic infections tend to have relatively high cell counts (>50,000 cells/mm3) and a predominance of neutrophils; however, similar findings can occur in RA and crystalinduced arthritis. Septic arthritis with relatively low synovial fluid cell counts (<25,000 cells/mm3) can occur on rare occasions. Synovial fluid glucose levels have low specificity and offer little help in the diagnostic scheme. Measurement of synovial fluid D-lactic acid, a product of bacterial metabolism, appears to have good positive and negative predictive values. Its widespread application in the clinical setting awaits further study. Synovial fluid analysis for the presence of crystals should be performed whenever acute monoarticular pain and swelling occur. However, the presence of crystals does not preclude a diagnosis of a coexisting infection. 1.7.2

Diagnostic Imaging

A variety of diagnostic imaging studies can be performed in the evaluation of an acutely painful swollen joint. These studies are sensitive but nonspecific and are unable to distinguish among the many causes of inflammation. Imaging modalities can add significant cost to the evaluation of a patient with an inflamed joint. Thus their application should be used judiciously and in those cases in which the information gained has significant impact on clinical management. Unfortunately, there are no large well-controlled prospective studies that delineate the sensitivity, specificity, and positive and negative predictive values of diagnostic imaging with respect to joint infections. Nor are there firm recommendations on when and how best to apply a specific modality in a particular setting. Moreover, new imaging modalities are rapidly evolving, and their applications to the diagnosis and management of patients with inflammatory joints remain to be determined. It is also important to emphasize that the choice and interpretation of a given imaging modality should be made in concert by the physician who is requesting the study and the radiologist who has been provided the pertinent clinical history and physical findings. Plain Radiographs. The plain radiograph is widely available and readily interpretable but limited in its ability to provide information that is likely to have an impact on management decisions. Early in the infectious process, plain radiographs may be able to demonstrate subtle signs suggestive of a joint effusion (Figure 2). However, once bony changes due to septic arthritis are evident on plain films, it is usually too late to prevent joint destruction (see Figure 3b and Figure 4). The role of plain radiographs in the evaluation and management of the patient with presumed pyarthrosis is controversial. Some radiologists advocate obtaining plan radiographs in order to establish a baseline and to exclude the presence of other articular and juxta-articular abnormality. Ultrasound. Ultrasonography can diagnose small joint effusions not apparent on physical examination or plain radiographs, can identify periarticular soft tissue abnormalities, and can provide guidance for joint aspiration. The practical utility of ultrasonography in the evaluation of suspected pyarthrosis and associated juxta-articular complications is dependent on the experience and expertise of the radiologist. Obvious advantages of ultrasonography include lack of ionizing radiation and ability to perform the procedure at the bedside. Disadvantages are inability to exclude complicating osteomyelitis in all cases and the limitation that relatively few radiologists are trained in its musculoskeletal applications. Computed Tomography. Computed tomography (CT) scan provides excellent visualization of bone detail and very good assessment of the juxta-articular soft tissues and

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can be used for joint aspiration guidance (see Figure 6). An advantage of CT scans over conventional radiography and ultrasonography is the ability to manipulate the window and level settings in order to emphasize different tissue characteristics. CT scans are limited by their inability to detect very early pyarthrosis and acquire images in multiple planes. Additional disadvantages of CT scans include limited availability, high cost, and relatively high radiation exposure. CT scans may serve a useful role in the evaluation of joints that are not readily accessible to physical examination and aspiration and in cases in which magnetic resonance imaging (MRI) is unavailable or contraindicated. Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) provides unsurpassed soft tissue contrast. MRI can detect extremely small joint effusions, cartilage and ligamentous damage, and subtle medullary bone and periarticular soft tissue edema (see Figure 7). MRI does not expose patients to ionizing radiation and can acquire images in multiple planes. Joint aspirations can be performed with MRI guidance. Disadvantages of MRI include relatively poor spatial resolution compared to that of CT scans and conventional radiographs, high cost, and limited availability. Additionally some patients cannot have MRI because of claustrophobia or the presence of in situ metallic foreign bodies. Although there are many methods of acquiring MR images (e.g., multiplanar gradient recalled [MPGR], fast low-angle shot (FLASH), and short tau inversion recovery [STIR]), the essential point is that there are only two key imaging parameters that the nonradiologist needs to be familiar with: the T1-weighted and T2-weighted sequences. For the purposes of this chapter, it is important to recognize that on T1-weighted images fluid and cortical bone appear dark (hypointense), and fat appears bright (hyperintense). On T2-weighted images fluid appears bright, cortical bone appears dark, and fat appears bright. When fatsuppression techniques are applied, it is possible to distinguish between fluid collections

Figure 7 Left sternoclavicular joint infection: Axial fat-saturated T2-weighted image obtained at the level of the sternoclavicular joints shows marked hyperintense signal within the sternum (solid arrow), the left clavicle (curved arrow), and the left pectoralis major muscle (open arrow), findings consistent with edema. This study was obtained for the same patient and on the same day as the computed tomography (CT) scan in Figure 6. Note how much better the soft tissue abnormalities are seen on magnetic resonance imaging (MRI) scan as a result of superior contrast resolution.

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and fat. MRI should be considered the imaging modality of choice for evaluating deep joints including the shoulder, sternoclavicular, sacroiliac, and hip. In addition, MRI lends itself to the evaluation of complicated joints including the wrist and ankle. Nuclear Scintigraphy. Nuclear scintigraphy has emerged as the modality of choice for imaging infected joint prostheses (see Figure 8). Unlike MRI and CT scans, nuclear medicine studies are not hindered by metallic artifact. The use of three-phase bone scans and radiolabeled autologous white blood cell scans has significantly improved the sensitivity and specificity of nuclear medicine studies in diagnosing septic arthritis. Disadvantages of nuclear medicine studies include very poor spatial resolution, potential limited availability, and exposure to ionizing radiation. 1.8

Therapeutic Options

The rapid development of joint destruction due to pyogenic infection dictates that early detection, diagnosis, and initiation of antibiotics are of utmost importance. Administration of empirical antibiotics should begin immediately after joint aspiration and should be based on the Gram stain findings. If the Gram stain does not demonstrate the presence of microorganisms, choice of empirical antibiotics must be guided by epidemiological characteristics, risk factors, exposure history, and likely primary source of infection (see Table 3). Once microorganisms are identified in culture, antibiotics should be modified accordingly. Recommendations on the duration of antibiotic therapy, although based on sound principles and clinical experience, have not been critically evaluated on the basis of large prospective studies. In general, 2 weeks of intravenous antibiotic therapy followed by an additional 2 to 4 weeks of oral therapy is recommended. When osteomyelitis or preexisting joint disease is present, longer courses of antibiotics may be required. There is no role for the administration of intra-articular antibiotics. Intriguing studies on the use of oral combinations of quinolones or minocycline plus rifampin suggest that these combinations may be useful in pyarthrosis due to staphylococci.

Figure 8 Infected prosthetic joint: Autologous white blood cell scan of the right knee obtained in anterior and lateral projections demonstrates abnormal tracer accumulation within the prosthetic knee joint (open arrows). Also identified is diffuse, intense, tracer localization surrounding the stems of both the femoral and tibial components (solid arrows). The H-shaped area of photopenia within the joint represents the metallic prosthesis.

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The role of joint aspiration and surgical drainage in the treatment of pyarthrosis remains controversial. Once again there are no large, prospective studies that have compared outcomes of different therapeutic courses. In most cases, successful therapy is accomplished by repeated daily needle aspirations during the first 5 to 7 days along with appropriate antibiotics. This can be monitored by demonstrating a decrease in synovial fluid volume and cell counts. Operative drainage should be performed if the response to therapy is poor, if the joint is not easily accessible by needle, or if synovial fluid is loculated or too thick to be aspirated. Arthroscopy has become the operative procedure of choice and accomplishes removal of debris and infected loose bodies, lysis of fibrous adhesions and loculations, and closed distension and irrigation. When pyogenic arthritis involves the hip or shoulder, early drainage by arthroscopy or arthrotomy is recommended. In general, gonococcal arthritis responds rapidly to antibiotics alone and drainage is rarely required. 1.9

Special Circumstances and Unique Pathogens

1.9.1

Prosthetic Joint Infections

Whereas rates of prosthetic joint infections are very low (<2%), their consequence are devastating. Infection most often results in prosthesis removal, prolonged antibiotic therapy, lengthy rehabilitation, and eventual need for reimplantation of a new joint. Although it is rarely life-threatening, infection frequently results in pseudoarthrosis and occasionally leads to limb amputation. Because of their limitations in design and weak statistical power, numerous published studies have led to controversy surrounding the prevention, diagnosis, and management of prosthetic joint infections. Since large, prospective, well-controlled studies do not exist, emphatic approaches to diagnosis and management should be avoided.

SEPTIC ARTHRITIS: 2 Differential diagnosis (see Figure 5) Rheumatoid arthritis (RA), crystal disease, trauma Reactive arthritis Mycobacterial or fungal (immune compromised host) Lyme disease (see Chapter 30) Viral hepatitis B virus (HBV), HCV, parvovirus B19 Prosthetic joint infection Pain, swelling, drainage, though generally more chronic in nature Aseptic joint loosening sometimes similar Early (<1 year postoperatively) Contamination at time of surgery Late (>1 year postoperatively) Hematogenous S. aureus and coagulase-negative staphylococcus > gram-negative rod (GNR) Hematogenous Possible salvage of prosthesis Well anchored Susceptible pathogen De´bridement and prolonged course of antibiotics

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This chapter discusses outpatient management issues and makes recommendations based on what appears, in the opinion of the authors, to make sound biological sense. S. aureus and S. epidermidis cause 75% of prosthetic joint infections. This microbiological feature suggests that the majority of early (<1 year) postoperative infections are due to contamination at the time of surgery. Late infection occurs via hematogenous seeding or contiguous spread of microorganisms. Host factors associated with increased risk of postoperative infection include development of a superficial infection at the surgical site, a high surgical risk index score, prior joint arthroplasty of the index joint, and a history of malignancy. Clinical signs of early postoperative infection include pain, swelling, erythema, and wound drainage. Fever, along with elevations of levels of peripheral white blood cells and acute phase reactants, is common. Determining whether the symptoms and signs are due to infection involving the prosthesis or are limited to the superficial and deep soft tissues is a challenge. Simply initiating a course of antibiotics without further evaluation makes little sense and compromises the sensitivity of culture results when the patient ultimately returns with ongoing or worsening symptoms. Efforts should be made to aspirate and analyze joint fluid. If there is no fluid to tap, open exploration of the joint with biopsy and microbiological analysis of periarticular tissues should be performed. Late prosthetic joint infection can occur either abruptly with pain, swelling, and erythema or indolently with nonspecific symptoms and signs. Pain may be the only symptom and may be due to a combination of inflammation and loosening of the prosthesis. Aseptic loosening due to mechanical failure of the prosthesis-cement-bone interface can occur in an identical manner. In both instances, plain radiographs may identify lucencies between the bone cortex and prosthetic cement. In addition, fever and leukocytosis are frequently absent and elevations in acute phase reactant levels are too nonspecific to be helpful. Nuclear scintigraphy can be of value, although false-negative and false-positive results are encountered. Communication with the interpreting radiologist is encouraged. Aspiration and analysis of joint fluid are required. However, recent prior antibiotics, the presence of fastidious microorganisms, improper specimen collection and handling, and incorrect Gram’s stain analysis may all contribute to inaccuracies in diagnosis. If microorganisms are seen on Gram’s stain and cultures grow compatible flora, one can be confident that infection is present. In the absence of positive Gram’s stain and culture results, the diagnosis is uncertain, a frustrating dilemma that occurs with some degree of regularity. If infection has been diagnosed and loosening exists, both prosthesis removal and antibiotic therapy are indicated. Reimplantation of a new prosthesis can be performed at the time of infected prosthesis removal (single-stage arthroplasty) or 6 weeks after removal of the infected prosthesis (two-stage arthroplasty). The decision to perform a single- or two-stage reimplantation arthroplasty depends on the anatomical and bacteriological characteristics, medical condition, and wishes of the patient. A single-stage reimplantation strategy may be adopted when less virulent bacteria such as S. epidermidis are the cause of infection. After single-stage reimplantation, antibiotics should be administered for 6 weeks. A two-stage approach should be considered for infections caused by more virulent bacteria such as S. aureus with an intercurrent 6-week course of antibiotics. If infection is established in a prosthesis that appears well anchored, efforts to salvage the prosthesis should be considered. Historically, attempts at prosthesis salvage failed in the majority of cases. However, recent preliminary clinical data suggest that suppressive and perhaps curative antibiotic therapy can be achieved in selected cases such as those with short duration of infection due to staphylococci. Retention of the prosthesis and cure

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of the infection may be possible after thorough de´bridement followed by administration of antibiotics that achieve high tissue and intracellular levels and possess activity against stationary growth phase bacteria. Whether this approach can be applied to a wider range of patients remains to be determined. In those instances in which antibiotics are likely to fail (e.g., resistant bacteria) or when antibiotic toxicity, allergy, or patient noncompliance exists, removal of the prosthesis and prolonged antibiotic therapy followed by reimplantation should be considered. Occasionally, prostheses that have been removed for presumed aseptic loosening are subsequently discovered by Gram stain and culture to have been infected. A reasonable approach to the management of this problem is to provide a 6-week course of antibiotics to which the organism is sensitive. If the bacteria are sensitive staphylococci, oral therapy with a combination of fluoroquinolone or minocycline plus rifampin should be considered. A similar problem that may be encountered is the growth of bacteria in broth cultures when Gram stain and solid media culture results are negative. This may represent contamination in either the collection or the handling of specimens. The submission of actual periarticular tissues is the preferred method for microbiological analysis. The practice of submitting swab specimens at the time of surgery should be discouraged. 1.9.2

Mycobacterial and Fungal Arthritis

Mycobacteria and fungi are rare causes of septic arthritis. Although the management of these infections often requires the expertise of specialists, various features of the clinical presentation should be recognized in the primary care outpatient setting. Joint infections due to these microorganisms tend to have similar clinical features, which include (1) chronic monoarticular involvement, (2) frequent absence of a primary extra-articular focus of infection, and (3) nonspecific synovial fluid inflammatory response. Granulomatous synovotis identified in biopsied synovium should prompt consideration of mycobacteria or fungi as the etiological agents. Other causes of granulomatous synovitis include brucellosis, foreign body reaction, sarcoidosis, and Crohn’s disease. Seeking epidemiological clues in the clinical history, such as exposures and country of origin, is a key element to developing a differential diagnosis that includes mycobacteria and fungi (see Figure 9). Approximately 50% of tuberculous arthritis patients lack a history of pulmonary infection with Mycobacterium tuberculosis (MTB). In highly endemic areas of the world, arthritis tends to occur more frequently in children and young adults. Multiple musculoskeletal sites may be involved and MTB skin test results are usually positive. In nonendemic areas, MTB arthritis occurs more frequently in elderly patients and is most often due to reactivation. Monoarticular disease is most common and the MTB skin test result is often negative. The knee, wrist, hip, and shoulder are the most frequently involved appendicular joints. Synovial fluid acid-fast bacillus (AFB) smears and cultures yield positive findings in 20% and 75% of cases, respectively, whereas synovial tissue culture results are positive in 95% of cases. Treatment regimens of MTB-septic arthritis are outlined in Table 3. Atypical mycobacteria rarely cause septic arthritis. Immunosuppressed patients appear to be at increased risk for hematogenous spread of infection. Mycobacteria are ubiquitous in the environment, and puncture or trauma to a joint could lead to direct inoculation in both immunosuppressed and normal hosts. Although the incidence of fungal pyarthrosis is relatively low, virtually any fungus is capable of causing joint infection via hematogenous seeding or direct inoculation. Immune suppression is a predisposing risk factor. Establishing a diagnosis usually requires

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Figure 9 Tuberculous sacroiliitis and abscess: Enhanced computed tomography (CT) scan of the pelvis photographed by utilizing ‘‘bone’’ (a) and ‘‘soft tissue’’ (b) windows demonstrating central erosions within the sacral and iliac bones (solid arrow). Additionally, there are cortical sclerosis and thickening of the left iliac wing indicative of chronic osteomyelitis (open arrow). Large, peripherally enhancing fluid collections within the left iliopsoas and paraspinal muscles represent abscesses (curved arrows). The patient is a 25-year-old Asian immigrant.

analysis of synovial tissue and depends on the identification of the microorganisms on smears and cultures. The choice of antifungal drug depends on the species of infecting microorganism, underlying host immune function, and pharmacological properties of the agent. 1.9.3

Lyme Arthritis

Details of the epidemiological features, clinical manifestations, diagnosis, and treatment of Lyme disease are reviewed in Chapter 30. During acute infection with Borrelia burg-

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dorferi, migratory polyarthralgias are common. If antibiotics are not administered, approximately 50% of individuals have single or recurrent episodes of frank monoarticular or oligoarticular arthritis. Although any joint can become inflamed, the knee is most commonly involved. Episodes of arthritis can last from weeks to months, may recur over a period of years, and usually remit spontaneously. Tendonitis and bursitis are frequent manifestations. Synovial effusions can be quite large, but joint pain is usually minimal. Chronic arthritis develops in 10% of individuals and is characterized by synovial hypertrophy and erosions of cartilage and bone. The risk of development of chronic arthritis is increased in individuals with the HLA-DRB*0401 gene. These patients often do not respond to antibiotic therapy and the pathogenesis of their arthritis appears to be due to molecular mimicry leading to an autoimmune inflammatory response. Antibiotics are effective in the treatment of the vast majority of cases of Lyme arthritis (see Chapter 30, Tables 5 and 6). 1.9.4 Viral Arthritis A variety of common and uncommon viruses cause rheumatological disease, including frank arthritis. It is important to appreciate that the clinical presentation of viral arthritis can be indistinguishable from RA, systemic lupus erythematosus (SLE) and other collagenvascular diseases. Furthermore, viral infections can cause nonspecific elevations in levels of rheumatoid factor and antinuclear antibodies, thus resulting in a diagnostic challenge. It is not uncommon for viral arthritis to be misdiagnosed. Erosive bone changes and cartilage destruction rarely result from viral arthritis. Hepatitis B Virus. Approximately 20% of patients with acute hepatitis B virus (HBV) infection experience oligoarticular or polyarticular arthritis. Symptoms usually occur during the prodromal phase and resolve once jaundice develops. Arthritis is frequently accompanied by urticaria or a maculopapular rash and reflects an immune-mediated pathogenesis. The exact mechanism underlying the joint symptoms is unknown, but immune complex deposition and complement activation appear to play a role. Liver biochemical levels may be normal or mildly elevated. HBV surface antigen is present in high titer and helps to establish the diagnosis. The rheumatoid factor result may be positive and is a nonspecific finding. HBV should be included in the differential diagnosis of patients with oligoarticular or polyarticular arthritis and should prompt relevant questions regarding risk factors (see Chapter 23). Hepatitis C Virus. Hepatitis C virus (HCV) can cause a variety of rheumatological disorders including frank arthritis. Approximately 70% of patients with HCV arthritis have a positive rheumatoid factor finding, frequently at high titer. In patients with chronic HCV infection, liver biochemical test results may be normal. Thus, the diagnosis of HCV infection as a cause of arthritis requires a high level of suspicion. If present, cryoglobulinemia and its associated clinical manifestations may be important associated features. Diagnosis is established by serological testing and virus can be quantified by PCR (see Chapter 23). Parvovirus B19. Parvovirus B19 is a single-stranded DNA virus with tropism for erythroid precursors. Infection is associated with a number of syndromes including erythema infectiosum, transient aplastic crisis, hydrops fetalis, and acute and chronic arthritis. The joint manifestations tend to occur in healthy adults who contract the infection from viremic individuals (frequently children) via the respiratory route. Blood-borne transmission can also occur. Infection is self-limited in most individuals.

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Chronic infection with parvovirus B19 can occur in the immunocompromised host. Arthritis occurs most often in women, frequently involves joints of the hands and feet, and usually lasts from one to several weeks. The rheumatoid factor finding is often positive. Infection should be considered in the context of a likely exposure (e.g., day care setting, classroom, children with erythema infectiosum, patients with aplastic crisis). Diagnosis is established by serological demonstration of B19 immunoglobulin M (IgM). The presence of B19 IgG is not diagnostic since this immunoglobulin remains positive for life after primary infection. Nonsteroidal anti-inflammatory drugs are frequently used to treat the arthritis, which is usually self-limited. Occasionally, arthritis symptoms can last for months to years. Miscellaneous Viral Arthritis. Less common viral infections including rubella and mumps are well-known causes of transient arthritis in adults. Women are at greatest risk for rubella arthritis, which is characterized as migratory symmetrical periarticular inflammation. Symptoms last for approximately 10 days. Live attenuated rubella vaccine is associated with arthritis in a small percentage of recipients, and women, again, are at highest risk of development of symptoms. Mumps is a rare cause of migratory polyarthritis in adults, and men appear to be at higher risk. Several zoonotic infections due to alphaviruses can cause arthritis as the major clinical manifestation. The usual route of transmission to humans is via mosquito vectors, and in endemic areas, outbreaks of infection by alphaviruses can cause significant morbidity rates in large sectors of the population. It is important to keep in mind their epidemiological associations with respect to individuals residing in or traveling to and from endemic areas (see Table 4). 2

SEPTIC BURSITIS

There are approximately 70 bursa in the human body, which are categorized as being either subcutaneous or deep. The vast majority of infections occur in the subcutaneous olecranon and prepatellar bursa. Macro- and microtraumatic injury cause cutaneous flora to migrate to subcutaneous tissues and contiguous bursa. S. aureus and streptococci (most commonly group A ␤-hemolytic streptococci) are the cause of septic bursitis in approximately 80% and 18% of cases, respectively. Farmers, laborers, athletes, carpet layers, gardeners, and others prone to trauma to their knees and elbows are at increased risk of infection (see Figure 10). In addition, diabetes mellitus, alcoholism, RA, and gout appear to increase the risk of septic bursitis. Clinical onset is typically acute or subacute. Approximately half of patients remember an episode of antecedent trauma. Patients experience pain, swelling, and overlying cellulitis. The associated skin and soft tissue inflammation can be extensive, occasionally

Table 4 Alphaviruses Associated with Arthritis Alphavirus Chikungunya O’nyong-nyong Ross River Mayaro Sindbis

Geographical distribution Africa, Asia Africa Australia, Oceania South America Africa, Asia, Europe, Australia

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SEPTIC BURSITIS Predominantly olecranon and prepatellar bursa Trauma-related S. aureus and S. pyogenes Pain, swelling, and overlying cellulitis No limitation of passive range of motion (ROM) Differential diagnosis Rheumatoid arthritis (RA), bleeding, gout Bursa tap Cell count Gram stain and culture Therapy Repeated needle aspirations vs. open drainage Parenteral or oral antibiotics

involving the entire extremity. Fever and leukocytosis are common. Usually there are marked tenderness and swelling directly over the bursa, although extensive overlying cellulitis may obscure these focal findings. Septic bursitis does not cause limitations in passive range of joint motion, a feature that helps distinguish it from pyarthrosis. Diagnosis is established on the basis of microbiological analysis of bursa fluid. Gram’s stain findings are positive in 50%–100% of cases; this range reflects the expertise of the microscopist. Culture results are positive unless recent prior antibiotics have been

Figure 10 Septic bursitis: Axial nonenhanced computed tomography (CT) scan image obtained through the knee reveals a large quantity of fluid within the prepatellar bursa (solid arrow). Stranding within the adjacent vastus muscles and posterior-medial subcutaneous fat represents inflammatory edema (open arrows). Air within the prepatellar bursa (curved arrow) was introduced by a previously performed needle aspiration. Bursa fluid culture grew methicillin-resistant Staphylococcus aureus.

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administered. Bursa fluid white cell counts are usually >20,000/mm3. Other fluid studies such as glucose and lactic acid levels are too nonspecific to be helpful. Blood culture results are positive in 20% of cases, and the likelihood of having a positive blood culture result is directly proportional to the severity of the bursitis. The differential diagnosis of septic bursitis includes traumatic bleeding into the bursa, RA, and gout. Diagnostic imaging can be helpful in evaluation of deep bursa and determination of the presence of fractures, foreign bodies, or joint involvement. Ultrasound is a sensitive modality for identifying fluid in both subcutaneous and deep bursa and can help guide fluid aspiration in the latter case. CT scans (see Figure 10) and MRI scans are sensitive imaging modalities, although their use should be limited to those cases in which diagnosis is uncertain or there is a need to evaluate possible presence of coexisting complications such as abscesses, joint effusions, fasciitis, or osteomyelitis. Treatment of septic bursitis has not been evaluated in a formal prospective manner. A consensus of opinion has developed on the basis of experience, anecdotal reports, and small case series. Antibiotics in themselves are not effective in eradicating the infection and relapse is common. Successful therapy usually requires a combination of repeated needle aspirations and antibiotic therapy. Aspirations should be performed daily for the first few days. If there are no systemic signs of infection and the skin and soft tissue involvement is limited, oral antibiotics are appropriate: dicloxacillin or a first-generation cephalosporin for S. aureus; penicillin or a first-generation cephalosporin for streptococci. If the patient is systemically ill or there is extensive skin and soft tissue involvement, parenteral antibiotics should be used initially and switched to oral therapy once clinical improvement occurs. When management is initiated within 7 days of onset of infection, bursa fluid usually becomes sterile in approximately 4 days, and antibiotics should continue for approximately 5 days beyond fluid sterility. Patients who seek medical attention late in the course of infection usually require a longer duration of antibiotics. In general, duration of antibiotics should be guided by the clinical response as there are no definitive recommendations on length of therapy. Surgical drainage is necessary when needle aspiration does not adequately drain the bursa, when there is coexisting soft tissue abscess, when the involved bursa is inaccessible, or when infection persists beyond 1 week despite therapy. Surgical intervention consists of either incision and drainage or partial or complete bursectomy. With early intervention, infection usually resolves within 10 days. However, inflammatory changes of the soft tissues may take weeks to months to resolve. Complications of septic bursitis include chronic sinus formation, bursa rupture, sympathetic joint effusions, and, rarely, extension of infection that leads to abscess, fasciitis, or pyarthrosis. BIBLIOGRAPHY Forrester DM, Feske WI. Imaging of infectious arthritis. Semin Roentgenol 31:239–249, 1996. Goldenberg DL. Bacterial arthritis. In: Kelley WM, Ruddy S, Harris ED, Sledge CB, eds. Textbook of Rheumatology, 5th ed. Philadelphia: WB Saunders, 1997, pp 1435–1449. Harrington JT Jr. Mycobacterial and fungal infections: In: Kelley WM, Ruddy S, Harris ED, Sledge CB, eds. Textbook of Rheumatology, 5th ed. Philadelphia: WB Saunders, 1997, pp 1450– 1461. Liebling MR, Arkfeld DG, Michelini GA, Nishio MJ, Eng BJ, Jin T, Louie JS. Identification of Neisseria gonorrhoeae in synovial fluid using the polymerase chain reaction. Arthritis Rheum 37:702–709, 1994. Mustafa K, Khan MA. Recognizing and managing reactive arthritis. J Musculoskelet Med 13:28– 38, 1996.

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Naides SJ. Rheumatic manifestations of Parvovirus B19 infection. Rheum Dis Clin North Am 24: 375–401, 1998. Norden C, Gillespie WJ, Nade S. Infection in Bones and Joins. Boston: Blackwell Scientific, 1994, pp 302–352. Resnick D, Niwayama G. Osteomyelitis, septic arthritis, and soft tissue infection: Mechanism and situations. In: Resnick D, ed. Diagnosis of Bone and Joint Disorders. Philadelphia: WB Saunders, 1995, pp 2325–2418. Schumacher HR Jr. Reactive arthritis. Rheum Dis Clin North Am 24:261–274, 1998. Segreti J, Nelson JA, Trenholme GM. Prolonged suppressive antibiotic therapy for infected orthopedic prostheses. Clin Infect Dis 27:711–713, 1998. Siegal LB, Cohen L, Nashel D. Rheumatic manifestations of hepatitis C infection. Semin Arthritis Rheum 23:149–154, 1993. Smith JW. Infectious arthritis. In: Norden CW, ed. Infectious Disease Clinics of North America. Philadelphia: WB Saunders, 1990, pp 523–538. Smith JW, Shabaz M. Infectious arthritis. In: Mandell G, Bennett MD, Dolin R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone, 2000, pp 1175–1181. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med 107: 725–731, 1987. Tobin EH. Prosthetic joint infections: controversies and clues. Lancet 353:770–771, 1999. Weaver SC, Shope RE. Alphavirus infections. In: Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases. Philadelphia: Churchill Livingstone, 1999, pp 1281–1287. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections. JAMA 279:1537–1541, 1998. Zimmermann B III, Mikolich DJ, Ho G Jr. Septic bursitis. Semin Arthritis Rheum 24:391–410, 1995.

28 Osteomyelitis Keith Collins Champlain Valley Physician’s Hospital, Plattsburgh, New York, U.S.A.

1

INTRODUCTION

Osteomyelitis is an infection of the bone and bone marrow. It is often difficult to diagnose and treat. Although accounting for only 3% to 4% of all infections, osteomyelitis can result in significant acute and chronic morbidity. Microorganisms can be implanted in the bone either hematogenously or by direct inoculation. In the adult, the hematogenous route most often affects the vertebral bodies. After a discussion of pathogenesis, the major forms of adult osteomyelitis are reviewed with an emphasis on vertebral osteomyelitis. In addition, bone infections due to human bites, puncture wounds, injection drug use, decubitus ulcers, and surgical wounds, and those associated with prosthetic joint implants are reviewed. Osteomyelitis associated with diabetic foot infections is reviewed in Chapter 29.

2

PATHOGENESIS

Bacteria reach bone and potentially cause infection by one of three routes: (1) hematogenous seeding (e.g., vertebral osteomyelitis after transient or continuous bacteremia), (2) contiguous spread from an adjacent focus of infection (e.g., osteomyelitis complicating sinusitis), or (3) direct inoculation during trauma or surgery (e.g., long bone osteomyelitis after open fractures). Because of developmental changes that alter local blood flow, hematogenous seeding of long bones is unusual in adults but is very common in childhood. During childhood before closure of the growth plate, the blood supply to the epiphsyis (developing head) and metaphysis (developing distal shaft) of growing tubular bones is physically separated by the physis (growth plate) (see Figure 1[A]). As a result, capillaries supplying the distal portion of the metaphysis end abruptly, forming hairpin loops that drain into venous channels with sluggish blood flow. Consequently, bacteria entering the bloodstream may lodge in these areas and cause infection. In adulthood, once long bone development is completed and the physis closes (Figure 1[B]), blood flow to the metaphysis diminishes. At the same time, capillaries now cross the physis and any areas of previous sluggish flow are eliminated. Given both of these events hematogenous long bone osteomyelits becomes quite rare in adults. Osteomyelitis due to sacral decubiti and that due to long bone fractures and nail puncture wounds all share the same pathogenesis: traumatic ischemic injury to bone that is then secondarily invaded by microbes. This is 557

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Figure 1 The vascular supply of long bones in children and adults. A, Child: The growth plate physically separates blood vessels supplying the epiphysis from those supplying the metaphysis of a developing long bone. Capillaries supplying the distal metaphysis end as terminal hairpin loops, forming venous channels with sluggish blood flow. Bacteria may subsequently lodge in these channels, causing infection. B, Adult: Local blood flow to the metaphysis diminishes once the growth plate closes. In addition, blood vessels now cross the growth plate, creating a network of anastomoses between the formerly separate epiphyseal and metaphyseal circulations, abolishing any areas of previously sluggish flow. As a result of these differences, long bone osteomyelitis is common in children but rarely encountered in adults.

an important clinical point as it explains why otherwise healthy viable bone is rarely (if ever) infected by an overlying cellulitis or venous stasis ulcer. Regardless of the initial route of entry, established bone infection causes increased intramedullary pressure and microthrombosis, often creating infarcted areas of dead bone known as sequestra. Having no blood supply, sequestra that are not resorbed behave as foreign bodies and provide a sanctuary where viable bacteria may continue to exist indefinitely, safely beyond the reach of both antibiotics and the immune system. If sequestra persist, the risk of treatment failure or relapse is high. Often chronic infection results with intermittent or chronic drainage from sinus tracts (fistulas) that eventually develop between the bone and the overlying skin. Although seldom encountered in adults, involucra (concentric layers of new bone that develop around a focus of osteomyelitis) can also lead to persistent infection. Thus, even seemingly ‘‘cured’’ osteomyelitis may occasionally relapse, sometimes decades later. For this reason ‘‘arrest’’ rather than cure may be the more appropriate way of thinking about chronic bone infections. 3

VERTEBRAL OSTEOMYELITIS

Of all adult bone infections, vertebral osteomyelitis presents the greatest diagnostic challenge, has the best prognosis if recognized early, may be the most devastating if the

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VERTEBRAL OSTEOMYELITIS Approach to the patients with suspected vertebral osteomyelitis stepwise (see Figure 1) Risk factors: diabetes, sickle cell disease, hemodialysis, long-term vascular access, ongoing intravenous drug use, and nosocomial bacteremia (see Table 1) Presentation: persistent or progressive back or neck pain, localized percussion tenderness (see Table 2) Laboratory evaluation nonspecific (see Table 3) Elevated erythrocyte sedimentation rate (ESR) Radiographs: plain films ordered first, followed by MRI or gallium scan as needed (see Table 4) Bacteriological testing: Most often due to S. aureus and other gram-positive cocci; gramnegative rods in >20% (see Table 5) Positive blood culture or tissue biopsy result needed to secure diagnosis and guide therapy Empirical therapy for hematogenous osteomyleitis (see Table 6) Definitive therapy based on blood or tissue culture results (see Table 7) Intravenous antibiotics given for 6–8 weeks Orthopedist or neurosurgeon consulted early to assess spinal stability, cord compression, and need for abscess drainage

diagnosis is missed, and is most often seen at the outset by the primary care physician. Vertebral osteomyelitis is considered rare, accounting for only 2%–4% of all bone infections. The annual incidence rate is about 1 to 2 cases per 200,000 adults. These figures are probably misleading as the true incidence is almost certainly higher and appears to be increasing. Men outnumber women in most series by at least 2:1. Infection occurs in all ages, but the incidence rises after the age of 50. 3.1

Anatomical and Pathophysiological Characteristics

With the exception of cases related to trauma or instrumentation, vertebral osteomyelitis almost always results from hematogenous seeding of the spine. Batson’s plexus, a lowpressure network of valveless veins, drains the vertebral column. Until recently, Batson’s plexus was thought to play a major role in the spread of urinary tract bacteria to the spinal column. Despite numerous experimental attempts, spinal infection via this retrograde venous route has never been demonstrated and is probably rare. Instead, an arterial bacteremia is nearly always involved. Initially, segmental arteries arise from the vertebral, intercostal, or lumbar vessels to supply corresponding vertebrae in the cervical, thoracic, and lumbar regions, respectively (see Figure 2). Paired anterior segmental arteries course along the middle of each vertbebra supplying blood to the body. Each segmental vessel also gives off numerous ascending and descending collateral branches that supply blood to the upper or lower poles (the metaphyseal regions) of the vertebra. The metaphyseal regions of adult vertebrae represent watershed areas where collaterals between the anterior segmental and posterior spinal circulations are sparse. For this reason, a few ascending or descending branches always span more than one level, bridging the intervertebral disk space to supply the metaphyseal region of a neighboring vertebra located one spinal segment above or below. Despite crossing the disk space, these bridging vessels supply no blood to the disk itself, which is completely avascular in adults.

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Figure 2 Blood supply to the vertebral bodies. Paired segmental arteries (SA), arising from the aorta (A), course along the middle of each vertebra. Ascending and descending collateral branches (CB) arise from each segmental artery to supply the metaphyseal regions (M) of the vertebral body. The metaphyseal regions of adult vertebrae represent watershed areas where the collateral circulation is sparse. A few bridging arteries (BA) always cross the disk space (D), supplying blood to the metaphyseal region of a neighboring vertebra located one spinal segment above or below. Pathologically, these bridging arteries provide a route for the rapid spread of infection between adjoining vertebral bodies.

Bacteria gaining access to the bloodstream may lodge in these metaphyseal watershed regions, to produce small areas of infarction. Once infarction occurs, infection is quickly established and rapidly spreads via the bridging arteries to involve the metaphyseal region of an adjoining vertebra. Simultaneously, bacteria directly invade the intervening disk, which is then rapidly destroyed. As shown in Figure 3, the earliest changes seen on plain radiographs include a loss of disk height combined with anterior endplate erosion of the two adjoining vertebral bodies. Left untreated, infection may not only spread to involve additional segments, but also result in paravertebral abscess, cord compression, vertebral column instability, and death of uncontrolled sepsis. Successful outcome depends on early diagnosis and treatment. 3.2

Risk Factors

Table 1 lists the major risk factors for vertebral osteomyelitis. In younger adults, sickle cell disease, renal failure, long-term vascular access, and perhaps early-onset type I diabetes mellitus represent the major risks. When these conditions are excluded, intravenous drug use is the most important factor, accounting for nearly all the remaining cases. Among ambulatory adults above the age of 50, the risks are less well defined and more controversial. Diabetes is the only well-established risk factor, present in roughly 20% of cases.

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Figure 3 The radiographic appearance of vertebral osteomyelitis. A, Loss of disk height may be apparent as early as 10 days after symptom onset. B, Superior and inferior end-plate erosion of adjoining vertebrae is often visible by 2 to 3 weeks. C, Advanced disease is characterized by ballooning of the disk space due to extensive destruction of the vertebral bodies. At this stage, vertebral column instability and paravertebral abscesses are common.

Table 1 Risk Factors for Vertebral Osteomyelitis Well established Age above 50 years Diabetes mellitus Sickle cell disease Hemodialysis Intravenous drug use Long-term vascular access Nosocomial bacteremia Probable increased risk Collagen vascular disease Malignancy Malnutrition Alcoholism Corticosteroids Other immunosuppressive agents Proposed Preceding minor trauma or fall Human immunodeficiency virus (HIV) infection Infective endocarditis

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Other proposed risks include preexisting collagen vascular disease, long-term steroid use, use of other immunosuppressive agents, alcoholism, malnutrition, and malignancy. A history of minor trauma or fall within the preceding month is also common. Recently, venous– and urinary catheter–related bacteremia has emerged as a major risk factor among hospitalized elderly adults and residents of long-term care facilities. 3.3

Presenting Symptoms and Signs

The patient usually experiences localized back or neck pain that has been present anywhere from 2 to 8 weeks before seeking treatment. The pain is usually constant, often severe, and unaffected by position or movement. Sometimes there is a radicular component. The upper lumbar or lower thoracic spine is usually involved. Neck pain is rare except in intravenous drug users, in whom cervical spine involvement occurs 25% of the time. Invariably, the pain persists and usually worsens during a 2-week trial of conservative management. In addition to pain, loss of appetite is surprisingly common when specifically sought. Problems of leg weakness or difficulty of urination occur less often but are not rare. On physical exam, the patient usually appears uncomfortable and may have visible or palpable paraspinous muscle spasm. Localized percussion tenderness is usually present and reflects the level of involvement. As many as 20%–40% of patients have a demonstrable neurological deficit (lower extermity weakness, hyperreflexia, or paresthesias) if carefully examined. Fever occurs in fewer than half of all patients, and its absence should not dissuade the clinician from entertaining the diagnosis. Table 2 lists the frequencies of these signs and symptoms. 3.4

Laboratory Tests

Table 3 lists the most useful laboratory studies and the expected findings. Although yielding positive results in only 20%–50% of the time, two sets of blood cultures should always be drawn. As discussed shortly, if the findings are positive, they may spare the patient an invasive diagnostic procedure. Although nonspecific, the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) level are almost always elevated. Serial measurements of these parameters are useful in monitoring the response to therapy. The complete blood count (CBC) is very nonspecific but may show a mild normochromic normocytic anemia. Leukocytosis is seen only 40%–60% of the time. Measuring the serum alkaline phosphatase level is seldom helpful.

Table 2 Presenting Signs and Symptoms Symptom or sign Localized pain (severe or progressive) Location Lumbar Thoracic Cervical Percussion tenderness Fever Anorexia Lower extremity weakness Septic picture

Percentage >90 60 35 5 85 50 90 20 10

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Table 3 Laboratory Tests Testa

Frequency abnormal

Blood cultures (two sets)

Positive result in 20%– 50%

ESR

Elevated rate in >95%

CRP CBC

Elevated level in >98% Increased WBC count in 40%–60%, mild anemia Elevated level in 50%– 60%

Alkaline phosphatase a

Comment Always draw before giving antibiotics; if finding positive, bone biopsy may not be needed Often over 80 mm/h; if normal, diagnosis is suspect; useful in monitoring response to therapy Has similar utility to ESR Nonspecific. WBC increase thought to suggest paravertebral abscess Requires fractionation; seldom helpful

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; CBC, complete blood count; WBC, white blood cell.

3.5

Radiographic Studies

Table 4 lists the radiographic studies routinely used to evaluate the spine and gives estimates of their sensitivity and specificity. Plain films should be the initial study whenever the diagnosis is suspected. The earliest changes, seen after about 2 weeks, are disk space narrowing combined with anterior end-plate erosion (see Figure 3). In young healthy adults with a compatable clinical history, these changes raise suspicion and are reasonably specific. Conversely, otherwise healthy young adults who have back pain but who lack risk factors, are afebrile, and have no percussion tenderness or neurological deficits indicated on exam are exceedingly unlikely to have osteomyelitis if their plain film results are normal. Unfortunately in older adults, many benign diseases can produce similar radiographic findings. Furthermore, although these changes may be present after only 2 weeks, they are often subtle and may not be evident for up to 2 months. Thus, although useful, given the difficulties with interpretation combined with a rising incidence of disease with advancing age, plain films should not be relied on to make or exclude the diagnosis for patients above age 50. Magnetic resonance imaging (MRI) has excellent sensitivity and specifity even very early in the disease process. It has the added advantage of producing detailed soft tissue images to allow for prompt diagnosis of serious complications such as paravertebral ab-

Table 4 Radiographic Studies Modality Plain radiograph Three-phase bone scan Gallium scan Gallium ⫹ bone scans Magnetic resonance imaging

Sensitivity, %

Specificity, %

78–82 86–92 89–92 90 92–96

57 49–78 85–100 78 92

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scesses or cord compromise. For these reasons MRI is now the imaging procedure of choice. Nuclear medicine studies are also sensitive and remain useful, particularly when MRI is unavailable or contraindicated. Gallium scanning (alone or combined with a three-phase bone scan) is the nuclear study of choice. The indium white cell scan, although highly specific, is very insensitive and should not be used as a screening study. Newer modalities such as radiolabeled antigranulocyte antibody studies appear promising but lack clinical experience and are not widely available. Areas of abnormality seen on plain radiograph or nuclear scans can be followed up by MRI or computed tomographic (CT) scanning. CT scanning is considerably less sensitive than nuclear scanning, especially for early disease; it should not used as a screening test. 3.6

Diagnostic Approach

The patient who reports severe back pain, percussion tenderness, fever, and a neurological deficit presents little diagnostic confusion (other than malignancy) and is likely to undergo prompt and appropriate evaluation (see Figure 4). The diagnosis should be considered whenever the folowing criteria have been met: (1) the patient has severe or persistent back pain, (2) common causes have been excluded, (3) localized percussion tenderness is present on exam, and (4) one or more of the risk factors outlined in Table 2 are present. Although the standard admittedly is arbitrary, moderately severe pain that persists or progresses over a 2-week period of observation should heighten clinical suspicion. Ultimately the decision to proceed with imaging studies rests on thoughtful clinical judgment guided by a thorough history and physical examination. A definitive microbiological diagnosis depends on isolating an organism from either blood cultures or a bone biopsy. Blood cultures must be drawn before starting antibiotics. Similarly, clinically stable patients without evidence of abscess or instability on MRI can safely remain off antibiotics until after the bone biopsy. Even under optimal conditions, percutaneous bone or disk space biopsy is successful in identifying the microbiological pathogens in only 40%–70% of cases. Ideally, if the first attempt was unsuccessful in identifying microorganisms, either a second attempt should follow or an open biopsy should be performed. In addition to Gram stain and aerobic culture, material obtained by open biopsy should have anaerobic culture as well as staining and culture for acid-fast bacilli and fungus. Even when following this aggressive approach, at least 30% of cases remain undiagnosed, making a prolonged course of empirical therapy unavoidable. 3.7

Microbiological Characteristics

Table 5 lists the microbes likely to be recovered from the majority of immunocompetent adults. A few points deserve emphasis. First, even though Staphylococcus aureus remains the most common organism, it is being recovered in proportionally fewer cases, underscoring the need for biopsy. Second, even though methicillin-resistant S. aureus (MRSA) is being reported more frequently than in the past, community-aquired disease is very rare. Third, although S. epidermidis can certainly be a real pathogen, it may also contaminate blood cultures and biopsy samples. Fourth, Pseudomonas aeruginosa is a very common pathogen among intravenous drug users but is rarely encountered in other patients. Finally, although polymicrobial infections are being reported more frequently (probably because more patients are undergoing biopsy), if blood culture results are positive, tissue biopsy is still unnecessary.

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Figure 4 Approach to the patient with possible vertebral osteomyelitis. The approach to the patient with back pain, suspected of having osteomyelitis, should proceed in a stepwise fashion, assessing the risk factors for infection, laboratory tests, and radiological testing. Focal neurological findings should raise the concern of spinal cord compression; this is a surgical emergency requiring orthopedic and/or neurosurgical consultation. Empirical antibiotics should be avoided before microbiological diagnosis is established.

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Table 5 Microbiological Characteristics Gram stain result Gram-positive: 71%

Gram-negative: 23%

Other: 6%

Mixed

3.8

Pathogen

Percent

S. aureus Methicillin-sensitive (MSSA) Methicillin-resistant (MRSA) S. epidermidis Streptococci (except group D) Group D Streptococcus spp. Enterococcus spp. Diphtheroids (Corynebacterium spp.) Pseudomonas spp. Escherichia coli Other gram-negative rods Anaerobes M. tuberculosis Brucella spp. Candida spp. Polymicrobial

45 (88) (12) 13 11 2 <1 11 4 8 2 <1 <1 <1 0–24

Treatment

Even though most patients are managed medically, an orthopedist or neurosurgeon should be involved in the care of these patients from the outset. Complications such as paravertebral abscesses, cord compression, or vertebral column instability all require surgery. The question of whether or not the vertebral column is stable is best left to the consulting surgeon. With early diagnosis most patients are successfully managed medically. Tables 6 and 7 provide general guidelines for choosing empirical and definitive therapy, respectively. Most patients should receive intravenous antibiotics for 6 to 8 weeks. Resolution of fever, improved appetite, diminished pain, and return of neurological function all suggest a favorable response. In addition, the ESR, which typically falls by one-half to two-thirds the pretreatment value by 4 to 6 weeks of therapy, is a reasonably useful laboratory adjunct. Unfortunately, many patients have comorbidities that may confound interpretaion of the ESR, underscoring the need to interpret persistently elevated results in the context of the overall clinical picture. Treatment failure is suggested by progression or persistence of symptoms (e.g., worsening pain, failure to defervesce, continued anorexia), the appearance of new symptoms such as neurological deficit, and/or a persistently elevated ESR. Depending on the particular constellation of signs and symptoms, the differential diagnosis of persistent pain or fever might include the following: (1) an undrained paravertebral abscess, (2) drug fever, (3) an unrelated new infectious focus, or (4) unrecognized spinal column instability. If a microbiological diagnosis was not made and empirical antibiotics were used, antibiotic failure should be considered. In a minority of patients persistent pain may be the result of altered spinal mechanics in the absence of uncontrolled infection or vertebral column instability. Practically speaking, when treatment failure is a concern, the spine should be reimaged.

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Table 6 Empirical Therapy for Hematogenous Osteomyelitisa,b Clinical presentation Stable patient, no history to suggest IDU Stable patient, known or suspected IDU Stable patient with sickle cell disease Hemodynamically unstable

Preferred therapy

Delayed PCN allergyc

Severe PCN allergyd

Cefazolin 2 g q8h

Cefazolin 2 g q8h

Clindamycin 600 mg q8h

Nafcillin 2 g q4h plus ciprofloxacine 400 mg q8h Ceftriaxone 2 g q24h

Cefazolin 2 g q8h plus ciprofloxacine 400 mg q8h Ceftriaxone 2 g q24h

Ceftazidime 2 g q8h plus gentamicin or tobramycinf plus vancomycing

Ceftazidime 2 g q8h plus gentamicin or tobramycinf plus vancomycing

Clindamycin 600 mg q8h plus ciprofloxacine 400 mg q8h Clindamycin 600 mg q8h plus ciprofloxacine 400 mg q8h Aztreonam 2 g q6h plus gentamicin or tobramycinf plus vancomycing

a

Dosage given assumes normal renal and hepatic function; PCN, penicillin; IDU, injection drug use. All drugs are given intravenously for 6–8 weeks. c Delayed penicillin allergy signifies morbilliform rashes. d Severe penicillin-allergic reactions include urticarial rashes (hives), angioedema, and anaphylaxis. e Patients must be at least 17 years of age. f See Chapter 4, Tables 3 and 4, for dosage and monitoring. g See Chapter 4, Table 5, for dosage and monitoring. b

3.9

Prognosis

Most patients experience a meaningful but incomplete recovery. The overall mortality rate is approximately 5%, and about 10% of survivors experience some degree of permanent neurological impairment. Over 80% of patients are cured of the infection, but as many as one-half to two-thirds experience at least mild to moderate chronic back pain. Approximately 15% experience relapse; those who do often have complex long-term management problems and ideally should be managed by a team approach involving the primary care physician, the orthopedist, and the infectious disease specialist. 3.10

Spinal Tuberculosis

Although accounting for less than 1% of all cases of vertebral osteomyelitis, spinal tuberculosis (Pott’s disease) is the form of tuberculous bone disease most likely to be encountered in adults. In the absence of active pulmonary disease no combination of presenting signs or symptoms reliably distinguishes Mycobacterium tuberculosis from pyogenic spinal infection. Compared with pyogenic spondylitis, disk destruction in spinal tuberculosis usually occurs much later, and bone sclerosis may not develop at all. For these reasons, plain film results can remain nondiagnostic for many weeks (even months). Nuclear scans cannot be used to make or exclude the diagnosis. The sensitivity of technetium bone scanning is ⬃70%. Gallium scanning is even less sensitive. In contrast, MRI is very sensitive and is now the imaging technique of choice. Spinal tuberculosis should be considered whenever patients have symptoms suggestive of vertebral osteomyelitis. Suspicion should be particularly high when patients (1) are

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Table 7 Definitive Therapy for Hematogenous Osteomyelitisa,b Primary

Delayed PCN allergyc

Methicillin-sensitive S. aureus (MSSA)

Nafcillin 2 g q4h

Cefazolin 2 g q8h

Clindamycin 600 mg q8h (preferred) or vancomycin 15 mg/kg q12h plus rifampin 600 mg PO or IV q24h

Methicillin-resistant S. aureus (MRSA)

Vancomycin 15 mg/kg q12h plus rifampin 600 mg PO or IV q24h Nafcillin 2 g q4h

Cefazolin 2 g q8h

Clindamycin 600 mg q8h (preferred) or vancomycin 15 mg/kg q12h plus rifampin 600 mg PO or IV q24h

Ceftriaxone 2 g q24h

Clindamycin 600 mg q8h (preferred) or vancomycin 15 mg/kg q12h Vancomycin 15 mg/kg q12h plus rifampin 600 mg PO or IV q24h Vancomycin 15 mg/kg q12h plus gentamicin 1 mg/kg q8hh Aztreonam 2 g q6h or ciprofloxacin 400 mg q8hi

Pathogen

Methicillin-sensitive S. epidermidis

Methicillin-resistant S. epidermidis

Steptococcus spp. (groups A, B, C, D, and S. viridans) Streptococcus pnemoniaef Enterococcus spp.

E. coli, Proteus, Klebsiella, Salmonella spp. Pseudomonas spp.

a

Vancomycin 15 mg/kg q12h plus rifampin 600 mg PO or IV q24h PCN G 4 million U q4h or ceftriaxone 2 g q24he PCN G 4 million U q4h or ceftriaxone 2 g q24he Ampicillin 2 g q6h plus gentamicin 1 mg/kg q8hh Ceftriaxone 2 g q24h

Ceftazidime 2 g q8h plus gentamicin or tobramycin 5 mg/kg q24hj,k or ciprofloxacin 400 mg q8hi

Ceftriaxone 2 g q24h

Vancomycin 15 mg/kg q12hg plus gentamicin 1 mg/kg q8hh Ceftriaxone 2 g q24h

Ceftazidime 2 g q8h plus gentamicin or tobramycin 5 mg/ kg q24hj,k or ciprofloxacin 400 mg q8hi

Severe PCN allergyd

Aztreonam 2 g q6h plus gentamicin or tobramycin 5 mg/kg q24hj,k or ciprofloxacin 400 mg q8hi

Dosages given assume normal renal and hepatic function; PCN, penicillin. Except where noted, all drugs are given intravenously for 6–8 weeks. Susceptibility testing should be performed on all isolates. c Delayed penicillin allergy signifies morbilliform rashes. d Severe penicillin-allergic reactions include urticarial rashes (hives), angioedema, or a prior history of anaphylaxis. e As a result of the advantages of once-daily dosing, ceftriaxone may be preferred to penicillin in this setting. f Intermediate (minimal inhibitory concentration [MIC] 0.1–2) or high- (MIC > 2.0) level resistance precludes penicillin use. Intermediate strains may be treated with ceftriaxone. High-level resistance requires vancomycin plus rifampin. Infectious disease consultation is advised. g Many of these patients can and should be treated with ampicillin, the most active drug against enterococcus. Infectious disease consultation is advised. h Aminoglycosides are used for synergy against enterococcus. Lower peak levels (⬃4 ␮g/mL) may be targeted. Infectious disease consultation is suggested. i There is limited clinical experience with ciprofloxacin in this setting. Patients must also be at least 17 years of age. j Infectious disease consultation is advised. Aminoglycoside levels and renal function must be monitored. k See Chapter 4, Tables 3 and 4, for dosage. b

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known to have active or latent tuberculosis (TB) (even though a positive purified protein derivative [PPD] test result is noted in up to 85% of all cases, a negative PPD result does not exclude the diagnosis); (2) have histological evidence of granuloma formation on biopsy (fungal and Brucella spp. infections and sarcoidosis can also cause granuloma formation); (3) are not responding to a course of empirical antibiotic therapy for presumed pyogenic spondylitis; and (4) are at high risk for harboring latent tuberculosis, including those sharing a living arrangement with someone known to have active TB, those who are immigrants from a country where TB is a common disease, anyone with human immunodeficiency virus (HIV) infection, or those who are homeless or incarcerated. Definitive diagnosis requires isolation of M. tuberculosis on biopsy. Unfortunately, this standard is achieved less than 40% of the time. The majority of patients ultimately must be treated on the basis of a presumptive diagnosis after all the evidence has been carefully weighed. An infectious disease specialist should assist in the evaluation and management of these patients.

4 4.1

SPECIAL HOSTS Injection Drug Use

Osteomyelitis related to injection drug use (IDU) usually results in hematogenous seeding of the spine. Rarely, other locations may be seeded, including the pubic symphysis, sacroiliac, or sternoclavicular joints (also see Chapter 35). Most patients are young, 90% of them between the ages of 20 and 49. When the spine is involved, the clinical presentation is no different from that of any other patient with vertebral osteomyelitis except that cervical spine involvement occurs more often (25% as opposed to 5% overall). Osteomyelitis of the sacroiliac and pubic bones is rare. Patients may experience increasing hip, groin, or thigh pain exacerbated by walking or lying on one side. Those with sacroiliac osteomyelitis usually describe increasing pain in the buttocks, lower back, or hip. The pubic symphysis is usually markedly tender to direct palpation when involved. The microbiological characteristics of bone infections associated with IDU differ substantially from those typically reported for hematogenous osteomyelitis. In most series, P. aeruginosa has been recovered more than 60% of the time (regardless of the bone involved); other gram-negative rods or S. aureus accounts for most of the remaining cases.

OSTEOMYELITIS IN SPECIAL HOSTS Injection drug users Hematogenous seeding of spine more often than pubic symphysis, sacroiliac, or sternoclavicular joints P. aeruginosa most common Antibiotic for 6–8 weeks (see Tables 6, 7) Sickle cell disease Hematogenous seeding of infarcted bone May be multicentered Difficult to differentiate bone infectin from aseptic bone infarction S. aureus or Salmonella spp. Antibiotic for 6–8 weeks (see Tables 6, 7)

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Medical treatment alone is usually successful. Antibiotics should usually be administered for 6 to 8 weeks as outlined in Tables 6 and 7. Whenever sequestra or abscesses develop, de´bridement and drainage are required. 4.2

Sickle Cell Disease

The pathophysiological characteristics of osteomyelitis in patients with sickle cell disease are unique and warrant description. Red cell sickling occurs in the microcirculation of many tissues, including during a painful crisis, inducing ischemia and infarction. Most patients with either classic sickle cell disease (homozygous S/S) or combined forms of hemoglobinopathy (S/C disease, sickle cell/thalessemia, etc.) suffer from recurrent bone infarctions throughout their lives. Individual episodes tend to be multifocal and symmetrical and commonly affect the proximal or distal humerus, femur, or tibia. Less frequently, the small bones of the hands or feet (dactylitis) or the vertebral column are involved. When transient bacteremia complicates a sickling crisis (as a result of either a separate infectious focus or simultaneous intestinal ischemia), osteomyelitis may evolve at one or more sites of bone infarction. Distinguishing an aseptic bland bone infarct from a seeded infected infarct is often difficult or impossible on initial presentation. With either form of insult, the patient usually experiences intense extremity pain (often at multiple sites), coupled with diffuse myalgias. Localized bone tenderness, soft tissue swelling, and erythema are common physical findings of both infected and aseptic infarction. Although serial radiographs are a useful means of eventually distinguishing many episodes of acute infarction from infection, these studies are seldom helpful initially. Early on, plain films may be entirely normal. Even after 2 weeks, both bland bone infarction and osteomyelitis can induce radiographically indistinguishable changes. Neither nuclear scans nor CT and MRI scans can reliably distinguish aseptic bone infarction from osteomyelitis. More recently, ultrasound has been shown to offer distinct advantages over other imaging modalities (William, 2000). Clinically suspicious sites should be sonogrammed looking for fluid collections contiguous with bone that can be aspirated at the time of the sonogram. Although not providing a definitive diagnosis, larger fluid collections (especially if greater than 4 mm in depth) are significantly more likely to be associated with an adjacent focus of osteomyelitis. Any aspirated material should have both aerobic culture and Gram staining. Two sets of blood cultures should always be obtained, especially if empirical antibiotic therapy is being considered. Given that most patients are also functionally asplenic, antibiotics are usually indicated once appropriate clinical specimens have been collected. Because either Salmonella species or S. aureus is responsible for more than 90% of all bone infections in these patients, initial therapy should be directed at these organisms (see Table 6). If a specific pathogen is eventually recovered, definitive therapy should be directed at the isolate, guided by the results of susceptibility testing (see Table 7).

5

OSTEOMYELITIS RELATED TO SINUSITIS, OTITIS, OR ODONTOGENIC INFECTIONS

Malignant otitis externa, the most important infection in this group of infections, is reviewed in the following. Table 8 provides a brief summary of other, more rare forms of osteomyelitis in this category.

Early: persistent frontal or retro-orbital headache with or without fever Late: signs or symptoms suggesting intracranial or orbital extension (see comments) Rare: forehead swelling (Pott’s puffy tumord)

Pain, swelling, or erythema over mastoid process Displaced pinna (down and out) Low-grade fever Chronic discharge from canal Middle-aged to elderly diabetic patient Severe otalgia and canal discharge Pain that often awakens patient at night

Localized mandibular pain and swelling Trismus Risks: poor access to medical care, age above 40, prior head and neck cancer, prior radiation therapy, and heavy alcohol and tobacco use

Sinusitis

Otitis media

Odontogenic

WBC variable ESR not well studied

ESR elevated in over 95% of cases WBC variable

CBC, ESR variable

CBC ESR often normal Two blood cultures

Laboratory studies

Bone scan MRI

Technetium bone scan; if positive result, CT scan to exclude intracranial or orbital extension Bone scan for diagnosis CT scanning to determine extent of disease

CT scan including sinuses and brain

Imaging studiesb

S. pneumoniae, H. influenzae, or S. aureus; some mixed

P. aeruginosa (responsible for over 90% of all infections)

Mixed, including streptococci, oral anaerobes, and often Eikenella corrodens

Tissue biopsyc usually required to exclude malignancy

Bone biopsyc often necessary to exclude malignancy

Frequently mixed including S. aureus, anaerobes and Haemophilus influenzae

Microbiological features

Usually clinical, based on characteristic exam and radiographic findings

Tissue biopsy often necessary to exclude malignancy

c

Definitive diagnosis

b

CBC, complete blood count; ESR, erythrocyte sedimentation rate; CT, computed tomography; MRI, magnetic resonance imaging; WBC, white blood cell. The studies listed assume plain film results are either negative or nondiagnostic. As always, plain radiographs should be ordered first. c Send material for histological testing, aerobic and anaerobic culture, and Gram stain. d Extension of infection through frontal sinus to soft tissue above the orbit, causing a mass effect.

a

Malignant otitis externa

Suspicious clinical findings

Focus of infection

Table 8 Clinical Features of Osteomyelitis Due to Sinusitis, Otitis, and Odontogenic Infectionsa

Surgeryc Plus antibiotics (see Table 9)

Frequent local de´bridementc plus antibiotics (see Table 9)

Antibiotics (see Table 9) De´bridementc sometimes necessary

Surgical de´bridementd Antibiotics (see Table 9)

Treatment

Bone scan not always necessary; referral to otolaryngologist (who usually confirms diagnosis clinically, orders staging CT scan, and performs biopsy) warranted by clinical suspicion Referral to oral surgeon to obtain necessary imaging studies warranted by clinical suspicion; despite extensive surgical de´bridement, infections often refractory to therapy; infectious disease consultation advised

Intracranial extension potential cause of meningitis, empyema, or brain abscess; exophthalmos, ptosis, and visual disturbances caused by orbital extension; osteomyelitis often overshadowed by complications; surgical and infectious disease consultation advised Most patients in early 20s; disease rare with antibiotics; surgical and infectious disease consultation advised

Comments

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CONTIGUOUS FOCUS OSTEOMYELITIS Osteomyeltitis involving the ear, mouth, or sinus (see Table 8) Therapy (see Table 9) Malignant otitis media Destruction of the floor of the external canal Diabetes and age >60 years Ear pain, discharge P. aeruginosa most common Therapy (see Table 9) Osteomyelitis involving trauma from bites, punctures, and pressure sores (see Table 10) Puncture wounds Nail punctures to feet most common Increased risk in those with diabetes Increasing pain when walking Fever, leukocytosis uncommon If plain radiographic finding negative MRI warranted P. aeruginosa most common Therapy (see Table 11) Ostemyelitis related to surgery (see Table 12) Prosthetic joint–related osteomyelitis Bacterial contamination at the time of prosthesis implantation and less often hematogenously Increased risk in those with diabetes, rheumatoid arthritis, malignancy, steroid use, malnutrition, and distant site of infection at the time of surgery Presentation geneally indolent with pain Difficult to differentiate from joint loosening Draining sinus tract highly suggestive of prosthesis infection Most commonly due to staphylococci Orthopedic and infectious disease consultation suggested

5.1

Malignant Otitis Externa (Mastoiditis)

Malignant otitis externa is a locally destructive infection originating in the floor of the external auditory canal. Almost all patients have long-standing type II diabetes mellitus. Most are above the age of 60. Severe microvascular angiopathy is probably the final common insult, leading to chronic ischemia of the ear canal with secondary bacterial invasion of the underlying cartilage and bone. Minor trauma presumably initiates infection. P. aeruginosa is the infecting organism more than 90% of the time. Ear pain is nearly always the presenting complaint. It is variously described as sharp, stabbing, boring, drilling, or shooting and may awaken the patient at night. Its intensity is probably its most distinctive feature. Severe temporal or occipital headache is common. Otorrhea is a nearly universal finding on examination. The discharge may be purulent or thin and sometimes has a greenish hue. The external canal is usually filled with debris and exuberant granulation tissue and may have a palpable defect. Tenderness may be pronounced over the temporomandibular joint region. Ipsilateral facial nerve palsy occurs in 20% of cases. Periauricular swelling and erythema are late findings. Systemic symptoms (fever, chills, anorexia, night sweats) are unusual.

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Plain films are insensitive but may show nonspecific clouding of the mastoid air cells. Temporal bone erosion is a late finding. Both technetium and gallium scans are more than 90% sensitive; either may be used as the initial study. Although CT scanning provides highly detailed images of cortical bone along with excellent soft tissue detail, its reported sensitivity is only 30%–80%. MRI demonstrates cortical bone detail inferior to that of CT scanning. Except those with far-advanced disease most patients are now successfully managed with a combination of frequent local de´bridement and antibiotics. Antibiotic therapy should be given for a minimum of 6 to 8 weeks as outlined in Table 9. Otolaryngology and infectious disease consultations are advised.

6

OSTEOMYELITIS RELATED TO TRAUMA

Osteomyelitis that occurs after puncture wounds is reviewed in the following. Table 10 provides a brief summary of osteomyelitis related to human and animal bites and decubitus ulcers. 6.1

Osteomyelitis Due to Puncture Wounds

Over 90% of puncture wounds are due to stepping on nails. Splinters, glass, and plastic are each responsible for a small percentage of cases. The depth of penetration, presence of a foreign body, and wound location (punctures involving the forefoot) are probably the most important factors leading to the evolution of septic arthritis or osteomyelitis. Patients with diabetes mellitus have a threefold increased risk of osteomyelitis. Aside from administering tetanus prophylaxis (see Chapter 43), initial wound management, including bedside

Table 9 Empirical Therapy for Osteomyelitis Due to Sinusitis, Otitis Media, and Odontogenic Infectionsa,b,c Infectious focus Sinusitis

Otitis media

Malignant otitis externa Mandible (odontogenic) a

Preferred therapy

Delayed PCN allergyd

Severe PCN allergye

Ceftriaxone 2 g q24h plus clindamycin 600 mg q8h Ceftriaxone 2 g q24h plus clindamycin 600 mg q8h Ciprofloxacin 750 mg PO q12hf,g or ceftazidime 2 g q8h Ampicillin 2 g q6h plus clindamycin 600 mg q8h

Ceftriaxone 2 g q24h plus clindamycin 600 mg q8h Ceftriaxone 2 g q24h plus clindamycin 600 mg q8h Ciprofloxacin 750 mg PO q12hf,g or ceftazidime 2 g q8h Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

Ciprofloxacin 400 mg q8hc plus clindamycin 600 mg q8h Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h Ciprofloxacin 750 mg PO q12hf,g or aztreonam 2 g q6h Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

Dosages given assume normal renal and hepatic function. Culture results and susceptibility testing should guide definitive therapy. c Unless otherwise noted, all drugs are given intravenously for 6–8 weeks. d Delayed penicillin allergy signifies morbilliform rashes. e Severe penicillin-allergic reactions include urticarial rashes (hives), angioedema, and anaphylaxis. f Patients must be at least 17 years of age. g Oral absorption may be poor for a variety of reasons. Infectious disease consultation is advised. b

Evidence of soft tissue infection after animal bite to hand or digits

Soft tissue infection or persistent pain on weight bearing; puncture tract drainage

Deep or draining pressure ulcer

Animal bites (see Chapter 37)

Puncture wounds

Pressure ulcers

ESR often elevated, but not specific for osteomyelitis in this setting

CBC and ESR findings often normal

CBC and ESR findings often normal

CBC and ESR findings often normal

Laboratory study results

Plain radiograph for evidence of foreign bodyc; bone scan or MRI if plain film finding normal Seldom helpful

Plain films examined for bone fragments and fracturesc

Plain radiograph for bone or tooth fragments, ‘‘boxer’s fracture’’ of fifth metacarpalc

Imaging studies

Surgical de´bridementd plus antibiotics (see Table 11)

P. aeruginosa cause of 90% of infections; in diabetics mixed infections common

Mixed P. aeruginosa Enteric gram-negative rods S. aureus Anaerobes

Surgical explorationd often necessary

Bone biopsyd

Surgeryd plus antibiotics (see Table 11)

Surgical de´bridementd plus antibiotics (see Table 11)

Mixed S. aureus Anaerobes Pasteurella multocida

Surgical explorationd

Surgical de´bridementd plus antibiotics (see Table 11)

Treatment

Mixed S. aureus Anaerobes Eikenella corrodens

Microbiological featuresb

Surgical explorationd

Definitive diagnosis

Human bites often occult and unintentional (inflicted when patient’s clenched fist strikes tooth of opponent) but can cause serious infections; tetanus status review necessary More than 90% of animal bites by cats and dogs; review of tetanus status and assessment of need for rabies prophylaxis required More than 90% of puncture wounds due to stepping on nails; review of tetanus status required; optimal treatment of diabetics unclear Plain radiograph, nuclear study, and CT scan results almost always abnormal regardless of presence of osteomyelitis; biopsy necessary; surgery principal form of treatment

Comments

b

CBC, complete blood count; ESR, erythrocyte sedimentation rate; CT, computed tomography; MRI, magnetic resonance imaging. Blood cultures (two sets) should always be drawn. c Findings listed are specific to the type of injury. Plain radiographs should be examined for evidence of bony erosions, sclerosis, soft tissue swelling, and joint space widening. d Send material for aerobic and anaerobic culture and Gram stain.

a

Human bite Laceration over knuckles after altercation

Suspicious clinical findings

Human bites

Form of trauma

Table 10 Clinical Features of Osteomyelitis Due to Bites, Puncture Wounds, and Pressure Ulcersa

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de´bridement, irrigation, probing, or prophylactic antibiotics, has not been shown to influence the risk of infectious complications including osteomyelitis. Usually a few days to 2 weeks after the injury the patient reports persistent or increasing pain exacerbated by weight bearing. Fever or other systemic symptoms are usually absent. Examination often shows soft tissue swelling, mild erythema, and pain on deep palpation. In diabetic patients persistent or increasing drainage from the puncture tract may be the only symptom. The white blood cell count (WBC) and ESR may be elevated or normal. Plain films should always be done and may show evidence of a foreign body, bone erosion, or joint swelling. If plain film results are normal, a bone or MRI scan may be indicated. Definitive diagnosis and treatment require operative exploration for removal of foreign bodies, drainage of infected joints or abscesses, and de´bridement of devitalized bone and cartilage. In normal hosts, more than 90% of infections are due solely to P. aeruginosa. Provided the de´bridement was adequate, these patients are usually treated successfully with a 3- to 4-week course of oral ciprofloxacin as outlined in Table 11. In contrast,

Table 11 Empirical Therapy: Osteomyelitis Due to Bites, Puncture Wounds, and Pressure Ulcersa,b,c Form of trauma Human bites

Animal bites

Puncture wound in normal host Puncture wound in diabetic patienth Pressure ulcersh

a

Preferred therapy

Delayed PCN allergyd

Severe PCN allergye

Aqueous PCN G 4 million U q4h or ampicillin 2 g q6h plus clindamycin 600 mg q8h Aqueous PCN G 4 million U q4h or ampicillin 2 g q6h plus clindamycin 600 mg q8h Ciprofloxacin 750 mg PO q12h for 3–4 wkf,g,i Pipericillin-tazobactam 4.5 g q6h

Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

Ceftriaxone 2 g q24h plus clindamycin 600 mg q8h

Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

Ciprofloxacin 750 mg PO q12h for 3–4 wkf,g,i Ceftazidime 2 g q8h plus clindamycin 600 mg q8h Ceftazidime 2 g q8h plus clindamycin 600 mg q8h

Ciprofloxacin 750 mg PO q12h for 3–4 wkf,g,i Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

Pipericillin-tazobactam 4.5 g q6h

Dosages given assume normal renal and hepatic function; PCN, penicillin. Culture results and susceptibility testing should guide definitive therapy. c Unless otherwise noted, all drugs are given intravenously for 4–6 weeks. d Delayed penicillin allergy signifies morbilliform rashes. e Severe penicillin-allergic reactions include urticarial rashes (hives), angioedema, and a prior history of anaphylaxis. f Patients must be at least 17 years of age. g Oral absorption may be poor for a variety of reasons. Infectious disease consultation is advised. h The optimal form of treatment is unclear. Infectious disease consultation is advised. i Regimen(s) assumes extensive surgical de´bridement has been performed. Infectious disease consultation is advised. b

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diabetic patients often have polymicrobial infections including P. aeruginosa, S. aureus, and anaerobic infections. In addition, they are at least 40 times more likely to need an amputation to control their infections (see Chapter 29). 7

OSTEOMYELITIS RELATED TO PROSTHETIC JOINT INFECTION

Prosthetic device infections that follow orthopedic surgery are reviewed in the following. Table 12 provides a brief summary of osteomyelitis related to other forms of surgery and Table 13 summarizes therapy for sternal and pelvic osteomyelitis. Osteomyelitis related to prosthetic joint infections is difficult to diagnose and manage. Many important clinical issues remain unresolved and are beyond the scope of this chapter. For the most part, the responsibility for specific management decisions rests most appropriately with the orthopedist and infectious disease specialist, both working in close concert with one another, the patient, and the primary care physician. Most prosthetic infections result from implant contamination at the time of insertion. Any orthopedic procedure that requires hardware insertion carries this risk. Fortunately, only about 1% to 2% of all joint arthroplasties are complicated by infection. Prior joint replacement, active infection elsewhere at the time of surgery, and severe rheumatoid arthritis are all firmly established risk factors for implant infection. Malignancy, diabetes, chronic steroid use, and malnutrition probably also increase the risk. More recently, postoperative bacteremia, local wound infection, and delayed wound healing have emerged as major risk factors for subsequent prosthesis infection. Patients seek medical care a few days to more than a decade after implant insertion, the majority within 6 months. Within the first few weeks of surgery patients occasionally have acute illness with pain, swelling, erythema and increased warmth over the implant site. Fever, chills, and malaise are common systemic symptoms. Wound dehiscence is sometimes apparent on exam. In the majority of cases, the presentation is deceptively indolent and subtle. Pain is the only consistent finding amd is reported more than 90% of the time. Many report that pain never totally subsided after surgery and is now getting worse. The pain is often constant and aching. Fever, chills, anorexia, or other systemic symptoms are infrequent. A history of superficial wound infection or poor wound healing after the original surgical procedure is occasionally reported. The examination findings are often nondiagnostic. Slight increased warmth over the prosthesis can sometimes be appreciated. Swelling and erythema are helpful indications when present but are often lacking. Rarely, a draining sinus tract may form on the surface of the skin overlying the implant site. When present, these fistulous tracts are nearly always diagnostic of an infected prosthesis. Laboratory and radiographic studies are of only modest value. The ESR is elevated in roughly 75% of cases but is not specific for infection in this setting. Usually the WBC is normal unless the presentation is acute and infection is already obvious. Plain films are neither sensitive nor specific. They may show lucent regions around the prosthesis, periosteal elevation, and cortical bone erosions, but identical findings can result from loosening of a sterile prosthesis. Similarly, although the sensitivity of technetium bone scanning is reportedly between 80% and 100%, a positive scan finding is very nonspecific. The indium white cell scan performs best overall, with a reported sensitivity and specificity of around 80%. Combining a technetium bone scan with an indium white cell study at best marginally improves the accuracy over that of an indium study alone. With the exception of a draining sinus tract, no combination of clinical signs, laboratory tests, or radiographic studies can reliably diagnose or exclude an infected pros-

d

Sternal wound dehiscence, superficial wound infection, persistent incisional pain, unexplained fever, within first 6 wk after surgery Severe groin or hip pain within 6 months after pelvic surgery; pubic symphysis usually very tender to palpation Persistent or progressive pain associated with a prosthetic implanth

Pain, swelling, erythema, or drainage overlying craniotomy site; may extend over forehead and/or involve orbit

Suspicious clinical findings Bone scan combined with tagged white cell study, CT scanning

Seldom helpful

Bone scan, CT scanning to detect sequestra Indium white cell scan; other studies seldom useful

CBC, ESR variable

CBC, ESR variable

CBC, ESR variable

Imaging studiesc

CBC, ESR variable

Laboratory studyb results e

S. aureus, S. epidermidis, or enteric gramnegative rods; some infections polymicrobial

P. aeruginosa, S. aureus; sometimes polymicrobial, including anaerobes Virtually any organism potentially involved, including saprophytic mycobacteria and fungi

Bone biopsye

Bone biopsye

Virtually any organism including saprophytic mycobacteria and fungi potentially involved

Microbiological features

Mediastinal aspiratione and/or operative exploratione

Bone biopsy

Definitive diagnosis

Prosthesis removale plus antibiotics

Antibiotics (see Table 13); de´bridemente sometimes necessary

Extensive surgical de´bridemente plus antibiotics (see Table 13)

Surgical de´bridemente plus antibiotics

Treatment

Referral to orthopedist and infectious disease specialist warranted by clinical suspicion; potential symptoms years after surgery

Treatment warranted by positive bone scan result even if culture findings negative

Meningitis, empyema, or brain abscess caused by intracranial extension; exophthalmos, ptosis, and visual disturbances caused by orbital extension; potential symptom development years after surgery Diagnosis not reliably confirmed or excluded by any imaging study; mortality approaching 50%

Comments

b

CBC, complete blood count; ESR, erythrocye sedimentation rate; CT, computed tomography. Two sets of blood cultures should always be drawn. If findings are positive, they usually obviate the need for an invasive biopsy. c All patients should have plain films. The consulting surgeon should order any additional imaging studies. d Includes any procedure requiring a craniotomy. e Send material for histological evaluation, aerobic and anaerobic culture, and Gram stain. If a craniotomy or an implant is involved, also send material for acid-fast bacillus (AFB) and fungal cultures and smears. f Includes any procedure involving a median sternotomy, including coronary artery bypass grafting (CABG). g Procedures include uterine or bladder neck suspension, forceps vaginal delivery, suprapubic or transurethral prostatectomy, inguinal hernia repair, and cardiac catheterization. h Nearly all open orthopedic procedures require the insertion of prosthetic implants.

a

Orthopedic procedures

Pelvic surgeryg

Cardiac surgeryf

Neurosurgery

Type of surgery

Table 12 Clinical Features of Osteomyelitis Related to Surgical Proceduresa

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Table 13 Empirical Therapy for Osteomyelitis Related to Cardiac or Pelvic Surgerya,b,c Infectious focus Sternal osteomyelitis in patient in stable condition Sternal osteomyelitis hemodynamically unstable

Pubic osteomyelitish

Severe PCN allergye

Preferred therapy

Delayed PCN allergyd

Ceftriaxone 2 g q24h plus vancomycin 15 mg/kg q12h Ceftazidime 2 g q8h plus gentamicin or tobramycin 5 mg/ kg q24hg plus vancomycin 15 mg/kg q12h Ceftazidime 2 g q8h plus clindamycin 600 mg q8h

Ceftriaxone 2 g q24h plus vancomycin 15 mg/kg q12h Ceftazidime 2 g q8h plus gentamicin or tobramycin 5 mg/ kg q24hg plus vancomycin 15 mg/kg q12h Ceftazidime 2 g q8h plus clindamycin 600 mg q8h

Ciprofloxacin 400 mg q8hf plus vancomycin 15 mg/kg q12h Aztreonam 2 g q6h plus gentamicin or tobramycin 5 mg/kg q24hg plus vancomycin 15 mg/kg q12h Ciprofloxacin 400 mg q8hf plus clindamycin 600 mg q8h

a

Dosages given assume normal renal and hepatic function; PNC, penicillin. Culture results and susceptibility testing should guide definitive therapy. c Unless otherwise noted, all drugs are given intravenously for 6–8 weeks. d Delayed penicillin allergy signifies morbilliform rashes. e Severe penicillin-allergic reactions include urticarial rashes (hives), angioedema, or a prior history of anaphylaxis. f Patients must be at least 17 years of age. g Infectious disease consultation is advised. Aminoglycoside levels and renal function must be monitored. h Types of procedures include uterine or bladder suspension, forceps delivery, suprapubic prostatectomy, and inguinal hernia repair. b

thesis. An uninfected implant that is merely loose can present identical clinical, laboratory, and radiographic findings. To complicate matters further, infection can also cause prosthetic loosening. Needle aspiration of the joint with Gram stain and culture of the aspirated fluid can sometimes provide useful information. Although a positive aspirate result may be helpful (or misleading), a negative study finding does not exclude infection. More often than not, preoperative diagnosis proves impossible and the distinction is made with certainty only in the operating room. The diagnosis of an infected orthopedic implant should be considered whenever the patient has persistent or progressive pain associated with the device. Whenever this criterion has been met, the patient should be referred to an orthopedist for formal evaluation. It is important to resist the temptation to begin empirical treatment with antibiotics. Antibiotics alone do not cure these infections but greatly diminish the chance of obtaining a positive joint or bone aspirate culture result. Treatment usually involves removal of all foreign material, followed by a prolonged course of antibiotics. BIBLIOGRAPHY Armstrong DG, Lavery LA, Quebedeaux TL, Walker SC. Surgical morbidity and the risk of amputation due to infected puncture wounds in diabetic versus nondiabetic adults. South Med J 90:384–389, 1997. Chelsom J, Solberg CO. Vertebral osteomyelitis at a Norwegian university hospital 1987–1997: Clinical features, laboratory findings, and outcome. Scand J Infect Dis 30:147–151, 1998.

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Cuckler JM, Star AM, Alavi A, Noto RB. Diagnosis and management of the infected total hip arthroplasty. Orthop Clin North Am 22:523–530, 1991. Haas DW, McAndrew MP. Bacterial osteomyelitis in adults: Evolving considerations in diagnosis and treatment. Am J Med 101:550–561, 1996. Schauwecker DS. The scintigraphic diagnosis of osteomyelitis. AJR Am J Roentgenol 158:9–18, 1992. William RR, Hussein SS, Jeans WD, Wali YA, Lamki ZA. A prospective study of soft-tissue ultrasonography in sickle cell disease patients with suspected osteomyelitis. Clin Radiol 55:307– 310, 2000. Wymenga AB, Van Dijke BJ, Van Horn JR, Slooff TJ. Prosthesis-related infection. Etiology, prophylaxis and diagnosis (a review). Acta Orthop Belg 56:463–475, 1990.

29 Diabetic Foot Infections Christopher J. Grace and Michael A. Ricci University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

A significant cause of morbidity in diabetes mellitus (DM) patients are foot ulcers and infections. Up to 25% of diabetic patients have a foot ulcer during their lifetime. Osteomyelitis eventually complicates two-thirds of these ulcers. Soft tissue foot infections and osteomyelitis are the most common causes of hospitalization for patients with DM, costing more than $200 million yearly. Foot ulcerations precede leg amputation in over 85% of patients with DM. Although the majority of foot ulcerations heal, 25%–50% may lead to foot sparing amputations and 10%–40% require major amputations. Unrecognized infection is a major reason that chronic ulcers do not heal. With appropriate care, 80%–90% of mild to moderate foot infections heal, and up to 50%–60% of patients with deeper, more severe infections recover without major amputation. The toll of diabetic foot problems in terms of medical costs, patients’ quality of life, and even mortality rate is staggering. The primary care provider plays a vital role in prevention, recognition, and management of these problems. 2

PATHOPHYSIOLOGICAL CHARACTERISTICS

The pathophysiological characteristics of diabetic foot ulcers and infections involve peripheral neuropathy (PN), vascular ischemia, trauma, and/or prolonged hyperglycemia. (see Figure 1). In the majority (>80%) of patients PN is the major contributing factor to ulcer formation. In about one-third of patients, a mix of ischemia and PN contributes to ulcer formation. Only about 10%–15% of diabetic foot ulcers are due solely to vascular ischemia. In addition, diabetic patients are more frequently colonized with Staphylococcus aureus and have more frequent superficial fungal foot infections, slow wound healing, and poorly characterized immune defects, all contributing to ulcer formation, persistence, and infection (Figure 1). 2.1

Peripheral Neuropathy

The PN of diabetes is a symmetrical distal polyneuropathy involving motor, sensory, and autonomic nerves. Motor nerve involvement results in atrophy of the small intrinsic muscles of the foot, causing imbalance, change in shape of the foot, and maldistribution of 581

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DIABETIC FOOT INFECTION: 1 Pathophysiological characteristics (see Figure 1) Clinical diagnosis Patient characteristics (see Table 1) Screening questions (see Table 2) Diagnosis of osteomyelitis (see Figure 2) Assessment of peripheral vascular disease (see Figure 4) Culturing No culture of superficial ulcers Aerobic and anaerobic culture of clean base of ulcer and curette material Aspiration of abscess cavities Intraoperative samples of bone of subcutaneous tissue Prevention (see Table 5)

the soft tissue cushioning protective of the pressure points on the foot. Abnormal pronation and supination result in increased stress on soft tissues and bones, leading to inflammation of the joints, tendons, and ligaments. Autonomic nerve damage causes decreased sweating, leading to dry skin, fissuring, and the potential for bacterial invasion. Autonomic neuropathy may also cause changes in the microvasculature as formation of arteriovenous shunts contributes to inadequate blood supply. The sensory neuropathy leads to a loss of sensation, allowing trauma to the foot to be undetected by the patient. The combination of the loss of the normal architecture of the foot and loss of sensation exposes poorly protected bony prominences to repetitive trauma from walking or shoe irritation. The patient does not notice the ongoing damage because of the lack of sensation. Despite a good blood supply, an ulcer forms. Classically the neuropathic ulcer forms on the plantar surface of the first metatarsal head. Once the skin is broken, the ulcer becomes colonized with bacteria, which can invade more deeply into the soft tissues and eventually to bone by contiguous spread. Occasionally, more widespread and invasive infection can also result. Peripheral neuropathy is also the major cause of diabetic neuroarthropathy of Charcot joint formation. This is a chronic progressive degenerative process due to repetitive trauma of weight-bearing joints (60% involve the midtarsal joints) caused by repeated fractures, subluxations, and dislocations. This disabling condition can contribute to ulcer formation by shifting the pressure points to the plantar portion of the collapsed arch of the midfoot. 2.2

Ischemia

Not infrequently, patients with neuropathy seem to be spared atherosclerotic occlusions and may have palpable pulses. However, peripheral vascular disease (PVD) and ischemia develop in 45% of patients who have had DM longer than 20 years. Calcification of the vessels can be seen in more than 90% of patients who have had DM for more than 35 years. Vascular ischemia is associated with more than 60% of nonhealing ulcers and 42% of amputations. Occlusion of the distal tibial and peroneal arteries typically develops in diabetic patients who have atherosclerosis. The resulting impairment in the blood supply contributes to atrophic skin changes, decreased tissue oxygenation, poor wound healing,

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Figure 1 Pathophysiological characteristics of the diabetic foot ulcer. Foot ulcers may develop as a result of peripheral neuropathy, ischemia, or both. Peripheral neuropathy involves sensory, motor, and autonomic components. Peripheral vascular disease generally involves calf vessels, although multiple levels can be involved. Repetitive trauma such as walking causes tissue breakdown and ulceration. Bacterial colonization may progress to infection. Without intervention, the infection progresses to deeper tissue layers, leading to limb and life threatening infection.

and inability to deliver antibiotics to sites of ulceration and infection. Ischemic ulcers typically form over pressure points but may form in the absence of apparent trauma. 2.3

Immune Suppression

Poor glycemic control results in impaired immunity, abnormal soft tissue formation, and interference with tissue oxygenation, all contributing to ulcer formation and infection. Glycosylation of collagen can lead to skin thickening and loss of elastic fibers that may lead to skin breakdown. DM has been associated with impaired humoral immunity, abnormal inflammatory response, and defects in white blood cell (WBC) chemotaxis and phagocytosis. Metabolic shunting of glucose leads to the accumulation of sorbitol, fructose,

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and lactate, which increases capillary leak and oxygen blockade. These changes contribute to skin breakdown, impairment of immunity, and development of infection. 2.4

Trauma

Trauma is required to initiate the neuropathic ulcer. This trauma can be compressive, torsional, or shearing in nature. Usually this takes the form of repetitive injury from walking or irritation from poorly fitting shoes. This trauma impacts the weight-bearing parts of the diabetic foot, most often the plantar surface of the first and fifth metatarsal heads. In patients who have had toe amputations, the site at risk is transferred to adjacent metatarsal heads. Usually this trauma is minor and unnoticed by the patient. Less commonly the trauma may be acute from puncture wounds or other trauma; for that reason we ask that DM patients never go barefoot. Since most diabetic foot ulcerations are related to neuropathy, the majority of ulcers are due to repeated trauma and, with proper patient education, are preventable. 3

DIAGNOSIS

Clinical characteristics of foot ulcers are straightforward and usually are not diagnostic dilemmas. Characteristics of 92 patients admitted to the hospital for limb-threatening infections are summarized in Table 1. Most patients were insulin-dependent and had significant peripheral neuropathy. Of note, the majority did not appear clinically ill or toxic. One of the most important and difficult diagnostic decisions is the determination of whether the bone underlying the ulcer is infected. Although the history, physical exam, and laboratory assessment may be helpful, often the determination is made through radiological imaging. 3.1

History

The patient with a diabetic foot ulcer is typically in his or her 50s, has type II DM with insulin dependence, and has been hyperglycemic for several decades. Patients at risk for plantar ulcerations include those with previous ulcers, prior surgery on the metatarsal heads, Charcot joints, prominent metatarsal heads or bony deformities, limited hallux dorsiflexion, and a history of calluses, blisters, or macerated skin.

Table 1 Characteristics of Patients with Limb Threatening Infections Characteristic Insulin dependence Sensory neuropathy Temperature >100⬚ F Ulcer Purulent discharge WBC > 10,000/mm3 Positive blood culture result Osteomyelitis a

Percentage a 79 90 44 100 77 50 4 68

Ninety two patients with 97 events. WBC, white blood cell count. Source: Adapted from Grayson et al. 1994.

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Besides any specific stated complaints, the elements of the patient history that are most important include a pattern of numbness or sensory loss suggesting neuropathy or pain. Early neuropathy may often be painful and difficult to distinguish from ischemic rest pain, although neuropathic discomfort commonly has a stocking-glove distribution. Pain may be localized to the site of an ulcer, but, more commonly, in the neuropathic foot, there is an absence of pain, which is a large part of the problem. Pain from ischemia typically involves the heel, forefoot, or toes (not the calf or ankle) and is associated with an absence of pedal pulses. Dependent rubor is present on physical examination in the toes or forefoot (rubor has a deep purple discoloration compared to erythema from infection, which tends to be a brighter red hue). Patients may have claudication pain or a sense of tiredness in the large bulky muscles of the calf, thigh, or buttocks when walking. The history should include some investigation regarding the patient’s preferred footwear to be sure it is comfortable and has adequate support. Table 2 contains questions that may be used to screen diabetes patients for potential foot problems. 3.2

Physical

Physical examination always begins with inspection, including the heel and the area between the toes. Areas of redness from shoe irritation that could be potential trouble spots should be noted. Be sure to examine the first and fifth metatarsal heads, heel, and points of bony prominence. Typically, patients with neuropathy have (or will have) Charcot-type deformities, including loss of the arch, bunions, and hammertoes. This condition alters the weight-bearing mechanics of the foot and places the patient at risk for cutaneous injury and ulceration, particularly when sensation is diminished. Note the skin color (normal pink, pale white, rubor), condition of the nails, and presence of any lesions. The diabetic foot is often dry, warm, and insensate. The skin is hyperkeratotic and the veins dilated. The toes may become clawlike. The pedal pulses are good unless there is also advanced peripheral vascular disease, as described previously. One should also feel pulses at the femoral, popliteal, dorsalis pedis, and posterior tibial locations in the leg and foot as this may be the first clue that the patient has an ischemic problem (with or without neuropathy).

Table 2 Foot Care Screening Questions Do your feet feel numb? Do your feet feel excessively cold or hot? Do you have ‘‘pins and needles’’ sensations in your feet or legs? Do you have any stabbing pain in your feet and legs? Do you have any deep dull pain (like a toothache) in your feet and legs?

No No No

Yes Yes Yes

No

Yes

No

Yes

No

Yes

No No

Yes Yes

When? Do you have any burning sensation in your feet and legs? Do the bedclothes irritate your feet or legs? Have you ever had an infection or ulcer of your leg or foot that did not heal or healed very slowly?

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Patients who have calluses (preulcerative lesions) or early neuropathic changes should have evaluation with the Semmes-Weinstein monofilament. This is a simple nylon filament calibrated to bend at 10 g. of force, which is a pressure associated with protective sensation. Examination proceeds by touching the patient in the areas at risk in the foot (metatarsal heads, bony prominences, ulcer area) and noting whether the patient can feel the touch. If not, the foot is at risk of development of ulceration and the patient should have special footwear. An evaluation by a podiatrist or orthopedist with an interest in problems of the diabetic foot should be sought. The neuropathic ulcer is usually surrounded by hyperkeratotic skin. The base may reveal pink granulation tissue and can bleed easily. It is painless. The arterial pulses of the foot are intact. The ischemic ulcer develops in areas of tissue atrophy without the associated hyperkeratotic buildup typical of the neuropathic ulcer; the foot is cool and pulses poorly palpated. The presence of the typical signs of infection (erythema, odor, drainage, lymphangitis) should be noted. In general, infections in the diabetic foot may be classified as follows: 3.2.1 Type I: Mild Type I infection is characterized by a superficial ulcer or minor break in the skin surrounded by a slight amount of erythema of the skin, usually extending less than 2 cm in diameter from the ulcer. There is no systemic toxicity or evidence of osteomyelitis, tissue necrosis, or deep plantar infection. 3.2.2

Type II: Moderate or Limb-Threatening

Type II infections are chronic deeper ulcers extending to the subcutaneous tissues. There is no bone exposed. The lesion may be draining small amounts of serous or purulent fluid, but no deep collection is suspected on the basis of inability to express pus from the wound and lack of edema in the arch of the foot. There may be erythema extending to the forefoot. Osteomyelitis may be present. Larger (more than 2 cm2 in diameter) and deeper ulcers (more than 3 mm2 in depth) are more commonly associated with a contiguous osteomyelitis. 3.2.3

Type III: Severe

Limb and life-threatening. The type III infections are extensive infections with large deep ulcers. Cellulitis may be widespread and associated with lymphangitis. There is malodorous, purulent drainage. Suspicion of a deep infection or abscess collection is based on ability to express pus from the ulcer. The ulcer and surrounding tissue may be necrotic with blackened dead skin and subcutaneous tissue. Bone may be visible or easily palpated with probing. Signs and symptoms of systemic involvement such as fever, elevated white blood cell count, and hyperglycemia are present. Typically, tissue destruction is extensive under the intact skin. 3.2.4

Osteomyelitis

The diagnosis of osteomyelitis by physical exam can be challenging. Bone infection related to diabetic foot infections is due to contiguous spread from the ulcer to bone. The bone is not infected hematogenously; usually it is by direct extension from a large deep ulcer or a fistulous tract from the ulcer to the bone. Therefore, demonstration of a fistulous tract or ulcer extending to the bone or in the direction of the bone (if the bone is not visible) is useful circumstantial evidence that the bone is involved. This may be particularly helpful

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when trying to differentiate an osteomyelitis of the midfoot tarsal bones from a Charcot joint. Lack of a tract to the suspected bone should raise doubt about a diagnosis of bone infection. Palpation of the bone with a sterile probe can be a valuable test for the detection of osteomyelitis. According to Grayson and associates (1994), the palpation of bone through the ulcer has a sensitivity of 66%, a specificity of 85%, and a positive predictive value of 89% in predicting the presence of osteomyelitis. The inability to palpate bone does not rule out bone infection, though. Osteomyelitis is typically associated with type II or type III infections, but long-standing type I infections can develop this complication as well. It is important to recognize that some patients with limb- or life-threatening diabetic foot infections do not appear toxic and are not febrile. Blood culture findings often are negative. Pain and tenderness are not consistent findings and should not be used to judge the presence of infection, especially in view of the peripheral neuropathy present in the majority of patients. 3.3

Laboratory

Results of the routine laboratory assessment including a complete blood count are generally nonspecific, although some patients with type II or III infection may have a leukocytosis. Despite bone destruction the alkaline phosphatase level is not elevated. Most patients have an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein level. Investigators have found osteomyelitis in 100% of patients with ESR >100 mm/hr. Others (Lipsky, 1995) have found a 12-fold increased risk of osteomyelitis in patients with ESR >40 mm/hr. Glycemic control may be lost during infections. 3.4

Radiological Evaluation

Radiographic modalities used to look for osteomyelitis include plain radiography; nuclear imaging, including bone and leukocyte tagged scans, and computed tomographic (CT) and magnetic resonance imaging (MRI) scans. The sensitivity, specificity, and costs of these tests vary greatly; they all have practical use in the diagnosis of deep tissue infection and osteomyelitis (see Table 3). If bone is visible or palpated through the ulcer and there is no evidence of a deeper abscess, radiological imaging is not necessary. If there is doubt about the presence of osteomyelitis, a plain radiograph may demonstrate periosteal reaction, focal osteopenia, bone destruction, and islands of dead bone (sequestra) that are characteristic of bone infection. The sensitivity of a plain radiograph is limited and a negative film result does not rule out bone infection. Repeating radiography in 2–3 weeks may demonstrate changes consistent with osteomyelitis. A technetium Tc 99 bone scan shows increased uptake in areas of osteoblastic activity or increased blood flow. Scans are more sensitive than plain film and can provide evidence for osteomyelitis weeks before changes can be seen on plain radiographs. Unfortunately, they are nonspecific and false-positive test findings can occur because of fractures; previous bone surgery, partially treated bone infection; Charcot joints; and tumors. Although leukocyte tagged scans such as indium-111 and Tc-99m-HMPAO are specific for infections, the degree of anatomical resolution is poor and differentiating bone infection from overlying cellulitis may be difficult. Some authorities recommend combining bone and leukocyte scans to improve the diagnostic specificity for bone infections. The accuracy of this double-scan approach nears 90%. This approach, however, is expensive and timeconsuming and does not yield adequate detail about soft tissue involvement.

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Table 3 Imaging the Diabetic Foot for Evidence of Osteomyelitis Imaging technique

Sensitivity, %

Specificity, %

PPV,a %

Comment

Plain radiograph

60 (28–93)

66 (50–92)

74–87

Bone scan b

86 (68–100)

45 (0–79)

43–87

Leukocyte scan c

89 (45–100)

78 (29–100)

75–85

MRI scan

99 (29–100)

83 (71–100)

50-100

Need 40%–70% bone resorption to visualize changes, which can lag up to 2 weeks False-positive results from diabetic osteopathy, fractures, and healing bone infections; false negative results are unusual and may be due to poor blood flow. Poor anatomical resolution; false-positive result due to overlying cellulitis Not as good as CTd scan for detecting cortical lesions but better for imaging bone marrow and soft tissue

a

Positive predictive value. Technecium Tc 99m diphosphonate three-phase bone scan. c Indium-111 or Tc 99m HMPAO leukocyte tagged scan. d Computed tomography. Source: Adapted from Lipsky 1997. b

Overall the most sensitive and specific imaging technique is MRI scanning. It can give excellent anatomical detail of the bone and soft tissue, helping in assessment not only for osteomyelitis but also for deep tissue abscess and fasciitis. Bone involvement shows a low T1 and high T2 signal. The improved sensitivity and specificity of the MRI scan must be weighed against the cost of the exam and its limited availability. MRI scanning should be reserved for patients whose diagnosis is in doubt after plain radiographs or nuclear scanning or for patients with suspected deep tissue involvement. The MRI scan may not be able to differentiate between osteomyelitis and a Charcot joint. An approach to the diagnosis to osteomyelitis is outlined in Figure 2. 4 4.1

BACTERIOLOGICAL CHARACTERISTICS Pathogens

The bacteria isolated from a diabetic ulcer can generally be predicted from the severity of the ulcer and the culturing technique used. Superficial or type I ulcers are usually monobacterial with cultures growing S. aureus or streptococci. As the severity of the infection worsens, the wounds (type II and III) are more likely to be polymicrobic, involving not only staphylococci and streptococci but also aerobic gram-negative rods (GNRs) and anaerobes. In a study by Lipsky and colleagues (1990) of 60 patients treated as outpatients for infections not involving abscess formation or osteomyelitis the average number of pathogens isolated per patient was 2.1. Monobacterial infections were found in 42% of patients; predominant isolates were S. aureus, coagulase-negative staphylococci, and strep-

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Figure 2 Diagnosis of osteomyelitis. All patients who have a diabetic foot ulceration, particularly one that does not heal with appropriate medical care, should be suspected of having an underlying osteomyelitis. Bone involvement occurs from a contiguous ulceration. Generally a pathway from cutaneous ulcer to bone can be demonstrated. The use of magnetic resonance imaging (MRI) or white blood cell (WBC) tagged nuclear scanning may be helpful when there is strong suspicion of osteomyelitis when initial plain foot film findings are nondiagnostic. Palpation or visualization of bone is highly predictive of osteomyelitis. (Adapted from Lipsky 1999, Figure 1.)

tococci. Aerobic GNRs were isolated from 23%; Klebsiella spp., Proteus spp., and Pseudomonas aeruginosa predominated. In more severe infections, multiple pathogens are isolated in up to 90% of patients. The number of bacteria isolated in these more severe infections averaged three to five, depending on the study. Most of the infections were due to an admixture of staphylococci, including S. aureus and coagulase-negative staphylococci; streptococci, including S. pyogenes, aerobic GNRs, including Escherichia coli, Proteus spp., Klebsiella spp., Enterobacter spp., and P. aeruginosa; and anaerobes such as Bacteroides spp., Clostridium spp., and Peptostreptococcus spp. Diabetic osteomyelitis is also usually polymicrobic; 70%–85% of patients have multiple pathogens isolated from bone biopsy culture. Staphylococci, streptococci, diphtheroids, and enterococci are often isolated along with aerobic GNRs and anaerobes. Pseudomonas spp. have been isolated from 10%–15% of patients. Anaerobes are more frequently isolated from more severe or long-standing infections. Although coagulase-negative staphylococcus, diphtheroids, and Enterococcus spp. are often considered colonizers or contaminants, in the patient with diabetic osteomyelitis they are often true pathogens.

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Culturing

The accuracy of the cultures from diabetic foot ulcers is dependent on the technique used to obtain the specimen. It is well recognized that swab cultures of superficial ulcers are inaccurate, overrepresent pathogenic bacteria, and should not be done. Cultures should be taken from tissue, bone, or loculated abscesses. Frequently, only the ulcer can be cultured. Comparisons of deep cultures (surgical biopsy or abscess aspiration) to those taken from the open ulcer showed a correlation in only 17%–27%. The rate of both false-positive and false-negative culture results from the ulcers was 50%. When only the ulcer is available for culturing, the base should first be cleaned with saline solution, povidine-iodine, or alcohol. A sample for culture is then taken by curettage of the base of the ulcer with a scalpel blade or curette. The scraping should be sent for aerobic and anaerobic culture. De´bridement of the ulcer may also produce suitable tissue for culture. Ideally, bone suspected of being infected should be cultured. This is easier said than done, especially in the outpatient setting. The ability to predict accurately the results of bone cultures from soft tissue cultures is extremely limited. One study showed identical pathogens from bone and soft tissue in only 13% of patients (Laveny, 1995). The difficulty of identification of true bone pathogens is compounded by the frequent use of antibiotics before biopsy, which makes interpretation of cultures challenging. 5

APPROACH TO THE PATIENT WITH A DIABETIC FOOT ULCER

The approach to the patient with a diabetic foot infection is summarized in Figure 3. The patient should have a thorough history and physical examination. The history should include duration and level of glycemic control, complications of diabetes such as peripheral neuropathy, and cigarette smoking. The ulcer should be probed to determine depth of the

DIABETIC FOOT INFECTION: 2 Approach to the patient with a diabetic foot ulcer (see Figure 3) Type I or mild Shallow ulcer <2 cm of surrounding cellulitis No osteomyelitis, abscess, or necrosis Usually monobacterial with Staphylococcus or Streptococcus spp. Type II, moderate or potentially limb-threatening Larger and deeper ulcer Greater area of cellulitis Osteomyelitis potentially present Generally polymicrobic Type III, severe or potentially life-threatening Deep purulent ulcer Extensive cellulitis Osteomyelitis generally present Necrosis of skin and subcutaneous tissue Systemic toxicity potentially present Generally polymicrobic Antibiotic treatment (see Table 4)

Figure 3 Approach to the patient with a diabetic foot infection. The ulcer should be assessed and categorized as type I, II, or III. The presence of bone involvement and peripheral vascular disease should be determined. Most ulcerations, except the most superficial ones, need de´bridement. Empirical antibiotic therapy should be based on the severity of the infection. Adjustment to antimicrobial selection can be based on cultures from abscess cavities, bone, or deep curettage of the ulcer.

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wound and presence of occult collections of pus and to determine palpability of bone. If there is concern about osteomyelitis, a plain radiograph of the foot is indicated. If a deep foot abscess or fasciitis is suspected, the patient should undergo MRI or surgical exploration of the wound. Assessment of the patient’s vascular status should be made (see late discussion). The type of foot infection can then be classified as mild (type I), moderate (type II), or severe (type III). Most patients who have type II or III infections require de´bridement of the ulcer and should be hospitalized. 5.1

Assessment of Arterial Status

All patients should be assessed for the presence of vascular obstruction and baseline tests performed as indicated (see Figure 4). In a patient without neuropathy, a history of burning pain in the heels, foot, or toes may be suggestive of ischemia, especially if unilateral. The physical exam includes signs such as dependent rubor, absence of pedal pulses, or a cool foot. A patient with normal pulses who is considered at risk for the development of foot problems because of severe bony deformities, Charcot deformities, advanced neuropathy or employment requiring extensive walking or standing (e.g., postal carriers) should receive baseline screening. Baseline noninvasive vascular laboratory tests should include segmental measurement of Doppler study–derived blood pressures and plethysmographic recordings (pulse volume recordings [PVRs]) of blood flow. This test determines the presence and location of vascular obstruction. An ankle-brachial index (ABI) is the ratio of ankle pressure to arm pressure. An ABI of less than 0.4 and flat or barely pulsatile tracings at the ankle indicate moderately severe to severe ischemia. A pitfall in interpreting limb pressures in diabetics is the presence of calcified vessels, which cause ‘‘falsely’’ elevated pressure and ABI findings. The plethysmographic tracings, however, are abnormal in the presence of obstruction in a diabetic patient. Figure 5 shows a PVR of a patient with severe peripheral vascular disease of the left foot. The waveforms are blunted and the ABI is quite low. If peripheral vascular disease is present, without limb-threatening ischemia (nonhealing ulcer, pain at rest in foot), the patient may report claudication, which is described as an aching pain or tiredness in the large bulky muscles of the calf, thighs, or buttocks. Claudication does not involve the foot and occurs only with exercise. In general, this problem should be managed nonoperatively with weight loss, smoking cessation, and exercise. In addition, a trial of cilostazol (Pletal), which has peripheral vasodilatory effect, is warranted. In general, this medication is well tolerated. The most frequent side effect, headache, usually subsides with time. If patients are unable to tolerate cilostazol, the hemorheological agent pentoxyfilline is usually worth a trial (at least 6 weeks is required before any effect of the drug is seen) but is usually less effective than cilostazol. Disabling claudication in an otherwise ‘‘good-risk’’ or younger patient may also warrant intervention. Assessment by a vascular surgeon for bypass surgery or angioplasty can then be made angiographically. 5.2

Consultation

Although routine consultation is not recommended, there is a need for consultation for diabetic foot problems in certain situations. Consultation with a podiatry specialist may be indicated for routine foot care, fitting for specialized shoes or inserts in patients at risk, nail cutting in patients at risk or those with impaired eyesight or other infirmities that would make this activity hazardous, and management of chronic noninfected ulcers in patients who have normal pulses and early neuropathic changes. Consultation with a vas-

Figure 4 Assessment for peripheral vascular disease. If the patient has symptoms of claudication (see text) or signs suggestive of ischemia on examination (palor, rubor, absence of pedal pulses), noninvasive testing such as plethysmography and determination of the ankle-brachial index (ABI) should be carried out. If ischemia is present or demonstrated by noninvasive testing, particularly in the presence of an ulcer, vascular surgery should be considered. (1) Noninvasive tests include ankle-brachial index, segmental limb pressures, and arterial plethysmography; (2) exercise, smoking cessation, weight loss, risk factor modification, cilostazol, or pentoxifylline; (3) disabling: inability to carry out activities of daily living, inability to work; (4) poor risk: individualized; may include life expectancy less than 1 year, severe congestive heart failure, unstable angina, home oxygen requirement, current nonuse of limb at risk.

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Figure 5 Noninvasive arterial tests. A noninvasive arterial test result from a patient with severe peripheral vascular disease of the left lower leg. Testing includes segmental limb pressures, arterial plethysmographic waveforms, and ankle-brachial index (ABI). The black bands on the leg demonstrate the positions of the recording cuffs. The brachial artery systolic blood pressure is 140 mm Hg and is assumed to be equal to pressure within the distal abdominal aorta. The systolic blood pressure in the calf is 45 mm Hg and 33 mm Hg in the ankle, demonstrating a drop from aortic pressure (a difference of 20 mmHg between levels is significant). The plethysmography waveforms show marked blunting at the calf level on the left, indicating tibial vessel disease. In diabetics, the waveforms are especially important since the pressure determinations may be falsely elevated as a result of noncompressible, calcified vessels. The ABI on the left is 0.24 (140/33), which is consistent with limb-threatening ischemia and/or a nonhealing ulcer. The ABI is normal on the right. This patient ultimately had below-the-knee amputation.

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cular surgeon is indicated for patients with moderate to severe evidence of peripheral vascular obstruction; those who have ischemic rest pain or infection with evidence of peripheral vascular obstruction; any diabetes patient who has type II or III infection, and patients with disabling claudication. Consultation with an infectious disease specialist may be indicated for osteomyelitis or complex deep infections; life-threatening infection; infections with resistant organisms such as methicillin-resistant S. aureus, enterococcus, P. aeruginosa; or no response to therapy. Consultation with a neurologist may be indicated for the patient with severe unrelenting neuropathic pain in the absence of vascular obstruction. 6

TREATMENT

The care of the patient with a diabetic foot infection generally involves local wound care, antibiotic therapy, and surgical de´bridement and/or revascularization as needed. It must be stressed that not all diabetic foot ulcers are infected and need antibiotic therapy. If the foot ulcer is dry without associated cellulitis or drainage and there is no evidence of osteomyelitis or deep infection, antibiotic therapy is not needed. Culturing these ulcers is counterproductive since the inevitable colonization leads to false-positive results and overtreatment. Ultimately the response to therapy depends on the severity of infection, vascular supply, presence of osteomyelitis, and extent of surgical de´bridement performed. For type II and III infections antibiotic therapy should be combined with wound de´bridement and possible bone resection. 6.1

Antibiotics

The type and duration of antibiotic therapy depend on the severity of the infection and presence of bone involvement (see Table 4). Mild type I infections are usually caused by staphylococci or streptococci. Patients with these infections can be treated as outpatients with oral antibiotics. Reasonable choices include cephalexin, dicloxacillin, clindamycin, and amoxicillin-clavulanate. Therapy is usually given for 2 weeks. Lipsky and colleagues (1990) found that 75% of these infections were eradicated with short-course oral antibiotics. Type II infections are more serious and potentially limb-threatening, involving deeper tissues, including bone sometimes. Evaluation for underlying osteomyelitis is needed (see Figure 2). These patients should generally be admitted to the hospital for intravenous antibiotics and surgical de´bridement of soft tissue and possibly bone. These infections are often polymicrobic with a mix of aerobic and anaerobic bacteria. Antibiotic choices include agents or combination of agents such as cefotetan and ampicillin or ceftriaxone, clindamycin and ampicillin or ciprofloxacin, clindamycin and ampicillin. Type III, severe or potentially life-threatening, infections are also polymicrobic, though the degree of necrosis, deep tissue involvement, and likelihood of bony involvement is greater than seen in type II. Antibiotics used to treat type II infections can also be used to treat type III infections, though usually agents with activity against P. aeruginosa are selected. Ciprofloxacin or ceftazidime combined with clindamycin and ampicillin can be used. Agents that have activity against both aerobes and anaerobes such as piperacillin-tazobactam or a carbapenem such as imipenem or meropenem are also reasonable choices. Aminoglycosides should be avoided because of the potential for nephrotoxicity in these diabetic patients, who may have underlying renal insufficiency. The duration and route of administration of antibiotics for type II and III infections are not well defined. Traditionally, parenteral antibiotic therapy has been given for 4–6

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Table 4 Antibiotic Management of Diabetic Foot Infections Type of infection

Antibiotic alternatives

Dosage a

Comment

Usual duration of therapy 2 wk; close follow-up needed to assess clinical response and reevaluate for more severe infection. Antibiotic combinations to provide Type II (moderate) Cefotetan plus 2 g q12h IV coverage for staphylococcus, ampicillin b,c 1 g q6h IV streptococcus, aerobic gramAmpicillin/sulbactam 1.5–3.0 g q6h IV negative rod, and anaerobes; Ceftriaxone plus clin- 1 g q24h IV need for enterococcus treatment 900 mg q8h IV damycin plus controversial 1 g q6h IV ampicillin b,c Ciprofloxacin plus 400 mg q12h IV clindamycin plus 900 mg q8h IV 1 g q6h IV ampicillin b,c Both agents have Excellent oral 750 mg bid PO Ciprofloxacin plus bioavailability and activity 300 mg qid PO clindamyin against more common pathogens of both agents Type III (severe) Ceftazidime plus Activity against Pseudomonas 2 g q8h clindamycin plus aeruginosa required; merope900 mg q8h ampicillin b nem preferred to imipenem for 1 g q6h renal insufficiency, seizure, enPiperacillin-tazobac- 3.376 g q6h cephalopathy patients tam 500 mg q6h Imipenem 1 g q8h Meropenem Type I (mild)

Cephalexin Clindamycin Amoxacillin-clavulanate

500 mg qid PO 300 mg qid PO 875 mg bid PO

a

Assuming normal renal function. Added to treat enterococci. c Use vancomycin for penicillin-allergic patients. b

weeks if osteomyelitis is present. More recent studies (Lipsky, 1997) suggest that the majority of therapy can be done with oral antibiotics that have excellent oral bioavailability such as the fluoroquinolones and clindamycin. Furthermore, most antibiotics have been shown to penetrate well into bone. If the patient’s condition is clinically stable and the patient is able to take oral medications, consideration can be given to initiating therapy with oral agents. If parenteral therapy is begun initially, the switch to oral agents can be done after clinical stabilization. If adequate bone or deep tissue cultures were performed, the choice of antibiotics can be tailored to the culture results. Also, consideration should be given to shortening the duration of antibiotic treatment if infected bone has been removed by surgical de´bridement or toe amputation. 6.2

Surgery and Wound Care

De´bridement of devitalized soft tissue and bone is the key to successful control of infection. Several studies have demonstrated that surgery combined with antibiotics is superior to use of antibiotics alone. De´bridement of type I and some type II infections can often be done in the outpatient clinic or at the bedside, since most of these patients do not have sensation. Generally, however, patients with type II or III infections should be hospitalized.

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Although amputations are often required to control infection, more limited de´bridement can sometimes control infection as long as widely open drainage with removal of devitalized tissue is achieved. Amputation of a digit may be the best approach if bone destruction has already occurred or previous attempts at more conservative therapy have failed. Factors that predict wound healing include absence of exposed bone, WBC <12,000 cells/ mm3, palpable pedal pulses, and an ankle pressure of >80 mm Hg. In addition to antibiotic therapy and surgical de´bridement, local wound care of the ulcer is important for healing and prevention of recurrence. Weight-bearing on the involved foot should be eliminated as much as possible. Superficial ulcers can be cushioned with foam inserts. Larger ulcers can be treated with bedrest or use of crutches, though the practicality of this approach is limited. Total contact casting for 8–10 weeks allows mobility while shifting weight bearing from the ulcer. Other means of removing pressure from the ulcer include use of a Carville splint or Scotch cast boot. Wound care tends to be highly individualized, and no clear superior method has emerged. The authors favor wet-to-dry dressings, particularly early after infection and de´bridement. Iodine, hydrogen peroxide, and other astringents should be avoided. Topical antibiotics are of limited value. Daily inspection of the wound should be made to assess healing, to look for evidence of new or relapsing infection, and to determine whether further sharp de´bridement is needed. Treatment of local callus formation and use of therapeutic footwear should be done in collaboration with a podiatrist or vascular surgeon. Growth factors and hyperbaric oxygen are expensive modalities and have not been proved to be of benefit to date. Becaplermin gel (Regranex, Ortho-McNeil Pharmaceuticals), a genetically engineered platelet-derived growth factor, may be of some value for chronic ulcers. When used in combination with regular de´bridement, Becaplermin gel can enhance

Table 5 Instructions for Care of Diabetic Feet Many problems that occur in the feet of individuals who have diabetes can be prevented with simple precautions: 1. Inspect your feet every day, top and bottom. You may need help. Look between the toes. Look for cuts, blisters, sores, swelling, cracks, and/or redness. 2. Always wear shoes that fit properly. Do not wear pointy-toed shoes or ‘‘flip-flops.’’ 3. Apply moisturizing lotion to dry skin. 4. Never soak your feet or use a heating pad or hot water bottle on your feet. 5. Cut your nails straight across and not too short. If you have problems with your vision, you may need help from a nurse trained in foot care or a podiatrist. 6. Do no ‘‘bathroom surgery’’ with knives, razor blades, or scissors. 7. Check inside your shoes before putting them on. 8. Wear clean, dry socks without bulky seams or holes. 9. Wash your feet daily. Check the water temperature very carefully. Dry your feet thoroughly, especially between the toes. 10. Never go barefoot. 11. If problems arise, call your doctor promptly. Call:

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healing of neuropathic ulcers (regular de´bridement alone in one study was also effective). It is not indicated for patients who have ulcerations and chronic ischemia or infection of necrotic debris. It is expensive, costing about $377 for a 15-g tube. Soft tissue de´bridement with fly larvae (maggots) may be of benefit, but patient acceptance may be limited. Further studies are needed to define better the role of these newer treatment approaches. 7

PREVENTION

An organized educational program for foot care can actually reduce the number of amputations of diabetic patients. It is important to spend time at each visit emphasizing the importance of proper foot care. In general, we ask patients or their caregivers to inspect both feet daily and to seek early medical attention for problems. Patients should avoid ‘‘bathroom’’ surgery, foot soaking, walking barefoot, and wearing improperly fitting shoes. Patients should be encouraged to seek early evaluation by their primary care provider when a new lesion or infection develops. Written materials are helpful reinforcements for patients as well (see Table 5). BIBLIOGRAPHY American Diabetes Association: Standards of medical care for patients with diabetes mellitus. Diabetes Care 19:S8–S15, 1996. Bridges RM, Deitch EA. Diabetic foot infections: Pathophysiology and treatment. Surg Clin North Am 74:537–555, 1994. Caputo GM, Vavanagh PR, Ulbrecht JS, Gibbons GW, Karchmer AW. Assessment and management of foot disease in patients with diabetes. N Engl J Med 331:854–860, 1994. Grayson ML, Gibbons GW, Balogh K, Karchmer AW. Probing to bone in infected pedal ulcers. JAMA 27:721–723, 1995. Grayson ML, Gibbons GW, Habershaw DV, Freeman FB, Pomposelli FB, Rosenblum BI and Karchmer AW. Use of Ampicillin/Sulbactam versus Imipenem/Cilastatin in the treatment of limb threatening foot infections in diabetics patients. 18:683–693, 1994. Jacques CHM, Jones RL, Houts P, Bauer LC, Dwyer KM, Lynch JC, Casak TS. Reported practice behaviors for Medical care of patients with diabetes mellitus by primary-care physicians in Pennsylvania. Diabetes Care 14:712–717, 1991. Laing P. The development and complications of diabetic foot ulcers. Am J Surg 176(suppl 2A):11– 19, 1998. Laveny LA, Sariaya AM, Ashay H, Harkless LB. Microbiology of osteomyelitis in diabetic patients. J Foot Ankle Surg 34:61–63, 1995. Lipinsky BA. Diabetic foot infections: Progress in a pedestrian problem. Contemp Surg 57(suppl): 7–19, 2001. Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 25:1318–1326, 1997. Lipsky BA, Pecoraro RE, Hanley JD. Foot bone lesions in diabetic patients. Diagnosis and natural history. Diabetes 40(suppl):553A, 1991. Lipsky BA, Pecoraro RE, Larson SA, Hanley ME, Ahroni JH. Outpatient management of uncomplicated lower extremity infections in diabetic patients. Arch Intern Med 150:790–797, 1990.

30 Tick-Borne Infections Robert P. Smith Maine Medical Center, Portland, Maine, and University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Ticks are major vectors of human disease. They are obligate blood sucking arthropods that parasitize many species of vertebrates. They are divided into hard ticks (Ixodidae) and soft ticks (Argasidae). Hard ticks are generally larger and have more prolonged feeding phases on the vertebrate host than the soft ticks. In addition, the bite of the Ixodidae ticks is generally painless, making patient awareness of tick contact less obvious. The basic life stages include larval, nymphal, and adult forms. Each form has a different vertebrate host. Humans can be incidentally infected when bitten by a host seeking ticks. Diseases spread by hard ticks include rickettsioses, ehrlichioses, Lyme borreliosis, tularemia, and Q fever. Indeed, Ixodes scapularis is the vector for Lyme disease, ehrlichiosis, and babesiosis and can potentially transmit them simultaneously. Soft ticks can transmit relapsing fever and Q fever. Ticks may become infected with transmissible bacteria either during the blood meal on the vertebrate host or in some cases transovarially (vertically from parent to offspring). Ticks not only transmit bacterial illness but may also serve as reservoirs for infection. This chapter reviews the clinical presentations, diagnoses, and treatment of the more common tick-borne infections: Lyme disease, relapsing fever, Ehrlichiosis, Rocky Mountain spotted fever, and Babesiosis. Other less common tick-borne infections such as tularemia, Colorado tick fever, and Powassan viral encephalitis are summarized. Tick-borne paralysis is reviewed. Although Coxiella burnetii (causative agent of Q fever) can infect many tick species, it is generally not transmitted by them and is not reviewed in this chapter.

2

LYME DISEASE

Lyme disease is the most common vector-borne infection in the United States. Because of its wide clinical spectrum and its potential for recurrence of symptoms, Lyme disease can prove a vexing diagnosis for clinicians. Nearly universal public awareness of the disease coupled with imprecise disease descriptions in some media has compounded the 599

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LYME DISEASE Spirochete illness due to Borrelia burgdorferi Transmitted by Ixodes tick (see Figure 2) Northeastern U.S., upper Midwest predominantly (see Figure 1) Spring and summer months Stages (see Table 3) Stage 1 (early) Erythema migrans (EM) rash Stage II (early disseminated) EM rash(s) Atrioventricular (AV) block, meningitis, cranial nerve VII facial palsy Oligoarticular arthritis Stage III (Late) Oligoarticular arthritis Subtle encephalopathy, sensory polyneuropathy EM rash (see Figure 3) Associated symptoms (see Table 2) Single or multiple Painless Expanding Differential diagnosis (see Table 1) Serological diagnosis (see Table 4) Treatment Antibiotic regimens (see Table 5) Recommended therapy (see Table 6) Prevention Barriers and repellents Chemoprophylaxis for deer tick bite Vaccine (currently not available)

challenge for physicians. During the past 25 years the clinical presentation of Lyme disease and the appropriate use of ancillary diagnostic tests have been well described. Few infectious diseases are as clearly recognizable at their onset. A careful history, targeted physical exam, and judicious use of serodiagnostic tests can identify most cases. 2.1

Ecological and Epidemiological Characteristics

Lyme disease is caused by the bacterium Borrelia burgdorferi. It is a gram-negative flagellated spirochete containing membrane lipoproteins referred to as outer surface proteins (Osp’s) A–F. Lyme disease occurs throughout the northern temperate zone, including Europe and northern Asia. The clinical features of the disease differ somewhat in Eurasia and North America as a result of differences in infecting strains. Tick species of the Ixodes ricinus complex are the vectors worldwide. In North America, the blacklegged or deer tick (I. scapularis, I. dammini) is the principal vector, except in the western United States, where I. pacificus, a closely related species, is responsible for transmission. The nymphal

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stage is responsible for most transmission, especially during the months of May through July. Rodents, particularly the white-footed mouse, serve as the principal reservoir hosts for the infection. It is these rodents that the nymphal stage feeds on predominantly. Although the white tailed deer is an important host for the I. scapularis tick, it is not a reservoir for B. burgdorferi. In the southeastern United States, erythema migrans–like rashes may occur after bites by lone star (Amblyomma) ticks. The cause of this illness may be another Borrelia species, but it does not appear to be due to infection by B. burgdorferi. The occurrence of Lyme disease is limited to areas in which the vector ticks are endemic. Although these ticks exist over a large geographical range in the United States (Figure 1), tick distribution is often very focal. The convergence of particular habitats, suitable climate, and high deer herd density is usually required to confer high risk of Lyme disease. For this reason, Lyme disease incidence is often quite low in many endemic states and counties. Northeastern coastal areas and several northern midwestern counties account for most reported cases in the United States. Exposure is primarily peridomestic, occurring in suburban or rural communities with high local deer populations and homes bordered by patches of bushy or wooded habitat. Risk is also seasonal: most human cases occur in May to July, when nymphal ticks are abundant. However, transmission can occur from early spring until late fall. Because deer tick nymphs are very small (see Figure 2) and their bite and attachment painless (Ixodidae ticks have anesthetic in their saliva), only one-third of patients who have Lyme disease recall a tick bite. Lyme disease transmission

Figure 1 Map of reported Lyme Disease vectors in the United States. (From CDC.)

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Figure 2 Nymphal Ixodes scapularis and adult female. (Photograph courtesy of Audio Visual Resources, Maine Medical Center.)

usually requires tick attachment for 36–48 hours. The great majority of persons find the tick during this period and remove it; Lyme disease develops in only 1%–2% of those who remove a deer tick. 2.2.

Clinical Characteristics

Most patients with Lyme disease develop a rash at onset. Erythema migrans (EM), the characteristic but not pathognomonic rash of Lyme disease, is present in the vast majority (65%–90%) of early cases. EM develops 3–30 days after the tick bite. The rash is almost universally greater than 5 cm in diameter and is flat, circular or oval in shape, and nontender. Single lesions occur at the site of the tick bite, most commonly on body areas where the tick would be unnoticed, such as the back, buttocks, groin, or axilla. A characteristic feature is its gradual enlargement at a rate of about 1 cm/day. Although classic descriptions of this rash emphasize central clearing or target formation, EM rashes seen early in their development often appear as a homogeneous erythema or a dense central erythema at the site of the tick bite (see Figure 3). Rashes at flexural creases such as the popliteal area may follow dermatological lines of least resistance with resulting bandlike patterns. In less than 10% of cases, vesicle formation or central necrosis may develop. Multiple EM lesions occur in <10% of cases after rapid dissemination of the spirochete. In these cases of disseminated disease, 2 to 20 similarly sized lesions, usually concentrated on the trunk, are present along with systemic symptoms. Unlike those of erythema multiforme, lesions are usually nonpruritic and do not involve the palms and soles. If the patient neither lives in an endemic area nor has traveled to one, and therefore does not have any exposure to Lyme disease, other diagnoses should be pursued. If the history includes a painful insect bite or the appearance of a rash immediately afterward, an allergic reaction to the bite is the likely cause. The differential diagnosis of EM is summarized in Table 1. About one-half of patients with solitary EM lesions have associated symptoms such as fatigue, headache, myalgias, or arthralgias (see Table 2). These symptoms may wax

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Figure 3 Erythema migrans with homogeneous erythema. (Photograph with permission by J. Nowakowski.)

and wane in character and intensity throughout the day. EM may also be accompanied by cranial neuropathy (especially Bell’s palsy) or other focal neurological signs and symptoms. Respiratory or gastrointestinal symptoms are notable by their absence. Within 1–2 months of untreated infection, cardiac complications (fluctuating atrioventricular [AV] or complete heart block), neurological symptoms (cranial neuritis, lymphocytic meningitis, radiculoneuritis and, in children, pseudotumor cerebri), or oligoarticular arthritis (Table 3)

Table 1 Differential Diagnosis of Erythema Migrans Rashesa Solitary EM Shape Painful to touch Scaly Rapid onset after bite Resolution over a few days Steady progression in size

Same size lesions Lesions on palm/soles Pruritic Systemic symptoms a

EM, erythema migrans.

Oval, circular, ‘‘bandlike’’ No Rare (on perimeter) No No Yes

Insect or arachnid bite

Ringworm

Cellulitis

Shape variable, often indurated Sometimes Sometimes

Circular

Variable

No Yes

Yes Sometimes

Yes Yes No

No No No

Sometimes No Sometimes

Multiple EM

Erythema multiforme

Urticaria

Yes (5–10 cm) No Sometimes Yes

Sometimes (variable) Yes No Variable

Sometimes Sometimes Yes Sometimes

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Table 2 Signs and Symptoms Associated with Erythema Migrans Symptoms

Number (%)

Fatigue Arthralgia Myalgia Headache Fever/chills Stiff neck Anorexia Dysesthesia Dizziness Nausea/vomiting Difficulty in concentrating Cough

43 35 35 33 32 28 21 16 16 11 7 5

(54) (44) (44) (42) (39) (35) (26) (20) (20) (14) (9) (9)

Signs Any objective finding Localized lymphadenopathy Generalized lymphadenopathy Fever (ⱖ37.8⬚C) Tender neck flexion Nuchal regidity Tender joints Joint swelling Conjunctivitis Seventh nerve palsy Tender abdomen Pharyngeal injection

Number (%) 33 18 5 13 7 1 6 1 3 1 1 1

(42) (23) (6) (16) (9) (1) (8) (1) (4) (1) (1) (1)

Source: Adapted from Nadelman et al. 1996.

may develop. The arthritis is usually asymmetrical and intermittent and commonly involves large joints such as knees. Occasionally patients may report one of these complications without a history of preceding EM. 2.3

Serological and Other Diagnostic Tests

Early Lyme disease with solitary or disseminated EM lesions is usually diagnosed on the basis of its clinical presentation. For the later complications of Lyme disease, the diagnosis usually rests on the combination of appropriate clinical presentation and serodiagnostic test results. Serodiagnostic tests for Lyme disease include immunofluorescent assay (IFA) and enzyme-linked immunosorbent assay– (ELISA)-based antibody tests to B. burgdorferi. Confirmatory immunoblot tests improve specificity but there are several pitfalls in the application of serological tests. In early Lyme disease, patients are often seronegative at presentation. With antibiotic treatments, seroconversion may not occur. Therefore, the utility of serodiagnostic testing in early Lyme disease is limited, although acute and convalescent serodiagnostic testing may prove helpful in the confirmation of the diagnosis of atypical cases. For late Lyme disease, however, serodiagnostic tests are highly sensitive (>90%). Positive or equivocal IFA or ELISA test results should be confirmed by immunoblot testing to improve specificity. A positive immunoblot finding for all but early Lyme disease should include the presence of five or more immunoglobulin G (IgG) bands, per Centers for Disease Control (CDC) criteria (see Table 4). A positive IgM immunoblot result is only helpful in early disease. Rare cases of seronegative Lyme disease with arthritis or other complications have been reported and may result from the treatment of Lyme disease with antibiotics before antibody development. However, the absence of antibodies to B. burgdorferi in patients with presumed Lyme arthritis or other complications should prompt a thorough search for other causes of the patient’s symptoms. Newer serodiagnostic tests such as assays for other B. burgdorferi surface antigens (i.e., C6 peptide) show promise. Polymerase chain reaction– (PCR)-based assays to detect B. burgdorferi deoxyribonucleic acid (DNA) have a 90% sensitivity in synovial fluid and

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Table 3 Clinical Spectrum of Lyme Disease Time after transmission

Stage I Early

3–30 days

II Early disseminated

Days to months

III Late

Months to years

Symptomsa EM Arthralgias, myalgias, headache, fever (see Table 2) Multiple EM Cardiac: AV block, myopericarditis Neurological Lymphocytic meningitis Cranial neuritis Radiculoneuritis Myelitis Mononeuritis multiplex Intracranial hypertension (in children) Rheumatological Oligoarticular arthritis Arthralgias Ophthalmological Panophthalmitis Uveitis Choroiditis Optic neuritis Dermatological Acrodermatitis chronica atrophicans (rare in United States) Rheumatological Oligoarticular arthritis Peripheral enthesopathy Neurological Axonal polyneuropathy Chronic encephalopathy Ophthalmological Interstitial keratitis

a

EM, erythema migrans; AV, atrioventricular.

are very specific. The sensitivity of these assays for neurological disease when performed on cerebrospinal fluid (CSF) is only 20%–30%. Although PCR for B. burgdorferi, in expert hands, is considered a specific test, false-positive results can occur, particularly when multiple samples are obtained. Cultures of blood or other body fluids are of low yield, though they occasionally yield a positive finding in early disease. Skin biopsy cultures, which have positive findings in 70%–90% of cases, are seldom needed. The overuse of serodiagnostic tests for Lyme disease may yield confusing falsepositive results. For example, their use for patients who have fibromyalgia or chronic fatigue syndrome has a positive predictive value of only 5%–10% (see Chapter 38). 2.4

Treatment

Treatment of Lyme disease with appropriate antibiotics is usually highly effective (see Table 5). Less than 5% of patients may experience a mild Jarisch-Herxheimer reaction

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Table 4 Interpretation of Serological Tests for Lyme Diseasea Stage Stage I (early, with EM)

Stage II, disseminated (noncutaneous) or Stage III (late)

Tests

Comment

Serological testing usually unnecessary If testing done, positive ELISA or IFA result adequate ELISA or IFA screen if positive or equivocal Immunoblot: 5 IgG bands required

If ELISA/IFA is equivocal, follow-up with immunoblot; positive immunoblot result designated as two or three IgM bands IgM positivity not of diagnostic significance except in early Lyme disease

Chronic fatigue syndrome or fibromyalgia

Benefit of serological testing not demonstrated

a

Center for Disease Control/ASTPLD criteria. EM, erythema migrans; ELISA, enzyme-linked immunosorbent assay; IFA, immunofluorescent antibody; IgG, immunoglobulin G. Source: CDC 1996.

with onset of fever for 1 to 2 days after the initiation of antibiotics. Doxycycline is the preferred antibiotic in most cases of early Lyme disease in adults because of its high efficacy, low cost, and equal effectiveness against possible ehrlichia coinfection. EM rashes begin to fade within 1–2 days of antibiotic treatment but often do not fully resolve for two weeks. Usual treatment duration is 14–21 days for early Lyme disease (Table 6). Patients with disseminated early Lyme disease (multiple EM rashes) are usually treated

Table 5 Antibiotic Regimens for Lyme Disease

Recommended drug Oral Preferred Amoxicillin Doxycycline Alternative Cefuroxime axetil Parenteral Preferred Ceftriaxone Cefotaxime Alternative Penicillin G a

Dose

Costsa per course (see Table 6 for duration of therapy)

500 mg tid 100 mg bidb

$19.60–$29.00 $14.50–$32.00

500 mg bid

$207.00–$311.00

2 g IV once/day 2 g IV tid 18–24 million U IV/day in divided doses q4hc

Actual wholesale price. 2000 Drug Topics: Redbook Tetracyclines are relatively contraindicated for pregnant and lactating women. c The penicillin dosage should be reduced for patients with impaired renal function. d Acute wholesale price only; infusion costs not included. Source: Adapted from IDSA Guideline: CID 2000, 31(suppl 1):51–54. b

$1260.00–$2520.00d $1176.00–$2352.00d $448.00–$598.00d

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Table 6 Recommended Therapy for Patients with Lyme Disease Indication Tick bite (deer tick)

Erythema migrans Acute neurological disease Meningitis or radiculopathy Cranial nerve palsy Cardiac disease First- or second-degree heart block Third-degree heart block Late disease Arthritis without neurological disease Recurrent arthritis after oral regimen Persistent arthritis after two courses of antibiotics Central nervous system disease or peripheral nervous system disease Chronic Lyme disease or post–Lyme disease syndrome

Treatment

Duration, days

None* (or single dose doxycycline for nonpregnant adults) Oral regimena,b

1

14–21

Parenteral regimenb,c Oral regimena

14–28 14–21

Oral regimena Parenteral regimena

14–21 14–21

Oral regimena Oral regimena or parenteral regimena Symptomatic treatment Parenteral regimena

28 28 28 14–28

Symptomatic therapy

a

See Table 5. Alternatives to amoxicillin, doxycycline, and cefuroxime include azithromycin, erythromycin, and clarithromycin. c Nonpregnant adults intolerant of penicillin and cephalosporins, doxycycline 200–400 mg/day. *NEJM 2001; 345:79–84. Source: Modified from CID 2000; 31(suppl 1). b

for 3–4 weeks, as are patients with neurological symptoms (Bell’s palsy, cranial neuritis) or arthritis. Response to oral antibiotics appears comparable to that to parenteral antibiotics for early Lyme disease and Lyme arthritis. Patients who have central nervous system (CNS) involvement (meningitis or radiculoneuritis) are usually treated for 2–4 weeks with intravenous (IV) ceftriaxone, although data from Europe have shown equivalent responses to oral doxycyline. Retreatment for Lyme disease is rarely required. No benefit has been shown with longer courses of antibiotics for treatment of persistent chronic fatigue or fibromyalgia symptoms. Of patients with Lyme arthritis 5%–10% may prove unresponsive to antibiotics as a result of an immunological response to B. burgdorferi antigens. Progressive monoarticular arthritis may ensue. Physicians should always be aware of the possibility of coinfection with human granulocytic ehrlichia or Babesia microti. These diseases are discussed in Sections 3 and 5. 2.5

Prevention

Prevention of Lyme disease begins with public education about local geographical risk. Measures aimed at decreasing risk of tick exposure include the selection of clothing that provides a barrier (i.e., pants with cuffs tucked into socks) when in high-risk habitats. As

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the ticks must be attached for 24–48 hours before Lyme disease transmission occurs, removal of ticks found by close inspection of the skin may be useful. Diethyltoluamide (DEET)-containing insect repellents or permethrin-treated clothing may decrease the risk of tick attachment. A vaccine engineered to stimulate antibody production against a major surface protein (OspA) of B. burgdorferi has been licensed for use for persons at significant risk of Lyme disease exposure, but was withdrawn from the market due to poor sales. The vaccine required an initial series of three doses at months 0, 1, 12 to achieve 76% preventive efficacy. The role of chemoprophylaxis after removal of attached deer ticks is controversial. Lyme disease occurs in only 1%–2% of untreated individuals following removal of a deer tick. The risk of Lyme disease is probably higher if a fully engorged tick is removed. A single dose of doxycycline (200 mg) has 87% efficacy in prevention of Lyme disease if given within 72 hours of a deer tick bite. It should be noted, however, that many tick bites in areas that are not highly endemic for deer ticks are due to other Ixodes species that do not transmit Lyme disease. 3

EHRLICHIOSIS

In certain geographical areas of the United States (see Figure 4) patients who report acute onset of fever, headache, and myalgias may be infected with one of three newly recognized and treatable ehrlichia species. Ehrlichias are rickettsia-like obligate intracellular coccobacilli that parasitize white blood cells. Ehrlichia that infect granulocytes cause human granulocytic ehrlichiosis (HGE). The erhlichia species that causes HGE has been named Anaplasma phagocytophila. E. chaffeensis, the cause of human monocytic ehrichiosis (HME), infects monocytes. It is transmitted by the lone star tick (Amblyoma americanum) (see Figure 5). Deer ticks transmit the agent of HGE. A third species of ehrlichia, E. ewingi (the agent of canine granulocytic ehrlichiosis), has been reported in a small number of patients from the midwestern United States. 3.1

Epidemiological Characteristics

These diseases occur in the ranges of their vector ticks. Relatively few cases of ehrlichosis are reported each year, and it is likely that most cases are unrecognized. As with other tick-borne diseases, the incidence of ehrlichosis is highest in summer months. Asymptomatic infection is two to three times more common than symptomatic infection. Annual incidence with active surveillance is about 50 cases/100,000 population in Connecticut and Wisconsin. In one study of residents of a southern United States golfing community, 12.5% of residents were seropositive for ehrlichosis (with seropositivity directly related to golf handicap, presumably due to increased tick exposure in the rough). Coinfection of patients with Lyme disease and HGE occurs in up to 5% of Lyme disease cases. 3.2

Clinical Presentation

An acute onset of an otherwise unexplained febrile illness with headache, myalgias, or arthralgias and unexplained leukopenia or thrombocytopenia, especially during summer months, should prompt consideration of ehrlichia, although those nonspecific symptoms are common in numerous viral and bacterial illnesses. Mild gastrointestinal symptoms and

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EHRLICHIOSIS AND BABESIOSIS Ehrlichiosis Rickettsia spp.–like intracellular coccobacilli Can infect granulocytes (human granulocytic ehrlichiosis [HGE] or monocytes (human monocytic ehrlichiosis [HME]) Tick transmission Regional US distribution (see Figure 5) Summer months Clinical presentation Fever, headache, myalgia Leukopenia, thrombocytopenia Hepatitis Gastrointestinal and respiratory symptoms Rash in 20%–30% of patients with HME Diagnosis Morulae in white blood cells (WBCs) on Wright or Giemsa stain (see Figure 6) Polymerase chain reaction (PCR) for Ehrlichia spp. deoxyribonucleic acid (DNA) in blood or cell culture Antibody by immunofluorescent assay (IFA) Treatment Doxycycline 100 mg bid ⫻ 7 days Babesiosis Malaria-like intraerythrocytic protozoon Northeastern coast and Wisconsin Clinical presentation May be asymptomatic or febrile Relative bradycardia and splenomegaly Hemolytic anemia and hemoglobinuria Diagnosis Thick/thin smear of blood IFA detection of antibody Polymerase chain reaction for babesial DNA Treatment Quinine and clindamycin Atovaquone and azithromycin

respiratory symptoms occur in one-third of cases. A rash is rarely present in HGE but occurs in 20%–30% of cases of HME. Unlike in Lyme disease, tick bites are reported by a majority of these patients. The usual incubation period is 7–14 days. HME can cause lymphocytic meningoencephalitis, and both HME and HGE can progress, particularly in the elderly, to produce a multisymptom illness with disseminated intravascular coagulation, hypotension, adult respiratory distress syndrome (ARDS), rhabdomyolysis, and myocarditis. Ehrlichiosis may rarely present clinical features suggestive of toxic shock syndrome. Unusual neurological manifestations include brachial plexopathy and demyelinating polyneuropathy. In HGE, secondary infections due to the bacterial or fungal pathogens may occur. Hospital-based series report fatality rates of 2%–5%.

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Figure 4 Geographical distribution of HME and HGE in the United States. HME, human monocytotropic ehrlichiosis; HGE, human granulocytotropic ehrlichiosis. (From CDC.)

Figure 5 Lone star tick (Amblyomma americanum), vector for HME (Ehrlichia chaffeensis) and E. ewingii infection. HME, human monocytotropic ehrlichiosis. (Photograph courtesy of Audio Visual Resources, Maine Medical Center.)

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In otherwise healthy patients, the illness is often brief and self-limited. Varying combinations of leukopenia, thrombocytopenia, and anemia are typically present. Transaminase level elevations are also common. 3.3

Diagnosis

Confirmation of ehrlichosis should not delay treatment if clinical suspicion is high. In published series cases of HGE, 16%–80% had characteristic morulae (clusters of intraphagosomal ehrlichia) present within polymorphonuclear leukocytes on Wright’s- or Giemsa-stained smears (see Figure 6). Sensitivity of buffy coat smear exam is 60% if 800–1000 granulocytes are examined. Such inclusions are rarely seen in HME. Falsepositive results may be due to Do¨hle bodies, platelets, or contaminants in the stain that may be mistaken for morulae. PCR of blood for ehrlichia DNA may yield a positive finding in 70%–80% of cases of HGE and HME. Specimens of whole blood are collected in ethylene diamine tetraacetic acid– (EDTA)-anticoagulated tubes and should be processed promptly. Cell culture of ehrlichia organisms is the most sensitive diagnostic test but it may require 3–14 days. In over 80% of patients infected by ehrlichia detectable antibodies develop. Serodiagnostic tests using IFA for both HGE and HME are available. Cross-reactions between

Figure 6 Intracellular inclusion (morulae) in polymorphonuclear leukocytes in human granulocytotropic ehrlichiosis. (Photograph courtesy of Audio Visual Resources, Maine Medical Center.)

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species may occur; therefore, serodiagnostic tests for both species should be done in areas where both vector ticks exist. For HME, a single antibody titer of >256, a fourfold increase in antibody on acute and convalescent sera, or seroconversion represents a positive test finding. Similar criteria, based on laboratory control samples, may be used for HGE, although a single IFA titer of ⱖ80 is considered a positive result. The tests should include both IgM and IgG antibodies. Additional serological tests (ELISA, immunoblot, recombinant protein ELISA) are also now in use. 3.4

Treatment

Doxycycline (100 mg bid for 7 days) is the treatment of choice and is highly effective. Rifampin may have a role in the treatment of pregnant women and children. Quinolones may also be effective, but clinical data are limited. Response to treatment is usually rapid. The persistence of fever or other symptoms in a patient treated for suspected ehrlichosis should lead to consideration of other infectious causes, including opportunistic infection facilitated by HGE or coinfection by other tick-borne agents. 4

BABESIOSIS

Babesia microti is a malaria-like intraerythrocytic protozoon. Human infection was first recognized in the United States in 1969 on Nantucket Island, Massachusetts. A related illness had been previously described in Europe. Early epidemiological studies demonstrated the deer tick was the vector in the eastern United States. Although white tailed deer are not infected with Babesia spp., their proliferation allowed the spread of the deer tick. The nymph and larva tick stages feed on white-footed mice, which serve as the reservoir for Babesia microti. With the spread of deer ticks, babesiosis has been recognized in other northern coastal sites and in Wisconsin. In addition, two newly recognized Babesia species have been reported from splenectomized patients in Washington state, California, and Missouri. Although most cases of babesiosis result from tick bites, a small number of transfusion-acquired cases have been reported. Babesiosis, when symptomatic, is usually a mild disease in the United States, characterized by indolent but recurring fatigue, fever, and malaise. Asymptomatic infection is common. Most symptomatic cases are reported in elderly patients. Physical exam may reveal a relative bradycardia and splenomegaly. Hemolytic anemia and hemoglobinuria may be present. In immunocompromised or splenectomized patients, the infection can become fulminant and life-threatening. Laboratory findings include mild anemia, lymphopenia, and/or thrombocytopenia. Elevations of alkaline phosphatase or transaminase levels are common. Parasitemia of red blood cells usually ranges between 1% and 10%. Coinfection with Lyme disease or HGE may occur. Because symptomatic babesiosis has nonspecific signs and symptoms the disease is often not suspected by physicians. The diagnosis is often first considered when intraerythrocytic inclusions are noted by laboratory personnel examining a Giemsa- or Wrightstained blood smear. Definitive diagnosis can be made by examination of thick and thin blood smears in a similar manner to the diagnosis of malaria. Although intracellular organisms are present in most patients with symptomatic babesiosis, low-level parasitemia may make diagnosis a challenge. The intraerythrocytic inclusions of babesiosis can be distinguished from malaria by the presence of extracellular merozoite and tetrad forms, but these are not always present. Indirect immunofluorescent antibody tests may confirm

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Babesia spp. infection. Patients with active infection usually have serum antibody titers of 1:1024 or greater with a gradual decrease in titer to 1:256 over several months. PCR for Babesia spp. DNA has a high sensitivity when used on blood in acute cases. Many infected patients are asymptomatic or only mildly ill and recover without therapy. Occasionally untreated infection can persist from months to years. Treatment is usually effective, though persistence of parasitemia for several weeks after treatment has been documented. Standard treatment includes the combination of quinine and clindamycin for 7–10 days. Toxicities due to quinine and clindamycin make this regimen difficult. Atovaquone with azithromycin is an alternative, less toxic combination. In patients with severe illness and parasitemias of >5–10%, exchange transfusion has been reported to be an effective adjunct to treatment.

5

ROCKY MOUNTAIN SPOTTED FEVER

Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii, a member of the spotted fever group Rickettsiae. The illness appears misnamed since most infections occur in the south central and southeastern United States. RMSF was first described in Idaho and was not recognized outside the western United States until 1931. It has occurred in all but a few states (see Figure 7). R. rickettsii is an obligate intracellular bacterium that targets endothelial cells and can cause a multiorgan disease through these vasculitic effects. Fatality rates without treatment reach 25%. As its presenting features are those of a nonspecific febrile illness, high suspicion and willingness to start empirical antibiotic treatment are essential in endemic areas. 5.1

Ecological and Epidemiological Characteristics

RMSF is transmitted by the dog tick Dermacentor variabilis in most of the United States except the western mountain states, where the wood tick, Dermacentor andersoni, is the vector (see Figure 8). The ticks serve as both reservoir and vector for R. rickettsii. Although these ticks are ubiquitous in many areas of the United States, RMSF tends to occur regularly in particular geographical foci. Dermacentor spp. ticks, unlike deer ticks, are abundant in grassy open areas as well as brushy habitats. Although R. rickettsii can be transmitted transovarially and from stage to stage in the tick, only the adult Dermacentor spp. ticks bite humans. In Central and South America, other tick genera including Amblyomma and Rhipicephalus spp. are vectors. RMSF may be transmitted by tick bites in <24 hours, and occasional infections have resulted from contact with removed ticks. The average incubation period is 7 days (3–12 days range). The majority of cases occur in the pediatric age group. 5.2

Clinical Manifestations

The clinical presentation is nonspecific with acute onset of fever, often accompanied by headache and myalgias. Nausea, vomiting, and abdominal pain may become prominent. Up to 85% of patients recall a recent tick bite. However, the classic triad of tick bite, fever, and rash is noted in only 3%–18% of first visits to physicians. The rash of RMSF usually appears after 2–5 days of illness; in 85%–90% of adults a rash eventually develops. ‘‘Spotless fever’’ may occur in the elderly or black population. Typical rashes start with a blanching maculopapular eruption around the wrists and ankles that then spreads toward the trunk. Palms and soles are involved in 36%–82% of patients.

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ROCKY MOUNTAIN SPOTTED FEVER AND RELAPSING FEVER Rocky Mountain spotted fever (RMSF) Rickettsia rickettsii Predominantly south central, southeastern, and northwestern United States Clinical presentation Fever, headache Rash after 2–5 days Maculopapular around wrists followed by central spread Palms and soles in 36%–82% May become petechial in 4–5 days Thrombocytopenia Elevated transaminase, creatine kinase (CPK), creatinine levels Diagnosis Immunofluorescent assay (IFA) of skin biopsy sample Polymerase chain reaction (PCR) of rickettsial deoxyribonucleic acid (DNA) in blood Serological findings Treatment Doxycycline Chloramphenicol Relapsing fever Tick-borne; due to Borrelia hermsii Western United States Rustic, rodent-infested settings Clinical presentation Intermittent fever altering with afebrile well-being Headache, arthralgias, myalgias Leukocytosis Elevated bilirubin level Diagnosis Giemsa or Wright stain of blood during febrile period Serological testing not helpful Treatment Doxycycline Penicillin

The rash may become petechial or purpuric at day 4 to 5 and can cause localized gangrene of digits or limbs. Meningoencephalitis may be characterized by headaches and focal neurological deficits. The vasculitic injury of RMSF may lead to acute respiratory disease syndrome (ARDS), cardiac arrhythmia, coagulopathy, and gastrointestinal bleeding. Nonspecific laboratory findings include thrombocytopenia (although usually with a normal white blood cell count), mild transaminasemia, and elevations of creatinine phosphokinase and creatinine levels. If treatment is delayed or the diagnosis not suspected, death may ensue 8–15 days after the onset of illness. Myocarditis is the most common cause of death.

Figure 7 Distribution of reported RMSF in the United States. RMSF, Rocky Mountain spotted fever. (From CDC.)

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Figure 8 Dog tick (Dermacentor variabilis), the vector of RMSF in the eastern United States. RMSF, Rocky Mountain spotted fever. (Photograph courtesy of Audio Visual Resources, Maine Medical Center.)

5.3

Diagnosis

Clinical suspicion of this diagnosis is the key to timely antibiotic treatment. Direct immunofluorescence staining of skin biopsy specimens for detection of the rickettsial agent yields a positive result in 70%–90% of cases. PCR detection of rickettsial DNA in blood has low sensitivity, and isolation of the agent of RMSF from blood or tissue is not an available option. Serological tests (latex agglutination, indirect hemagglutination, indirect immunofluorescence, and enzyme immunoassay) that detect antibodies to specific rickettsial antigens are useful for retrospective confirmation of the diagnosis. The Weil-Felix test is no longer used. 5.4

Treatment

Oral tetracyclines (25–50 mg/kg/day) or chloramphenicol (50–75 mg/kg/day) given in divided doses are effective therapies for RMSF. Doxycycline (100 g bid) has the lowest minimal inhibitory concentration (MIC), against this Rickettsia sp. and is well tolerated. Treatment is usually given for 7 days. Longer courses may be indicated in the event of persistent fever. In one large retrospective study, tetracycline appeared superior to chloramphenicol, but it is contraindicated in pregnancy. Many pediatricians treat children in endemic areas with tetracyclines despite the relative contraindications to their use in pediatric patients. A single short course of doxycycline is highly effective and unlikely to result in toxicity. Severely ill individuals require intensive care unit support for close monitoring of fluid and electrolyte levels and for complications that may occur with multiorgan system involvement.

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617

Prevention

There is no vaccine available for protection against RMSF. Personal protective measures such as use of repellents, avoidance of heavily infested areas, and regular tick checks may be helpful. Ticks should be removed with forceps and not handled directly.

6

RELAPSING FEVER

Tick-borne relapsing fever is another infection due to Borrelia spp. spirochetes. There are 13 species worldwide capable of transmitting this illness. In North America it is limited to the western United States (Borrelia hermsii) and Mexico. It is transmitted by the bite of a soft or argasid tick (Ornithodoros sp.). These ticks bite humans who sleep in rustic, rodent-infested cabins, lean-tos, or other unenclosed structures. The tick bite is brief, painless, and usually unnoticed. Another form of relapsing fever, due to B. recurrentis, is transmitted by the human body louse under circumstances of overcrowding and poor sanitation. It is not discussed further in this chapter. Tick-borne relapsing fever can be recognized by the characteristic fever pattern. The patient has an average of 3 days (range 12 hr to 17 days) of high fever due to spirochetemia followed by several days to a week or more of afebrile well-being (when the spirochetes are sequestered in internal organs). Associated symptoms during these episodes often include headache, stiff neck, arthralgias, and myalgias. Hepatosplenomegaly may be present. Complications may include lymphocytic meningitis, cranial neuritis, radiculopathy, myocarditis, and iridocyclitis. Laboratory evaluation may show leukocytosis and elevations in bilirubin level and erythrocyte sedimentation rate. The diagnosis is confirmed by inspection of a blood smear (Giemsa or Wright’s stain or wet mount) for the spirochetes. The sensitivity of these techniques is 70% during a febrile episode and decreases with relapses. The use of acridine orange stains may improve sensitivity. Centrifugation and examination of a buffy coat may also improve spirochete detection. Phase contrast or dark-field microscopy can detect motile spirochetes. Culture in Kelly’s or Barbour-Stoner-Kelly (BSK) medium may prove successful but requires 2– 3 weeks for growth. Serological assays to date do not have high specificity. Penicillin and tetracycline (doxycycline 200 mg orally once) are effective first-line antimicrobials. As with treatment of other spirochete infections the patient may experience a Jarisch-Herxheimer reaction.

7 7.1

OTHER TICK-BORNE INFECTIONS Tularemia

Tularemia is caused by Francisella tularensis, an aerobic gram-negative coccobacillis. It may be transmitted by tick, fly, and mosquito bites; directly from infected animals such as rabbits, squirrels, beaver, and muskrat; or inhalation of aerosol of infected material. The illness thus has myriad monikers, including rabbit fever. In the south central United States, a significant number of summer cases of tularemia follow transmission by tick bites. Ticks of the Dermacentor (D. andersoni, D. variabilis) and Amblyomma species are the usual vectors. Tularemia may present with a nonspecific febrile illness, pneumonia, or regional lymphadenopathy and ulceration related to inoculation of the bacterium from insect bites or trauma. Patients with tick-borne tularemia often have acute fever and localized lymph-

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adenopathy. A tender ulcerated lesion with a raised border is usually present at the site of the bite. Diagnosis is based on clinical presentation and confirmed by the presence of antibodies to F. tularensis. Serological tests include microagglutination, hemagglutination, and ELISA. A titer of 1:160 or more dilutions coupled with a consistent clinical illness is suggestive of infection. It must be kept in mind, though, that both IgG and IgM titers may remain elevated for many years post infection. Streptomycin is the drug of first choice for treatment, although gentamicin is also effective. Less effective agents include doxycycline and chloramphenicol. 7.2

Colorado Tick Fever

Colorado tick fever is caused by coltivirus, a ribonucleic acid– (RNA)-based virus with worldwide distribution. Colorado tick fever is endemic to the mountainous areas of the western United States where the vector D. andersoni is prevalent. Most cases occur with summertime exposure to ticks at 4,000–10,000 feet. The incubation period is usually 3–4 days. Over 90% of patients recall a tick bite. The illness is self-limited and characterized by abrupt onset of fever, headache, retroorbital pain, nausea, abdominal pain, and photophobia. A biphasic fever pattern persisting for 7–10 days is typical. Physical exam findings may be notable for a rash (5%–12%) and conjunctival injection. Rare cases may be complicated by meningoencephalitis, myocarditis, pericarditis, or atypical pneumonia. Diagnosis may be made during acute illness by direct immunofluoresent staining of infected red blood cells or by isolation from cell culture. Serological antibody test (paired acute and convalescent) results are usually positive. There is no therapy. Tick avoidance measures, as outlined, can help prevent transmission of the virus. 7.3

Powassan Viral Encephalitis

The rarely documented Powassan viral encephalitis has been reported primarily from the northeastern United States and southeastern Canada. The vector tick, Ixodes cookei, is morphologically similar to the deer tick and frequently bites humans in these geographical areas. Powassan encephalitis can be fatal or can result in residual neurological deficits. 7.4

Tick Paralysis

Recognition of the rare disease of tick paralysis by an astute clinician produces one of the most dramatic recoveries in medicine. This neurotoxin-induced disease, associated with an embedded tick, is characterized by an ascending bilateral flaccid paralysis that progresses rapidly. Several species of ticks have been implicated, but those of the genus Dermacentor are most often associated with this disease in the United States. If the offending tick is removed, recovery is rapid. Most cases are reported in children <8 years old. Symptoms usually occur about 5 days after tick attachment. The overall frequency of tick bites in the United States contrasts with the rarity of this disorder. Although a neurotoxin has been implicated, the reason for its expression after tick bites remains to be elucidated. BIBLIOGRAPHY Baaken JS, Krueth J, Wilson-Nardskog C, Tilden R, Asanovich K, Dumler JS. Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA 275:199–205, 1996.

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Clin Infect Dis 31(suppl 1):51–54, 2000. Gerber MA, Shapiro ED, Burke GS, Parcells VJ, Bell GL. Lyme disease in children in southeastern Connecticut: Pediatric Lyme Disease Study Group. N Engl J Med 335:1270–1274, 1996. Krause PJ. Babesiosis. Med Clin N Amer 86:361–373, 2002. Morb Mort Wkly Rep 44:590–591, 1996. Nadelman RB, Wormser GP. Lyme borreliosis. Lancet 352:557–565, 1998. Nadelman RB, Nowakowski J, Forseter G, Goldberg NS, Bittker S, Couper D, Worinser GW. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med 100:502–508, 1996. Nadelman RB, Horowitz HW, Hsieh TC, Wu JM, Aguero-Rosenfeld ME, Schwartz I, Nowakowski J, Varde S, Wormser GP. Simultaneous human granulocytic ehrlichosis and Lyme borreliosis. N Engl J Med 337:27–30, 1997. Philippe P, Raoult D. Ticks and tickborne bacterial diseases in humans: An emerging infectious threat. Clin Infect Dis 32:897–928, 2001. Smith RP, Schoen RT, Rahn DW, Sikand VK, Nowakowski J, Parenti D, Holman MS, Persing OH, Steere AC. Clinical characteristics and treatment outcome of early Lyme disease in patients with microbiologically confirmed erythema migrans. Ann Intern Med 136:421–428, 2002. Steere AC. Lyme disease. N Engl J Med 345:115–125, 2001. Thomer AR, Walker DH, Petri W. Rocky Mountain spotted fever. Clin Infect Dis 27:1353–1360, 1998. Wormser GP, Nadelman RB, Dattwyler RJ et al. Practice guidelines for the treatment of Lyme disease. Clin Infect Dis 31(suppl 1):s1–s14, 2000. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

31 Endemic Fungal and Viral Infections Harold Henderson University of Mississippi Medical Center, Jackson, Mississippi, U.S.A.

1

INTRODUCTION

This chapter focuses primarily on the epidemiological characteristics, clinical manifestations, diagnosis, and treatment of the three major endemic dimorphic mycoses that affect adults in the United States—histoplasmosis, blastomycosis, and coccidioidomycosis. Other common fungal infections, such as cryptococcosis, aspergillosis, mucormycosis, sporotrichosis, and candidiasis, that are found throughout the United States are discussed. The chapter concludes with an overview of the hantavirus pulmonary syndrome and the endemic viral encephalitides most commonly encountered in the United States. 2

ENDEMIC FUNGAL INFECTIONS

Dimorphic fungi grow as round or oval yeasts in the infected individual but as cylindrical hyphae (molds) at room temperature. Other less common dimorphic fungi include the agents of sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, and chromoblastomycosis. The geographical distribution, major clinical syndromes, susceptible hosts, means of diagnosis, and therapy are summarized in Table 1 for histoplasmosis, blastomycosis, and coccidioidomycosis. 2.1

Histoplasmosis

Histoplasma capsulatum is the dimorphic fungus that causes histoplasmosis. Although cases of histoplasmosis have been diagnosed worldwide, it is endemic in the central United States, occurring with increased frequency in the states bordering the Ohio and Mississippi Rivers. The endemic region in the United States extends as far east as Maryland, Virginia, and the Carolinas and as far west as parts of Texas, Oklahoma, and Kansas. The moderate climate and particular soil characteristics found in these parts of the United States presumably account for this distribution. H. capsulatum exists in nature as a mold (hyphae form) growing particularly well in soil mixed with droppings from bats or birds such as starlings or chickens. Chicken coops, caves inhabited by bats, or new construction sites on grounds formerly used as starling or blackbird roosts serve as prime resting sites for this fungus. Physical disturbance of these areas may cause aerosolization of the spores. Infection occurs when airborne 621

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ENDEMIC FUNGAL INFECTIONS Geographical distribution (see Table 1) Histoplasmosis Exposure generally the cause of asymptomatic infection Acute pneumonia Flulike illness Diagnosis by serological testing Generally self-limited Chronic pneumonia More common in patients with chronic lung disease Thick-walled cavities Diagnosis by sputum culture or serological testing Disseminated disease Immune-compromised hosts Fever, weight loss, hepatosplenomegaly Diagnosis by culture, biopsy, serological testing, urinary antigen Blastomycosis Acute flulike illness in 50% Chronic pneumonia Disseminated disease Cutaneous papules, ulcers Osteolytic bone lesions Diagnosis by culture and biopsy Coccidioidomycosis 40% Self-limited flulike illness (valley fever) Acute segmental pneumonia Erythema nodosum and erythema multiforme Disseminated disease Rare Immune compromised hosts, pregnant women, dark-skinned populations Diagnosis by culture, biopsy, serological testing

spores are inhaled and deposited in pulmonary alveoli. Conversion of the organism into the pathogenic yeast form then takes place with phagocytosis by macrophages and dissemination to lymph nodes and organs of the reticuloendothelial system (liver, spleen, and bone marrow). Low-level exposure in healthy persons generally results in asymptomatic or minimally symptomatic pulmonary infection in about 90% of those exposed. Heavier exposure may cause acute and at times severe pulmonary disease. Chronic pulmonary disease may occur in susceptible hosts with preexisting chronic lung disease. Progressive disseminated disease primarily occurs in individuals who are immunocompromised. 2.1.1

Acute Pulmonary Histoplasmosis

Symptomatic pulmonary disease that occurs shortly after a heavy inhalational exposure is referred to as acute pulmonary histoplasmosis. The incubation period is about 10–20 days. A flulike illness with fever, chills, myalgias, cough, headache, and chest pain is characteristic. Physical findings on exam are generally unremarkable except for fever. The chest radiograph often shows bilateral patchy, nodular infiltrates with mediastinal or hilar lymph-

Southwestern United States

Coccidioidomycosis

All

All

Immune compromised African American Hispanic Filipino

Acute pulmonary

Chronic pulmonary

Extrapulmonary (meningitis, skin, bone, joint)

Disseminated

AIDS

Immune compromised AIDS Transplantation Steroids All

Disseminated

Pulmonary; skin, bone, GU tract

All Patients with COPD

Susceptible hosts

Acute pulmonary Chronic pulmonary

Major syndromes

Culture Pathological testing Culture pulmonary secretions Serological tests Culture pulmonary secretions Serological tests Culture Histopathological testing CF

Culture Histopathological testing

CF CF Culture of pulmonary secretions Culture Histopathological testing Histoplasma antigen

Diagnosis

CF, complement fixation; AIDS, acquired immunodeficiency syndrome; GU, genitourinary; COPD, chronic obstructive pulmonary disease.

Mississippi and Ohio River valleys, Great Lakes region

Blastomycosis

a

Mississippi and Ohio River valleys

Geographical distribution

Histoplasmosis

Mycosis

Table 1 Endemic Mycoses of the United Statesa

Meningitis Fluconazole Amphotericin B Nonmeningeal Itraconazole Amphotericin B

Itraconazole Amphotericin B

Amphotericin B Itraconazole

Amphotericin B

Itraconazole

Amphotericin B Itraconazole

None Itraconazole

Usual therapy

Endemic Fungal and Viral Infections 623

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adenopathy. Pleural effusion is uncommon. Less common manifestations include pericarditis, elevations of alkaline phosphatase level, and either leukopenia or leukocytosis. The diagnosis is usually based on a combination of clinical findings and serological testing results. A complement fixation (CF) titer of 1:32 or greater, together with compatible symptoms, is strongly suggestive of acute pulmonary histoplasmosis. The majority of patients with acute pulmonary disease have high titers within 6 weeks. Titers of 1:8 to 1:16 are less helpful since false-positive results in healthy persons and in some individuals with other fungal or granulomatous diseases sometimes fall into this range. The immunodiffusion test may detect precipitating antibodies to the H and M antigens and is more specific than complement fixation. However, it is not particularly sensitive, and precipitins may not be detectable for more than 3 weeks after infection. Isolation of H. capsulatum in the sputum is uncommon. Histoplasma antigen is detected in the urine of only 20% of patients. The large majority of patients with the acute pulmonary syndrome have self-limited disease and do not require antifungal therapy. For patients with mild to moderate disease persisting after 2–4 weeks of observation, treatment with oral itraconazole 200–400 mg daily for 6–12 weeks has been advocated. Patients with more severe symptoms requiring ventilatory support should be treated with amphotericin B. 2.1.2

Chronic Pulmonary Histoplasmosis

In the setting of underlying lung disease, typically chronic obstructive pulmonary disease (COPD), chronic pulmonary histoplasmosis sometimes occurs after exposure to H. capsulatum. Symptoms, which are usually subacute or chronic, include dyspnea, productive cough, and weight loss. The chest radiograph initially has the appearance of an interstitial infiltrate, usually in the lung apices. With progressive disease, thick-walled cavities can form. The differential diagnosis includes tuberculosis and malignancy. Other less common manifestations of chronic disease include formation of a calcified mass (histoplasmoma) and mediastinal fibrosis. The diagnosis is generally made on the basis of a compatible clinical syndrome and the result of either culture of the organism from pulmonary secretions or positive complement fixation titers. The urine antigen test is positive in 40% of patients. The treatment of choice for progressive chronic pulmonary histoplasmosis is itraconazole 200–400 mg daily for at least 6 months. 2.1.3

Disseminated Histoplasmosis

Disseminated histoplasmosis generally occurs in the presence of immunosuppression. Acquired immunodeficiency syndrome (AIDS), organ transplantation, chronic use of steroids or other immunosuppressive therapy, and lymphoma are common predisposing conditions, although on occasion, disseminated disease may develop in normal hosts. Fever, fatigue, and weight loss are the most common symptoms. Nausea and diarrhea are also common. Ulcerations in the mouth or other parts of the gastrointestinal tract or larynx may occur. Examination may reveal hepatosplenomegaly and rales or rhonchi if pulmonary involvement is present. Bone marrow involvement causing anemia, leukopenia, and/or thrombocytopenia is common. Liver and renal function test results may also be abnormal. The diagnosis of disseminated disease may be made by biopsy with histopathological evidence of H. capsulatum in tissue or culture of the organism from tissue specimens. Specimens for biopsy and culture are most commonly taken from the bone marrow, liver, lung, and gastrointestinal tract. Blood cultures are frequently positive, particularly if lysis centrifugation bottles are used. A Wright’s stain of peripheral blood may reveal intracellular

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yeasts on occasion, especially in persons with AIDS. Detection of the polysaccharide antigen of H. capsulatum from serum or urine is also diagnostic of disseminated infection (the urine antigen test is particularly sensitive) and is available commercially from the Histoplasmosis Reference Laboratory in Indianapolis. Tuberculosis and disseminated infections with other fungi may mimic disseminated histoplasmosis, and these conditions must be ruled out. Disseminated histoplasmosis is life-threatening, and treatment is always indicated. Patients with mild to moderate disease not requiring hospitalization who are human immunodeficiency virus (HIV)-negative may be treated with itraconazole 200–400 mg daily for at least 6 months. HIV-negative patients with more severe disease requiring hospitalization should be treated with amphotericin B. Patients with AIDS and disseminated disease requiring hospitalization should be treated initially with amphotericin B. Amphotericin can be stopped and replaced by itraconazole 200 mg bid for 12 weeks once sufficient improvement to eliminate the need for intravenous therapy has occurred. Patients with AIDS and mild disease not requiring hospitalization can be treated with itraconazole alone, 200 mg tid initially for 3 days, then 200 mg bid for 12 weeks. After the 12-week induction period, persons with AIDS should be continued on itraconazole 200 mg daily as chronic maintenance to prevent relapse. 2.2

Blastomycosis

Blastomycosis is caused by infection with Blastomyces dermatitidis, a dimorphic fungus that may be found in soil enriched by decaying vegetation. The endemic area for blastomycosis in North America includes states along the Mississippi and Ohio Rivers, states and Canadian provinces in the Great Lakes region, and an area of New York and Canada bordering the St. Lawrence River. Clinical disease is most commonly due to chronic infection of the lungs, although extrapulmonary disease with skin, bone, and genitourinary manifestations is also common. After exposure, acute symptomatic disease occurs in less than 50% of persons. The presentation is a flulike illness that occurs 30–45 days after exposure. Chronic pneumonia with a productive cough, chest pain, and weight loss is a typical presentation of blastomycosis. The appearance of the chest radiograph may range from alveolar infiltrates to mass lesions to nodular infiltrates with or without cavitation that can appear similarly to malignancy, tuberculosis, or other fungal infections. Cutaneous lesions are the most common extrapulmonary forms of blastomycosis. They typically appear initially as papules or pustules often on the face or extremities that may evolve over a period of weeks to form larger verrucous, crusted, or ulcerative lesions. Bony lesions are osteolytic and usually involve the long bones, vertebrae, or rib and have been reported in up to 50% of patients. Genitourinary tract disease such as epididymitis, prostatitis, or orchitis has been reported in up to 30% of patients. Central nervous system (CNS) disease occurs uncommonly. Immunocompromised patients such as those with AIDS or transplantation recipients may infrequently have widely disseminated overwhelming infection and are at risk for life-threatening disease. A presumptive diagnosis of blastomycosis may be made by visualization of the characteristic broad-based budding yeast forms in clinical specimens such as sputum, pus, skin scrapings, or tissue obtained with biopsy. Serological tests such as complement fixation and immunodiffusion lack sensitivity and specificity and are often not helpful in making the diagnosis. Definitive diagnosis requires growth of B. dermatitidis in culture. Itraconazole is highly effective in the treatment of patients with non-CNS, non-lifethreatening blastomycosis and is better tolerated than ketoconazole. It has become the

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treatment of choice for mild to moderate disease. Patients should receive a minimum 6month course of itraconazole 200–400 mg/day. Of these patients 90% are cured. Patients with life-threatening infection should be treated with a full course of amphotericin B (at least 2 g), although a switch to itraconazole for completion of antifungal therapy after clinical stabilization is advocated by many clinicians for selected patients. Immunocompromised patients should be treated with a full course of amphotericin B. Alternatively, they can be treated with an initial course of amphotericin B followed by oral itraconazole as noted once clinical stabilization has occurred. The penetration of itraconazole across the blood-brain barrier is poor, so patients with CNS disease should be treated with a full course of amphotericin B. Chronic suppressive therapy with itraconazole in persons with AIDS and blastomycosis is recommended to prevent relapse. 2.3

Coccidioidomycosis

Coccidioides immitis is different from other dimorphic fungi as it forms spherules instead of the usual yeast form within the host. On maturation in the lung, these spherules develop daughter progeny (endospores) that are released at rupture of the spherule. Infection with C. immitis is endemic in the arid regions of the southwestern United States, Mexico, and parts of Central and South America. Patients who have traveled to or who have resided in endemic areas may have coccidioidomycosis years after acquisition of the original infection. This is especially true of those who are immune-compromised. A thorough travel history is thus critical in the evaluation of persons with a febrile illness of unknown cause. Infection occurs on inhalation of the spores of C. immitis. In most persons, it is usually subclinical and self-limited. About 40% of patients have flulike symptoms 1–3 weeks after exposure with fever, malaise, anorexia, cough, or pleuritic chest pain. This is so-called valley fever, which has an increased incidence in the San Joaquin Valley of California. Some patients experience arthralgias and an erythematous maculopapular rash. Fewer than 25% of patients have erythema nodosum or erythema multiforme. The most common chest radiograph finding is a segmental pneumonia. Hilar lymphadenopathy and pleural effusions occur less commonly. Nodules or cavities may also be seen. Respiratory failure with diffuse lung injury is less common, as is the development of nodules and cavities. Patients may have eosinophilia. The large majority of persons with primary coccidioidal infection recover without antifungal therapy. Occasionally, symptoms of chronic pneumonia persist for months or years. Extrapulmonary (disseminated) disease develops in <1% of infected persons. Those at highest risk are immunocompromised hosts (patients with AIDS or lymphoma, transplantation recipients, or those receiving immunosuppressive therapy), pregnant women, and dark-skinned persons such as Filipinos, Hispanics, and African Americans. The most common sites for dissemination are the bones and joints, skin, and meninges. Lytic lesions of the skull, vertebrae, and bones of the hands and feet are the most common forms of osteomyelitis; joint infection usually involves the knee or ankle. Skin lesions vary in appearance from pustules to wartlike nodules. Meningitis usually appears subtly with fever, headache, and weight loss. Examination of the cerebrospinal fluid usually reveals a mononuclear pleocytosis and an elevated protein level. The diagnosis of coccidioidomycosis generally involves culture or serological tests. The organism may sometimes be cultured from sputum or pulmonary secretions obtained via bronchoscopy of patients with pulmonary disease or be seen on histopathological specimens obtained from the lung. Alternatively, serological tests are often diagnostic in pulmonary disease. Serum precipitins are immunoglobulin M (IgM) antibodies detectable

Endemic Fungal and Viral Infections

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in more than 75% of patients within 3 weeks of the onset of pulmonary symptoms but usually cannot be detected after 4 weeks. Complement fixation detects IgG, which develops later (usually by 3 months) and persists longer than do the precipitins. Most positive CF titers in chronic pulmonary disease are less than 1:32. Complement fixation titers of 1:32 or higher are quite common in disseminated infection. The exception is meningitis, in which serum CF titers are much lower, resembling those seen in pulmonary disease. Detectable CF titers in the spinal fluid of patients with meningitis are present in more than 75% of patients. An enzyme-linked immunoassay for IgG and IgM is commercially available. Skin testing has limited application for clinical diagnosis. Definitive diagnosis of disseminated coccidioidal infection may be made by culture or histopathological evidence of the organism from infected sites such as skin or synovial fluid. CSF cultures are positive in only about one-third of cases of meningitis. In most patients, acute pulmonary coccidioidomycosis resolves without treatment. Antifungal therapy should be considered if symptoms persist for more than 6–8 weeks, CF titers remain persistently high (>1:16) or in the presence of the conditions noted previously that predispose to dissemination. Progressive pulmonary disease and disseminated nonmeningeal infections have traditionally been treated with lengthy courses of amphotericin B, which remains the treatment of choice for patients with severe, rapidly progressive disease. However, itraconazole (200 mg bid for 6 months or more) is an effective oral alternative. It is now used often by experienced clinicians instead of amphotericin B for slowly progressive infections or after an initial induction with amphotericin B in persons with more serious disease. Treatment of meningitis has relied in the past on intrathecal amphotericin B, but more recently prolonged therapy with oral fluconazole 400 mg daily has yielded encouraging results and has become the preferred treatment. Treatment of all forms of coccidioidal infection is challenging, and consultation with an experienced infectious disease consultant is advisable.

3

OTHER COMMON FUNGAL INFECTIONS

3.1

Cryptococcosis

Cryptococcus neoformans, in contrast to the dimorphic fungi discussed so far, grows only in a yeast form. Found worldwide, C. neoformans generally causes disease after its inhalation. Many patients with cryptococcal infection are immunologically normal. Persons receiving chronic steroid therapy or those with immunosuppressive conditions are at highest risk. Pulmonary infection and meningitis are the most common forms of infection, although skin, joint, and bone involvement can occur. Patients may have a concomitant fungemia with the infection. Definitive diagnosis is by culture or histopathological identification of the organism. Antigen detection in serum or spinal fluid can aid in the diagnosis. Serological tests are not useful clinically. 3.1.1

Pulmonary Disease

Pulmonary infection is often asymptomatic. Symptomatic infection with cough, fever, dyspnea, and chest pain may occur. Chest radiograph findings range from isolated nodules to focal or diffuse infiltrates. The differential diagnosis includes the endemic mycoses, mycobacterial infection, and malignancy. Diagnosis of pulmonary cryptococcosis usually requires culture or histopathological evidence of the organism from specimens obtained via bronchoscopy or lung biopsy.

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Sputum cultures are insensitive. A lumbar puncture should be performed for patients with pulmonary infection to rule out meningitis. Many immunocompetent hosts with pulmonary cryptococcosis have recovered without treatment. Symptomatic disease or infection in an immunosuppressed host requires antifungal therapy. Mild to moderate disease in HIV-negative persons may be treated with oral fluconazole 200–400 mg daily for 6 months or more. Fluconazole should be continued indefinitely in the setting of HIV disease. Severe pulmonary disease should be treated with amphotericin B. 3.1.2

Meningitis

Patients with meningitis may report acute symptoms of fever, headache, and altered mental status of a few days’ duration. Others may have a more subacute to chronic illness for weeks or months. The majority of cases of cryptococcal meningitis currently occur in persons with AIDS who often have an acute presentation. Patients with meningitis usually have elevated cerebrospinal fluid (CSF) protein level or a lymphocytic pleocytosis. Persons with AIDS-related cryptococcal meningitis may have a limited pleocytosis, which has been associated with a poorer prognosis. An India ink smear of the CSF may show yeast forms. The CSF cryptococcal antigen test is positive in more than 90% of cases. Many patients with meningitis also have a positive serum cryptococcal antigen result. Definitive diagnosis requires growth of the organism in CSF culture. Immunocompetent patients with meningitis may be treated with a full course of amphotericin B with or without flucytosine, or with amphotericin B initially followed by fluconazole 400 mg daily for 8 weeks or more. Immunosuppressed HIV-negative patients are treated similarly but with more prolonged courses of fluconazole. Patients with AIDS and cryptococcal meningitis are generally treated with an initial period of amphotericin B followed by fluconazole indefinitely. Treatment of cryptococcal meningitis is complex, and consultation with an infectious disease specialist is advisable. 3.2

Sporotrichosis

Sporothrix schenckii is found worldwide although more commonly in tropical or subtropical areas. It has been isolated most commonly from the soil and on various types of vegetation. Infection usually results from cutaneous inoculation after contact with thorny plants. Cutaneous disease is the most common form and usually manifests as erythematous, subcutaneous nodules on the hands and/or arms. Spread may occur along lymphatic routes, causing a series of painless nodules. Pulmonary and other extracutaneous forms occur but are uncommon. In patients with AIDS, dissemination can occur. Culture or histopathological examination of drainage or tissue specimens is needed for diagnosis. The preferred treatment of cutaneous sporotrichosis is itraconazole 100–200 mg daily for 3–6 months. A saturated solution of potassium iodide (SSKI) can be used if itraconazole is contraindicated. 3.3

Aspergillosis

Aspergillus species are ubiquitous molds found in all parts of the world. They are common laboratory contaminants. Invasive infection most commonly involves the lungs in hospitalized immunosuppressed hosts with prolonged neutropenia. Allergic bronchopulmonary aspergillosis (ABPA) is seen in ambulatory settings and results from a hypersensitivity response by the airways to Aspergillus sp. antigens present in the bronchial tree. ABPA is characterized by recurrent episodes of bronchospasm with wheezing, cough, dyspnea, and

Endemic Fungal and Viral Infections

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fleeting infiltrates on chest radiograph. The diagnosis is suggested by typical clinical findings in combination with peripheral eosinophilia, elevated serum IgE levels, and positive serum Aspergillus sp. precipitin results. Steroids remain the mainstay of therapy. Itraconazole may be useful as a steroid sparing agent. 3.4

Mucormycosis

The term mucormycosis refers to infection due to fungi of the order Mucorales (Absidia, Mucor, Rhizomucor, and Rhizopus spp.). These organisms may cause severe, rapidly progressive invasive disease with a high mortality rate. Common predisposing conditions include diabetes mellitus, leukemia, lymphoma, and chronic steroid use. Rhinocerebral infection with invasion of the sinuses and subsequent extension into the brain is characteristic. The diagnosis usually is made by tissue biopsy. Immediate treatment with amphotericin B and surgical de´bridement are indicated. 3.5

Candidiasis

Candida species are common causes of dermal and mucocutaneous infections. Cutaneous candidiasis tends to occur in intertriginous areas such as the axillary, inguinal, and perianal regions. It appears as erythematous papules or macules that are highly pruritic and may become confluent. Erythematous ‘‘satellite lesions’’ around the primary rash are common. Nail infections in the form of paronychia and onychomycosis occur as well. Topical antifungal agents such as nystatin or miconazole are generally effective for mild to moderate skin infections. More severe skin infections, particularly in the setting of AIDS or diabetes mellitus, may require systemic therapy with oral itraconazole or fluconazole. See Chapter 19 for further discussion of cutaneous candidiasis, onychomycosis, and cutaneous infection with dermatophytes. Oral and vulvovaginal candidiasis are common mucosal infections. 3.5.1

Oral and Esophageal Disease

Oral candidiasis (thrush) may sometimes occur in normal hosts such as denture wearers but more often is seen in the setting of predisposing factors such as antibiotic or steroid use, diabetes mellitus, malignancy, and especially HIV infection (also see Chapter 11). Thrush most commonly appears as raised, white plaques on the tongue, buccal mucosa, or posterior oropharynx. Oral candidiasis may be treated effectively in many patients with the nystatin oral suspension 5 mL qid or clotrimazole troches qid for 7–10 days. These agents are generally less expensive than the oral azoles. Therapy with oral fluconazole and itraconazole 100–200 mg daily for 7 days is usually very effective and should be used particularly in refractory cases. Esophageal candidiasis generally occurs in immunosuppressed hosts such as those with AIDS. Dysphagia is the most common symptom. Most patients have oral candidiasis on exam. Topical therapy is not effective in esophageal disease. Systemic therapy with an oral azole, usually fluconazole 100–200 mg daily for 10-14 days, is required. 3.5.2

Vulvovaginal Candidiasis

Vulvovaginal candidiasis is a common infection, which usually causes perivaginal pruritis and discharge (also see Chapter 15). A wet mount of vaginal discharge treated with 10%– 20% KOH reveals yeasts in more than 50% of infected women with vaginitis. Treatment may be with topical creams, tablets, or suppositories such as miconazole or clotrimazole, commonly given in 3- to 7-day regimens. Single-dose oral fluconazole 150 mg is also

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ENDEMIC VIRAL INFECTIONS Geographical distribution (see Table 2) Encephalitis Ribonucleic acid (RNA) viruses transmitted from animal by mosquito bite Fever, headache, altered mental status Mononuclear pleocytosis and elevated protein level in spinal fluid Diagnosis by serological testing Supportive therapy only Hantavirus pulmonary syndrome Exposure to mouse excreta Acute onset of fever, myalgia, progressive respiratory failure Consider in patients with unexplained acute respiratory distress syndrome (ARDS) Diagnosis by serological testing Supportive therapy only

effective. Women with frequently recurring vaginitis or infection refractory to topical therapy should be tested for HIV infection. Disseminated candidiasis has become a common nosocomial infection, which occurs primarily in severely ill hospitalized patients in an intensive care unit setting, those with prolonged neutropenia, and indwelling central venous catheters. A discussion of this potentially lethal infection is beyond the scope of this book. 4 4.1

ENDEMIC VIRAL INFECTIONS Encephalitis

Viral encephalitis endemic within the United States is caused by ribonucleic acid (RNA) viruses transmitted from their animal hosts to humans by mosquitoes. They are limited geographically by the range of their mosquito vectors (Table 2). The eastern equine encephalitis (EEE) and western equine encephalitis (WEE) viruses were originally isolated from the brains of horses with encephalitis. EEE is most common in the Great Lakes region and in the states along the Atlantic and Gulf Coasts. WEE is most common in the western United States. Most cases of LaCrosse encephalitis (the most common form of California encephalitis) have been identified in the midwestern and eastern states. Cases of St. Louis encephalitis (StLE) have been reported throughout the United States. These are uncommon infections overall and have been declining in frequency. StLE was responsible for more than 50 outbreaks from 1933 to 1990. It is the most important cause of epidemic encephalitis in the United States. Those with viral encephalitis typically experience fever, headache, and altered mental status, which can vary from mild lethargy to confusion and coma. Focal neurological signs may be present and seizures may occur. CSF examination reveals a mononuclear pleocytosis (10–2000 cells/mm3) with an elevated protein but a normal glucose level. Outbreaks tend to occur in the late summer and fall. Severe disease is most common in the elderly. The differential diagnosis includes bacterial meningitis, aseptic meningitis, and herpes encephalitis. Diagnosis is by serological testing. There is no specific therapy for the endemic viral encephalitides and treatment is entirely supportive. The most common

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Table 2 Endemic Viral Infections of the United States Disease Eastern equine encephalitis (EEE) Western equine encephalitis (WEE) LaCrosse encephalitis St. Louis encephalitis West Nile virus encephalitis Hantavirus pulmonary syndrome

Geographical distribution Great Lakes region, Atlantic and Gulf Coasts Western states Midwestern states Throughout the United States New York City area, eastern seaboard, Midwest, West Mainly southwestern United States

Transmission to humans

Clinical syndrome

Mosquito bite

Encephalitis

Mosquito bite

Encephalitis

Mosquito bite Mosquito bite

Encephalitis Encephalitis

Mosquito bite

Encephalitis

Inhalation of aerosols from rodent saliva, urine, feces

Adult respiratory distress syndrome

treatable form of sporadic viral encephalitis, herpes virus type 1 infection, is discussed in Chapter 2. In August 1999, an outbreak of encephalitis occurred in New York City. Cases were characterized by fever, myalgias, altered mental status, muscle weakness, and, in some, progressive paralysis. The causative agent was ultimately determined to be the West Nile virus (WNV), a mosquito-transmitted flavivirus with an avian reservoir. It had previously been found only in Europe, Africa, and Asia. Sixty-two cases of WNV encephalitis were documented, with 7 deaths. Serological testing indicated infection in over 1000 persons in the New York area, most with asymptomatic disease. Most severe cases occurred in the elderly, and the median age of persons with encephalitis was 71. Further investigation resulted in isolation of the virus in birds (mostly crows) in several northeastern states, including New York, New Jersey, Connecticut, Massachusetts, and Rhode Island. By September 2000, the WNV was again being isolated from birds in the same geographical region. It appears that the WNV has established endemicity in New York City and surrounding areas. It is expected to spread to states up and down the eastern seaboard, the Midwest, South, and the West. 4.2

Hantavirus Pulmonary Syndrome

Hantaviruses are RNA viruses that had formerly been associated with hemorrhagic illnesses and renal failure. The hantavirus pulmonary syndrome (HPS) was initially recognized in the United States in 1993 when an outbreak of febrile illnesses with respiratory failure occurred in the Four Corners area of Utah, Colorado, Arizona, and New Mexico. More than 90% of diagnosed cases of HPS have since occurred in states west of the Mississippi River, more than half in the southwestern United States. There has been a case reported in northern Vermont. The agent of the 1993 outbreak was a previously unknown hantavirus now referred to as the Sin Nombre virus. At least two other newly discovered hantaviruses have been associated with HPS in other areas of the United States. Rodents are the animal reservoirs of hantaviruses; the deer mouse is the primary reservoir of the Sin Nombre virus. The mode of transmission to humans is thought to be

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via exposure to aerosolized rodent excreta. Clinical manifestations consist of an abrupt febrile illness with headache, myalgias, and abdominal discomfort progressing rapidly (within 3–5 days) to the adult respiratory distress syndrome (ARDS) with hypotension, thrombocytopenia, and noncardiogenic pulmonary edema. The key to diagnosis is a high level of suspicion. All cases of acute unexplained ARDS in a previously healthy person with no predisposing condition should be suspected of indicating HPS. Members of the state health department and the Centers for Disease Control and Prevention (CDC) should be contacted to help assist with hantavirus testing. Diagnosis is by serological testing. There is no specific therapy for HPS, and treatment is entirely supportive. The mortality rate in the 1993 Four Corners outbreak was 60%. BIBLIOGRAPHY Anderson J, Andreadis T, Vossbrinck C, et al. Isolation of West Nile virus from mosquitoes, crows, and a Cooper’s hawk in Connecticut. Science 286:23331–2337, 1999. Dismukes W, Bradsher R, Cloud G, et al. Itraconazole therapy for blastomycosis and histoplasmosis. Am J Med 93:489–497, 1992. Johnson R. Acute encephalitis. Clin Infect Dis 23:219–226, 1996. Kauffman C. Old and new therapies for sporotrichosis. Clin Infect Dis 21:981–985, 1995. Khan A, Khabbaz R, Armstrong L, et al. Hantavirus pulmonary syndrome: The first 100 cases. J Infect Dis 173:297–303, 1996. Rex J, Walsh T, Sobel J, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis 30:662–678, 2000. Saag M, Graybill R, Larsen R, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 30:710–718, 2000. Stevens D. Coccidioidomycosis. N Engl J Med 16:1077–1082, 1995. Stevens D, Schwartz H, Lee J, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 342:756–762, 2000. Wheat J, Sarosi G, McKinsey K, et al. Practice guidelines for the management of patients with histoplasmosis. Clin Infect Dis 30:688–695, 2000.

32 Common Manifestations of Parasitic Infections Sampath Kumar and Gordon M. Trenholme Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois, U.S.A.

1

INTRODUCTION

With increased international travel, immigration, outbreaks of food- or water-borne parasitic infections, and the pandemic of the acquired immunodeficiency syndrome (AIDS), the spector of parasitic infections will loom larger in the day-to-day practice of all health care providers. This chapter focuses on the evaluation of the patient who has the most common symptoms or signs of parasitic infections seen in people living in industrialized nations: peripheral blood eosinophilia, diarrhea, rashes, and the visualization of worms in stool. In addition, helminthic infections still endemic in the United States are reviewed. Other relevant chapters in this book include Chapter 2, Chapter 8, Chapter 22, Chapter 30, and Chapter 40. An overview of parasite classification is presented in Table 1. 2

EOSINOPHILIA

Eosinophiia is defined as >500 eosinophils per microliter of blood. The causes are multiple and diverse (see Table 2). Eosinophil counts greater than 10% of the white blood cell differential are almost always associated with either drug reactions, helminthic infections (intestinal parasitic worms), or a primary eosinophilic disorder. Primary eosinophilic disorders are associated with normal serum immunoglobulin E (IgE) levels, whereas parasite disorders characteristically have very high serum IgE levels. Eosinophilia associated with helminthic infections suggests tissue invasion. Helminths confined to the bowel lumen may not have any associated eosinophilia. Generally the level of eosinophilia tends to correlate with the extent of tissue invasion by helminthic larvae or the adult worm. However, helminths that dwell in tissues chronically may not be associated with eosinophilia. In evaluating a patient with eosinophilia from a parasitic infection, a careful history and physical examination may yield the likely cause. The history should focus on occupational, dietary, and recreational exposures, especially in those who have traveled to rural areas in underdeveloped countries (Table 3). A history of contact with fresh water may suggest schistosomiasis, either human (Schistosoma mansoni, S. japonica, S. haematobium, S. mekongi) or avian (swimmer’s itch, Trichobilharzia spp.). Walking barefoot in sand or soil is a risk factor for acquiring cutaneous (Ancylostoma braziliense, dog hookworm) or vis633

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EOSINOPHILIA Noninfectious causes (see Chapter 8) >500 Eosinophils/␮L blood (see Table 2) >10% Eosinophilia Tissue-invasive parasites Hookworm and cutaneous larva migrans Ascariasis and visceral larva migrans (toxocariasis) Schistosomiasis Stronglyloidiasis Trichinosis Filariasis Echinococcosis Drug reactions Primary eosinophilic disorders Parasitic infections Occupational and travel history (see Table 3) Skin exam (see Table 4) Elevated immunoglobulin E (IgE) level Stool ova and parasite exam

ceral (Toxocara canis or cati, dog or cat ascarid) larval migrans syndromes or strongyloidiasis. Exposure to insects may suggest filariasis (infections due to tissue dwelling nematodes such as Wucheria bancrofti and Brugia malayi). Unsatisfactory preparation of foods, particularly salads, has been linked to cysticercosis (tissue infection with larval cysts of the tapeworm Taenia solium) and fascioliasis (infection with the liver fluke Fasciola hepatica). Ingestion of snails, slugs, freshwater crabs, or shrimp suggests angiostronylosis (abdominal pain, right lower quadrant mass due to Angiostrongylus costaricensis or A. cantonensis). Ingestion of poorly cooked pork or large wild mammals may be linked to trichinosis (fever and myalgia due to infection with the tissue roundworm Trichinella spiralis). Physical examination should be directed to the involved organ system. Cutaneous lesions are often the first sign of parasitic infection (see Table 4). Skin rash is seen with cutaneous larva migrans syndromes. Skin thickening syndromes, subcutaneous nodules, and lymphatic enlargement are seen with filariasis. Wheezing and shortness of breath occur with tropical pulmonary eosinophilia. Muscle swelling and periorbital edema are symptoms of trichinosis. Diagnostic tests are limited. Stool exam for parasitic ova and larva may be useful in schistosomiasis, strongyloidiasis, fascioliasis, hookworm, enterobiasis, and ascariasis (roundworm, Ascaris lumbricoides). Biopsy of subcutaneous nodules may be diagnostic for onchocerciasis (river blindness caused by Onchocerca volvulus). Generally serological tests indicate prior exposure and are not useful for patients from endemic areas. Peripheral blood smears and skin snips may help in detecting microfilaria due to infection with Wucheria sp. or Brugia sp. filariasis.

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Table 1 Parasite Classification Protozoa

Helminths (worms)

Amoebae Entamoeba histolytica (amebiasis), E. hartmani, E. coli, Endolimax nana Free-living amoebae Acanthamoeba, Naegleria spp. Flagellates Giardiasis Trichomoniasis Blood/tissue flagellates Leishmaniasis Trypanosomiasis Babesiosis Cilophora Balantidium Coccidia Toxoplasmosis Cryptosporidiosis Isosporiasis Cyclosporiasis Sarcocystis Blastocystis Plasmodium (malaria) Babesiosis Microsporidia

Intestinal nematodes (roundworms) Trichuriasis (whipworm) Enterobiasis (pinworm) Strongyloidiasis (threadworm) Hookworm: Necator, Ancylostoma spp. Animal hookworm (cutaneous larva migrans), Ancylostoma braziliense Ascariasis (giant intestinal worm) Animal ascarids (visceral larva migrans): Toxocara canis, T. cati Tissue nematodes (filaria) Wucheria Brugia Onchocerciasis (river blindness) Loa loa Dracunculus Trichinosis Cestodes (tapeworms) Cysticercosis; Taenia solium and T. saginata Echinococcosis Hymenolepis Diphyllobothriasis Trematodes (flatworms or flukes) Schistosomiasis Clonorchiasis Fascioliasis Paragonimiasis

Table 2 Differential Diagnosis of Eosinophilia Allergy Asthma Allergic rhinitis Drug reactions Food allergy Insect bites Invasive helmintic parasites Hookworm and cutaneous larva migrans Ascariasis and viseral larva migrans (toxocariasis) Schistosomiasis Strongyloidiasis Trichinosis Filariasis Echinococcosis

Skin disorders Eczema Acute urticaria Pemphigoid Pemphigus Malignancy Lymphoma Acute myelogenous leukemia Mycosis fungoides Carcinoma of lung, stomach, pancreas, ovary Angioimmunoblastic lymphadenopathy

Collagen vascular disease Systemic lupus erythematosus (SLE) Rheumatoid arthritis Polyarteritis nodosa Allergic angiitis Miscellaneous Job’s syndrome Churg-Strauss syndrome Loeffler’s syndrome Chronic granulomatous disease Hypoadrenalism Eosinophic gastroenteritis Hypereosinophilic syndrome

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Table 3 Eosinophilia Secondary to Helminthic Parasitic Disease (Eosinophilia ⱖ3,000/(␮L) Exposure Raw or lightly cooked snails, slugs, freshwater crabs, or prawns or unwashed vegetables

Barefoot contact with soil

Parasite

Eosinophilia present/clinical syndrome

Angiostrongylus cantonensis

Larva migration into the brain; meningoencephalitis

Angiostrongylus costaricensis

All stages of infection; abdominal pain, fever, appendicitis Early transpulmonary larval migration mild in mature worms; pulmonary infiltrates, iron deficiency anemia Early transpulmonary larval migration pronounced during hyperinfection syndrome; pulmonary infiltrates Pronounced during stage of encystment of larvae in muscles; fever, myalgia, periorbital edema Visceral larva migrans; fever, cough, hepatomegaly, or asymptomatic Only during early transpulmonary larval migration; pulmonary infiltrates During early infection in nonimmune hosts; fever, cough, hepatosplenomegaly, lymphadenopathy (Katayama fever) Parasite migration in soft tissues; cutaneous larva migrans, meningitis Severe infestation of large bowel; iron deficiency anemia, rectal prolapse Asymptomatic or during acute phase of disease; may be absent in chronic disease; lymphangitis, fever, orchitis, tropical pulmonary eosinophilia Raised serpiginous pruritic rash (cutaneous larva migrans) Early phase of localization in biliary tract; asymptomatic, cholangitis Migration of adult worms into liver with heavy infestation; fever, hepatomegaly, right upper quadrant pain

Hookworm

Strongyloides stercoralis

Ingestion of undercooked pork or meat of wild carnivores

Trichinella spiralis

Geophagic children

Toxocara canis and T. cati Ascaris lumbricoides

Freshwater exposure

Schistosoma spp.

Ingestion of improperly cooked fish, frogs, birds, and snakes Uncooked vegetables from gardens fertilized with human excreta Insect bites in Southeast Asia

Gnathostoma spinigerum

Trichuris trichiuria

Brugia malayi, Wucheria bancrofti

Dog or cat feces

Ancylostoma braziliense

Ingestion of raw fish

Clonorchis sinensis

Consumption of aquatic plant in tropical area

Fasciola hepatica

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Table 4 Cutaneous Lesions Associated with Parasites Clinical syndromes Severely pruritic serpiginous tract (cutaneous larva migrans) Pruritic erythematous rash on exposed areas Pruritic follicular dermatitis Subcutaneous swelling, worm migration across conjunctiva, large hives Pruritis with maculopapular rash, predominantly on buttocks and back; lesions potentially hyperkeratotic and severely pruritic Chronic lymphadema, acute lymphangitis with fever, orchitis, funiculitis Subcutaneous nodules, painless fixed nodules around bony prominences; also chronic pruritic dermatitis, lymphadema Painful erythematous papule or furuncle with opening for fly maggot (myiasis) Painless ulcer, raised edges, slow healing on face, limbs Perianal and perineal nocturnal pruritus

3

Exposure/contact Skin exposed to contaminated soil

Cause

Geographical locale

Ancylostoma spp., Gnathostoma spinigerum Strongyloides spp.

Worldwide, tropics

Avian schistosomiasis Loa loa

North American Great Lakes Northern West Africa

Simulium fly bite

Onchocerca volvulus

Central and West Africa, Latin America, and Arabian peninsula

Mosquito bite

Brugia malayi, Wucheria bancrofti

Southeast Asia

Blackfly (Simulium sp.) bite Skin exposed to contaminated soil

Onchocerca volvulus

Rural Africa, Central and South America

Fly bite transmitting larvae (ecoparasite)

Dermatoba hominis (botfly), Cordylobia anthrophaga (tumba fly) Leishmania spp.

Skin exposed to contaminated soil Skin exposed to contaminated water Fly (Chrysops spp.) bite

Sandfly bite

Person-to-person in families and institutions

Worldwide, tropics, and subtropics

Gnathostoma spinigerum

Enterobius vermicularis

Central and South America, Africa

Africa, Central and South America, Middle East Children, worldwide

DIARRHEA

Diarrhea that lasts for more than 1 week or acquired during international travel should prompt a search for a parasitic infection. Most commonly, these infections are acquired from contaminated food or water. Diagnosis is generally by stool exam for ova and parasites. Treatment is available for the majority of infections (see Table 5). The most commonly encountered parasites include Giardia lamblia, Entamoeba histolytica, Cryptospor-

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DIARRHEA (Also see Chapter 22 and Chapter 39) Generally chronic May be associated witih weight loss, steatorrhea, nausea, abdominal pain, flatulence Giardiasis Amebiasis Also acute proctocolitis Hepatic abscess, ameboma Cryptosporidiosis, cyclosporiasis, isosporiasis, microsporidia, balantidiasis, Blastocystis hominis More common in immune compromised patient Diagnosis by stool ova and parasite or antigen detection May need samples on 3 different days Therapy (see Table 5)

Table 5 Treatment of Intestinal Protozoa Intestinal protozoon Giardiasis

Treatment Metronidazole 2 g/day ⫻ 3 days or 250 mg tid ⫻ 7 days or paromomycin 10 mg/kg tid ⫻ 5–10 days

or albendazole 400 mg/day ⫻ 5 days Amebiasis Asymptomatic cysts

Invasive colitis

Cryptosporidiosis

Cyclosporiasis Isoporiasis Microsporiasis a b

Iodoquinol 650 mg tid ⫻ 20 days or paromomycin 10 mg/kg tid ⫻ 5–10 days

or metronidazole 750 mg tid ⫻ 10 days metronidazole 750 mg IV/PO tid ⫻ 5–10 days then iodoquinol or paromomycin as above Paromomycin 500 mg tid ⫻ 7 days or azithromycin 600 mg/day ⫻ 4 wk TMP-SMZ2 DSa bid ⫻ 7 days TMP-SMZ DS qid ⫻ 10 days Albendazole 400 mg bid ⫻ 21 days

TMP-SMZ, trimethoprim & sulfamethoxazole (co-trimoxazole); DS, double-strength. Average wholesale price: 2000 Drug Topics Redbook.

Costb $36.00 $63.00 $113.00–$226.00 For 70-kg person $10.00 $31.50 $113.00–$226.00 For 70-kg person

$180.00

$133.00 $486.00 $18.00 $52.00 $84.00

Manifestations of Parasitic Infections

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idium parvum, Isospora belli, Cyclospora cayetanenis, Microsporidia spp., Balantidium coli, and Blastocystis hominis. 3.1

Giardiasis

Giardiasis, an enteric infection caused by the flagellated protozoon Giardia lamblia (also called G. duodenalis or intestinalis), is the most common gastrointestinal parasitic infection in the United States. Giardia spp. have been found in 2%–5% of stool samples in the industrialized world and in 20%–30% of samples from the developing world. Giardia spp. are spread by ingestion of oocysts usually from contaminated water but also from person-to-person contact and from contaminated foods. After ingestion, excystation occurs in the small bowel, allowing attachment and proliferation of the trophozoite in the gut. High-risk groups for giardiasis include infants, young children, travelers, and those who have common variable immunodeficiency human immunodeficiency virus (HIV) infection, and gastric surgery or hypochlorhydria. Although giardiasis accounts for less than 5% of traveler’s diarrhea, travelers to certain areas such as St. Petersburg, Russia, have an attack rate as high as 30%–40%. Even within the United States, prevalence is quite variable, as outbreaks have been associated with drinking from clear mountain streams. Immunodeficiency predisposes to chronic infection. The ability of the cyst to survive in fresh water and its relative insensitivity to chlorination are responsible for water-borne epidemics. Human-to-human transmission occurs in day care centers, schools, and residential institutions. Food handlers have been implicated in epidemics, and there is evidence to suggest that there is a reservoir in wild and domestic animals. The clinical syndromes include an asymptomatic carrier state and acute and chronic diarrhea. The incubation period is generally 1 to 2 weeks. Acute giardiasis causes a voluminous and watery diarrhea though without associated blood or mucus. Mild weight loss occurs in 60%–70% of patients. Other symptoms may include abdominal discomfort, nausea, flatulence, mild fever, and lassitude. Steatorrhea may be present. The vast majority of infections are self-limited and last 2–4 weeks. In 25% of patients chronic diarrhea, lasting months with associated weight loss, malabsorption, steatorrhea, macrocytic anemia, and secondary lactase deficiency, develops. Periods of normal stools and/or constipation may be interspersed during this chronic infection. The appropriate clinical history suggests the diagnosis. Stool sample findings should be negative for blood and fecal leukocytes. The detection of Giardia sp. cysts or trophozoites in the stool confirms the diagnosis. The sensitivity of parasitic detection in the stool rises to 85% when specimens are submitted on 3 different days. Commercially available antigen detection assays have sensitivities of 87%–100%. An immunofluorescence test for both Giardia spp. and Cryptosporidium spp. is available. Therapy is summarized in Table 5. The drug of choice is metronidazole, which has an 80%–95% cure rate. Albendazole has been used successfully, though experience is limited. Paromomycin may be the drug of choice in pregnant women with severe symptomatic disease. Consideration should be given to delaying treatment until after delivery or at least during the first trimester if symptoms are not severe and hydration can be maintained. 3.2

Amebiasis

Amebiasis, caused by the pseudopod forming protozoa Entamoeba histolytica, is most often manifested clinically as acute colitis. Less commonly, systemic invasion results in

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hepatic abscess formation. E. histolytica infects more than 100 million people worldwide, contributing to significant morbidity and mortality rtes. In the United States the overall serological prevalence is 4% of the population. Institutionalized populations, especially the mentally challenged, have a higher incidence of infection. The prevalence of this infection in men who have sex with men is high, although many are actually infected with Entamoeba dispar, which is morphologically identical to E. histolytica but does not produce clinical disease. The clinical spectrum of intestinal amebiasis includes asymptomatic infection, symptomatic noninvasive infection, invasive protocolitis (amebic dysentery), fulminate colitis, toxic megacolon, and ameboma. Symptomatic noninvasive disease occurs 2 to 6 weeks after exposure and produces lower abdominal pain and mild diarrhea. This may progress to dysentery and, rarely, fulminant colitis characterized by bloody diarrhea, abdominal pain, fever, and leukocytosis. Proctocolitis, more common in malnourished persons, pregnant women, and recipients of steroid therapy, is associated with a high mortality rate. Perianal infection of skin with fistula formation can rarely occur. Less commonly, patients may have symptoms and signs of an intestinal mass (ameboma) mimicking carcinoma or an abscess. Extraintestinal disease such as a liver abscess is a rare complication. The finding of either the cyst or the trophozoites in the stool confirms the diagnosis. Administration of three stool exams increases the sensitivity to 70%–90%. Other amebas such as E. dispar, E. hartmanni, Endolimax nana, and Chilomastix mesnili are considered nonpathogenic. The stool is always heme-positive. Serological tests such as the indirect hemagglutination antibody (IHA) tests are useful for the diagnosis of invasive disease. Antibody levels indicated by IHA may remain elevated for years after acute invasive infection. E. dispar cannot be distinguished microscopically from E. histolytica, but infection with E. dispar does not generate serum antibodies. Therefore, asymptomatic patients with presumed E. histolytica oocysts or trophozoites in their stool should have antibody testing performed to rule our E. dispar. Antibody-negative patients do not require treatment. Therapy is summarized in Table 5. Asymptomatic E. histolytica cyst passers should be treated with luminal agents such as iodoquinol or paromomycin. Invasive colitis is treated with metronidazole plus a luminal agent. All patients should have follow-up stool testing to confirm eradication of the parasite. 3.3

Cryptosporidiosis

Cryptosporidium parvum is an intracellular coccidian protozoon. It can be transmitted by the fecal-oral route to humans from other humans and animals and by contaminated water. The oocysts are resistant to standard water purification techniques and chlorination and can survive for many months outside the host. After ingestion, the oocysts excyst and replicate in the bowel lumen, leading to a repeating cycle of autoinfection. Seroprevalence studies in industrialized nations suggest that up to 25%–35% of the population have been infected and stool studies show that 3% of patients with diarrhea are infected with Cryptosporidium spp. The rates are considerably higher in nonindustrialized nations. After an incubation period of 7–10 days, cryptosporidiosis produces bloating, abdominal pain, and diarrhea. Diarrhea is usually voluminous and can total 12–17 liters a day. In addition, patients may report low-grade fever, general malaise, nausea, fatigue, and anorexia. The diarrhea is usually self-limited but may become chronic in immunocompromised patients. Acalculous cholecystitis and cholangitis have been reported in patients with AIDS.

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The diagnosis is confirmed by finding oocysts in the stool by direct examination or antigen detection. Stools are concentrated and then stained by a modified acid-fast method or examined for antigen by immunofluorescent antibody tests. The stool is heme-negative. There is no reliable curative or palliative treatment for cryptosporidiosis. In the immunocompetent host, it is a self-limited illness. Supportive measures including hospitalization for hydration may be necessary. In immunocompromised patients, including those with HIV infection, paromomycin and azithromycin have been used with variable efficacy (see Table 5). 3.4

Isosporiasis

Isospora belli is a coccodidian protozoon related to Cryptosporidium, Cyclospora, and Toxoplasma spp. Fecally contaminated food or water transmits the infection. Isospora spp. have worldwide distribution but are more common in the tropics. In the United States infection is more common in persons who have HIV or are institutionalized, attend day care, or are immigrants from tropical areas. After ingestion, the parasite excysts and replicates in the small bowel. After a brief incubation period of 1 to 2 days, the acute illness begins with low-grade fever; profuse watery, nonbloody diarrhea; and abdominal cramps. In the immunologically normal host, the disease can be self-limited or less commonly can become chronic. In patients with HIV infection and other immune suppressed states, isosporiasis can lead to chronic diarrhea refractory to treatment. The diagnosis is made by identification of oocysts in the stool. Multiple stool samples may be needed to identify the parasite. The cysts are elliptical in shape and much larger in size than those of Cryptosporidium spp. Modified acid-fast staining or autofluorescence under ultraviolet light is used to identify the oocysts from stool concentrates. The treatment is trimethoprim & sulfamethoxazole (TMP-SMZ or co-trimoxazole) (see Table 5). Immune-suppressed patients, especially those with AIDS, may need lifelong suppressive therapy with TMP-SMZ three times weekly. 3.5

Cyclosporiasis

Infection with Cyclospora cayetanenis causes a diarrheal illness similar to that caused by Cryptosporidium and Isospora spp. It occurs worldwide and is relatively uncommon in the United States. Infections have been reported in travelers, children, and those with HIV infection. Local outbreaks in the United States due to ingestion of imported fruit and vegetables have been reported. Person-to-person transmission has not been reported. The clinical features are similar to those produced by other coccidian protozoa. The incubation period can be as short as several days but averages about 1 week. Symptoms include fever, watery diarrhea, fatigue, crampy abdominal pain, and flatulence. Diagnosis requires identification of the oocyst in the stool. The modified acid-fast stain is the preferred method. Fluorescent microscopy is rapid and sensitive. The treatment of choice is TMP-SMZ (see Table 5). For patients with AIDS, TMP-SMZ should be used qid for 10 days and chronic suppression should be considered. 3.6

Microsporidia

The microsporidia are a group of small, obligate intracellular spore-forming protozoa. They have a worldwide distribution and produce serious infections, most commonly in immunocompromised patients such as those with HIV infection and organ transplantation. Reports have been made of infection in travelers. Person-to-person transmission and water-

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borne transmission are the primary modes of transmission. Eleven species of micropsoridia have caused infection in humans. Infection can occur in the gastrointestinal, respiratory, and urinary tracts. Infection with Enterocytozoan bieneusi and Encephalitizoon intestinalis can cause chronic diarrhea associated with wasting, anorexia, abdominal pain, nausea, and fever. Stool microscopy with special staining techniques such as the Weber chromotrope stain are necessary for confirmation of diagnosis. Species identification with electron microscopy or polymerase chain reaction may be important since only some species respond to therapy. Intestinal disease due to Encephalitozoon spp. can be treated with albendazole (see Table 5). 3.7

Balantidiasis

Balantidium coli is a large ciliated protozoan parasite. Pigs are the major reservoir. Human infection is uncommon, though achlorhydria increases risk. Most patients are asymptomatic. If clinical infection occurs, it is characterized by chronic diarrhea, weight loss, and abdominal pain. Less commonly, infection can mimic amebic dysentery. Doxycycline, iodoquinol, and metronidazole can be used for treatment. 3.8

Blastocystis hominis

Many questions about taxonomic characteristics, number of species, morphological features, and virulence remain about the protozoan parasite Blastocystis hominis. This protozoon should not be considered a pathogen unless all other intestinal infections have been ruled out, it is found in multiple stool samples, and the patient continues to be symptomatic. If symptomatic infection occurs, it is generally self-limited and does not require treatment. Reports of treatment are anecdotal. Metronidazole and iodoquinol have been used with variable efficacy. 4

WORMS SEEN IN THE STOOL

Rarely a patient may report seeing a worm or fragment of a worm in feces. Generally the patient does not have other symptoms. A luminal helminthic infection should be considered. These patients do not have blood eosinophilia. If the worm is described as similar to an earthworm, Ascaris sp. is likely. If the description is of segments of a worm, then the intestinal tapeworms Diphyllobothrium latum, Tania soluim, and Tania saginata should be considered. Fresh stool should be submitted for ova and parasite examination. The lab

WORMS IN STOOL Wormlike: Ascaris lumbricoides Worm segments: intestinal tapeworms (Cestodes) Diphyllobothrium latum Tania solium, T. saginata Stool ova and parasite exam Worm to parasitology laboratory Therapy with mebendazole, albendazole, or praziquantel Hysterical parasitosis?

Pruritic rash, Loeffler’s syndrome, diarrhea, abdominal pain, autoinfection in immune-compromised

Small bowel

Small bowel

Southeastern United States; transmission from contaminated soil through skin Southeastern United States; transmission from contaminated soil through skin

Hookworm (Acylostoma duodenale, Necator americanus) Threadworm (Strongyloides stercoralis)

Average wholesale price: 2000 Drug Topics Redbook.

a

Asymptomatic, Loeffler’s syndrome, malabsorption, bowel obstruction, ‘‘passing of worms’’ Pruritic rash, Loeffler’s syndrome, iron deficiency anemia

Small bowel; migration to lungs and heart

Southeastern United States

Giant intestinal worm (Ascaris lumbricoides)

Cecum, perianal area

Family and institutional spread

Asymptomatic, rectal prolapse, iron deficiency anemia Asymptomatic, perianal pruritis

Syndromes

Pinworm (Enterobiasis vermicularis)

Cecum

Anatomic location

Southeastern United States

Risks

Whipworm (Trichuris trichuria)

Common name (genus and species)

Table 6 Helminth Infections Endemic to the United States

$2.80

Mebendazole 100 mg ⫻ 1 day; repeat in 2 wk Albendazole 400 mg ⫻ 1 day; repeat in 2 wk Mebendazole 100 mg bid ⫻ 3 days

$6.00

Albendazole 400 mg/ day ⫻ 3 days or ivermectin 200 ␮g/kg ⫻ 1 day

$25.00 For 70-kg person

As above

Mebendazole or albendazole ⫻ 1 day

$4.00 As above

$8.50

Costsa

Mebendazole 100 mg bid ⫻ 3 days

Therapy

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should be informed of the possible diagnosis under consideration. If the finding is negative, the patient should submit a stool that he or she thinks shows the characteristic parasite. This should be confirmed by the parasitology lab. If helminthic infection cannot be confirmed, parasitosis, a hysterical disorder, should be considered. Luminal helminthic infection can be treated with mebendazole (100 mg bid ⫻ 3 days) and albendazole (400 mg once) for Ascaris sp. and praziquantel (5–10 mg/kg once) for tapeworms. 5

HELMINTH INFECTIONS ENDEMIC IN THE UNITED STATES

The parasites that cause endemic U.S. helminth infections have the following characteristics in common: (1) they are intestinal nematodes called roundworms; (2) they are mostly seen in the southern United States with the exception of pinworms, which are seen throughout the United States; (3) they are transmitted by ingestion of ova from fecally contaminated food and hands, with the exception of Stronglyloides spp. and hookworm; and (4) they are most common in children. Infections may present a variety of symptoms but may also be asymptomatic. Eosinophilia may be present during certain stages of parasite migration (hookworm and Strongyloides spp.) through the human host, though absence of eosinophilia does not exclude infection. Diagnosis is generally made by detection of ova and parasite in the stool. Risk factors for infection, clinical manifestations, and therapy are summarized in Table 6. Infection with Strongyloides spp. in the immune-compromised host (as a result of AIDS, organ transplantation, high-dose corticosteroid use, lymphoma, or leukemia) can be life-threatening as a result of superinfection and dissemination of the parasite. These patients may experience pneumonia, severe abdominal pain, shock, eosinophilia, and gramnegative bacteremia superinfection. BIBLIOGRAPHY Ackers JP. Gut coccidia—isospora, cryptosporidium, cyclospora and sarcocystis. Semin Gastrointest Dis 8(1):33–44, 1997. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH. The idiopathic hypereosinophilic syndrome: Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 97:78–92, 1982. Goodgame RW. Understanding intestinal spore forming protozoa: Cryptosporidium, Microsporidium, Isospora and Cyclospora. Ann Intern Med 124(4):429–441, 1996. Herwalt BL. Cyclospora cayetanensis: A review, focusing on the outbreaks of cyclosporiasis in the 1990s. Clin Infect Dis 31:1040-1057, 2000. Maguire JH, Keystone JS, eds. Parasitic Diseases. Infect Dis Clin North Am 7(3), 1993. Mahmoud AA. Strongyloidiasis. Clin Infect Dis 23(5):949–952, 1996. Ortega TR, Adam RD. Giardia: Overview and update. Clin Infect Dis 25(3):545–549, 1997. Petri WA, Singh U. Diagnosis and management of amebiasis. Clin Infect Dis 29:1117–1125, 1999. Sarinas PS, Chitkara RK. Ascariasis and hookworm. Semin Respir Infect 12(2):130–137, 1997. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics.

33 The Pregnant Patient Mary-Margaret Andrews Dartmouth-Hitchcock Medical Center, and Dartmouth Medical School, Lebanon, New Hampshire, U.S.A.

1

INTRODUCTION

Primary care providers are often ill at ease about infections that occur during pregnancy; a working knowledge of how to approach infectious complications during the prenatal, perinatal, and postpartum periods can streamline care delivered in the outpatient clinic. The range of infections complicating pregnancy includes common infections not unique to pregnant patients but seen with increased frequency in pregnant women such as urinary tract infections (UTIs), infections that have more severe sequelae during pregnancy (hepatitis E virus, influenza, or varicella pneumonia) and infections unique to pregnant women (chorioamnionitis and endometritis). Pregnant women can also have common infections such as pneumonia, cellulitis, and gastroenteritis during pregnancy. These infections are managed as in the nonpregnant patient and are reviewed in other chapters; special attention to antibiotic selection is required. A broad array of pathogens can cause perinatal or congenital infection of the neonate (Table 1). Subclinical infection of the upper genital tract may be responsible for infertility, premature labor, and low-birth-weight deliveries. The lower female genital tract is colonized by a diverse microbial flora. This normal flora includes Lactobacillus spp., streptococci, Staphylococcus epidermidis, Bacteroides and Prevotella spp., and Gardnerella vaginalis. Typical aerobic and anaerobic bacteria dominate the flora; however, atypical bacteria (Chlamydia, Mycoplasma, and Ureaplasma species), yeast (Candida albicans), viruses (herpes simplex virus), and parasites (Trichomonas vaginalis) may also reside in the lower genital tract. Many of these species are true colonizers but can become pathogens in the appropriate clinical setting. The upper female genital tract is normally sterile. Lower tract flora can ascend in the context of surgery, instrumentation, or childbirth. Infections of the uterine cavity (endometritis), the gravid uterus and amniotic sac (chorioamnionitis), and fallopian tubes and ovaries (salpingitis, tubo-ovarian abscess, and pelvic peritoneum) are generally polymicrobial. Sexually transmitted pathogens also can play a significant role. This chapter reviews the principles of antibiotic selection for the pregnant woman and the more common infectious syndromes encountered. Table 2 outlines some general principles regarding the approach to infections in the pregnant patient. 645

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Table 1 Agents That Cause Congenital Infections Bacteria Listeria monocytogenes Treponema pallidum (syphilis) Leptospirosis spp. Mycobacterium tuberculosis Viruses Rubella Cytomegalovirus Herpes simplex virus Varicella zoster virus Parvovirus B19 Human immunodeficiency virus (HIV) Hepatitis B virus Enteroviruses Protozoa Toxoplasma gondii Plasmodium spp. (malaria)

2

ANTIBIOTIC SELECTION IN THE PREGNANT PATIENT

Pharmacokinetic principles of antibiotic use in pregnancy are unique. The physiological changes of pregnancy result in a net lowering of drug bioavailability. Drug absorption may vary with altered gastrointestinal motility and gastric emptying. The blood volume is expanded by as much as 50%, resulting in an expanded volume of drug distribution. Renal clearance of many drugs is increased by the increased renal blood flow and glomerular filtration rates of pregnancy. Elevated progesterone levels may affect hepatic metabolism of some drugs. Consequently, there is a tendency to underdosage of antibiotics during pregnancy. Antibiotics are distributed in all body compartments. Concentration gradients, low molecular weight, and low protein binding favor excretion of all antibiotics into breast milk and transfer across the placenta to the fetus. Adverse effects on neonates from antibiotic exposure, however, are rare. The U.S. Food and Drug Administration (FDA) developed risk categories for drugs (see Table 3). Most antibiotics can be used safely in pregnancy (see Table 4). ␤ -Lactams are core agents used to treat infections during pregnancy. In particular, ampicillin continues to be an excellent choice for UTIs and for polymicrobial infections involving lower genital

Table 2 Infections in Pregnant Patients: General Principles Consider potential pregnancy in female patients. Take a complete sexual, travel, and exposure history. Search for common illnesses first. Test and treat at a lower threshold. Prevent underdosage of antibiotics. Coordinate care with obstetrical service providers.

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Table 3 Pregnancy Risk Categories Pregnancy risk category X

D

C

B

A

Descriptiona Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience, or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant. There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.

a

The descriptions for the risk categories are those used by the Food and Drug Administration. Source: Federal Register 1980; 44:37434–37467.

tract flora because of its activity against streptococci, including group B streptococci (GBS), enterococci, and enteric gram-negative rods (GNRs) such as Escherichia coli. It can be combined with additional agents (e.g., clindamycin) or with a ␤ -lactamase inhibitor (clavulanate or sulbactam) to expand coverage to include anaerobes, Klebsiella spp., resistant E. coli, and Staphylococcus aureus. Cefotetan and cefoxitin are excellent drugs that can be used to treat polymicrobial lower genital tract infections. Other ␤ -lactam antibiotics such as imipenem, a carbapenem, and aztreonam, a monobactam, have both been used safely during pregnancy. Additional agents can be used during pregnancy with a few cautionary notes. Macrolides (erythomycin, azithromycin, and clarithromycin) may be indicated for respiratory infections in the pregnant or lactating woman and have been used successfully. Metronidazole in combination with gentamicin or a ␤ -lactam can be used for mixed aerobicanaerobic infections. Metronidazole can be used as a single agent for bacterial vaginosis but solely during the second or third trimester. Because it is a mutagen, it is used more stringently during the first trimester. Trimethoprim & sulfamethoxasole can be used safely during pregnancy, although the trimethoprim component should also be avoided during the first trimester. Sulfonamides should be avoided near the time of delivery to prevent fetal hyperbilirubinemia. Aminoglycosides are not contraindicated in pregnancy but are used cautiously. In the past, rare instances of eighth nerve damage were reported in women treated for tuberculosis with long courses of streptomycin.

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Table 4 Antibiotic Risk During Pregnancy Risk category Antimicrobials generally considered to be safe in pregnancy Amphotericin B Azithromycin Aztreonam Cephalosporins Clindamycin Erythromycin Famciclovir Metronidazole Nitrofurantoina Penicillins Valacyclovir Antimicrobials to be used with caution in pregnancy Acyclovir Aminoglycosides Clarithromycin Ganciclovir Fluconazole Imipenem-cilastatin Indinavir Ketoconazole Lamivudine Nelfinavir Nevirapine Nystatin Rifampin Ritonavir Sulfonamidesa,b Stavudine Trimethroprim & sulfamethoxazolea,b Trimethoprim Zalcitabine Vancomycin Zidovudine Amprenavir Didanosine Lopinavir/r Delavirdine Antimicrobials which should be avoided in pregnancy Efavirenz Quinolones Ribavirin Tetracyclines a

B B B B B B B B B B B C D C C C C C C C B C C C B B C B C C C C C B C C C C X D

Do not administer to pregnant patients who have (G-6-PD) deficiency because of the risk of hemolysis to the mother and fetus. b Risk factor D applies if administered near term. Source: Briggs G et al. Drugs in Pregnancy and Lactation. Fifth edition. Philadelphia: Lippincott, Williams & Wilkins, 1998; Department of Health & Human Services. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. February 4, 2002. http://www.hivatis.org.

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Acyclovir can be safely used to treat genital herpes simplex infections and disseminated varicella zoster infection, including pneumonia. In general women with human immunodeficiency virus (HIV) infection should be managed in a similar manner to nonpregnant patients (as discussed later). Several antimicrobials should be avoided during pregnancy and breast-feeding, especially for empirical treatment. Ciprofloxacin and other newer quinolones are not recommended because of an arthropathy demonstrated in animal studies associated with drug deposition in bone. Tetracyclines, including doxycycline, can inhibit long bone growth and may cause deposition in teeth with subsequent lifelong discoloration. Fluconazole and ribavirin have been associated with fetal malformations, and their use in pregnancy is not recommended. 3

URINARY TRACT INFECTIONS

UTIs are the most common medical complication associated with pregnancy. Acute symptomatic cystitis occurs in up to 1.3% of pregnant women, and acute pyelonephritis complicates 1%–2.5% of pregnancies. The incidence of asymptomatic bacteriuria (ASB), defined as >105 colonies/mL of a single organism, is at least 4%–7%. Pregnant women with ASB have a 20%–30% risk of development of acute pyelonephritis, associated with morbidity and potential mortality risks to both the mother and the fetus, including premature labor. Of pyelonephriits cases 70%–80% can be prevented by screening and treatment for ASB. Women are predisposed to UTI by the proximity of the urethra to the gastrointestinal tract and the urethra’s short length. In pregnancy urine flow is diminished as a result of decreased ureteral peristalsis and ureteral and bladder compression by the gravid uterus. The bladder also empties incompletely because of relaxed detrusor muscle tone. During

URINARY TRACT INFECTIONS Approach to asymptomatic bacteriuria (see Figure 1) Screening of all asymptomatic women for bacteriuria during first trimester Bacteriologic features same as for nonpregnant patients Treatment of all women with asymptomatic bacteriuria Treatment of symptomatic cystitis as a complicated urinary tract infection (UTI) (see Chapter 15) Goal of urine sterility throughout pregnancy Contraindicated antibiotics (see Table 4) Quinolones Tetracyclines Sulfa drugs (Bactrim) in third trimester Trimethoprim in first trimester Pyelonephritis Parenteral therapy Ampicillin and gentamicin Outpatient treatment of clinically and psychosocially stable patients without comorbidities Amoxicillin-clavulanate (Augmentin) Trimethoprim & sulfamethoxazole (Bactrim)

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pregnancy, bacterial growth in urine is enhanced by increasingly alkaline pH and relative glucosuria. These changes result in a significant risk for UTI for the pregnant patient. UTI pathogens in pregnant women are similar to those seen in nonpregnant women. E. coli is detected in 60%–90%. Proteus mirabilis, Klebsiella species, enterococci, and GBS are also major pathogens in this setting. Bacterial virulence factors combined with host genetic characteristics likely explain why some bacteria are particularly good at adhering to the uroepithelium. For example, strains of E. coli possessing P fimbriae are uniquely able to bind to the uroepithelium and ascend to cause upper tract disease. ASB should be assessed at the first prenatal visit and reassessed later in pregnancy for those with treated ASB early in pregnancy or those with a history of frequent or recurrent UTI. Women without these risk factors are generally not rescreened because <1.5% of women acquire bacteriuria during pregnancy. A single midstream clean catch urine culture detects 80% of cases of ASB. Obtaining two successive positive urine culture results increases the sensitivity significantly but is not standard practice because of the added cost. Urinalysis and urine dipstick technique do not have the needed sensitivity to be used as a screening tool for ASB. Rapid enzymatic urine screening tests with increased sensitivity are in development, but results need to be confirmed in larger clinical studies. Urine cultures should be transported to the laboratory immediately; if necessary, they can be stored at 4⬚C for 24 hours if immediate processing is not available. Urine culture cost is approximately $45 each. Results are generally available in 24–48 hours. Cystitis presents clinically with urinary frequency, urgency, discomfort, or hematuria. Cystitis needs to be differentiated from urethritis caused by herpes simplex, Neisseria gonorrhoeae, and Chlamydia trachomatis or vaginitis caused by anaerobes, Candida spp., or Trichomonas spp. Many regimens have been used successfully to treat ASB and cystitis. A 7-day course of antibiotics eradicates the bacteriuria in 70%–80% of women and is the generally preferred duration of therapy. Single-dose and 3-day regimens have been advocated by some because of their reduced cost and side effects. The relapse rate for these shorter regimens compared to that of traditional 7-day regimens remains to be elucidated in clinical trials. Agents used in single-dose therapy include nitrofurantoin (200 mg), amoxicillin (3 g), cephalexin (2 g), and sulfisoxazole (2 g). The 3- to 7-day regimens include nitrofurantoin (100 mg qid), trimethoprim & sulfamethoxazole (one double-strength tablet bid), and cephalexin (250–500 mg/day). Local bacterial resistance patterns must be taken into account when choosing empirical therapy. An approach to the pregnant women with asymptomatic bacteriuria is summarized in Figure 1. The goal of therapy is to maintain sterile urine throughout the course of pregnancy. After a course of treatment, the woman should be retested and, if the finding is positive, retreated. Those women who have recurrent ASB should receive long-term prophylaxis until delivery. Acute pyelonephritis causes fever, rigors, nausea and vomiting, and flank pain with or without symptoms of cystitis. Sepsis, respiratory distress, and transient renal insufficiency can be present in severe cases. Anemia is common. Urinalysis may reveal white cell casts in addition to pyuria. Urine culture confirms the diagnosis; blood culture results are positive in 10%–15% of cases. Traditionally, pregnant women with pyelonephritis have been hospitalized because of the need to deliver parenteral antibiotics and to observe closely to prevent further complications. Newer studies suggest that a subset of pregnant women may be treated successfully on an ambulatory basis. These patients should be otherwise healthy, hemodynamically stable, and able to maintain good hydration. Patients who are in preterm labor,

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Figure 1 Approach to the pregnant woman with asymptomatic bacteriuria (ASB). All women should have urine cultures performed during the first trimester. Those with significant bacteriuria should be treated and retested. The goal is to maintain sterility of urine throughout the course of the pregnancy. Repeated episodes of ASB may require chronic suppressive therapy.

noncompliant or underaged patients, substance abusers, and those who have significant comorbid medical illnesses such as diabetes or renal insufficiency should be hospitalized. Oral agents that can be prescribed include cephalexin (500 mg qid), amoxicillin-clavulanate (875 mg bid), and trimethoprim & sulfamethoxazole (bid) if there are no contraindications. Therapy can be adjusted on the basis of culture results and should be continued for 2–3 weeks. Standard empirical regimens for hospitalized women with pyelonephritis include ampicillin (2 g IV q6h) with gentamicin (1 mg/kg q8h), ampicillin-sulbactam (3 g IV q6h), cefazolin (1 g IV q8h), and ceftriaxone (1–2 g IV or IM q24h). The antibiotic regimen should be adjusted on the basis of the results of the urine culture to less broad-spectrum, toxic, or expensive drugs. Therapy is continued parenterally until the patient has been afebrile for 48 hours. The dosage can be switched to oral antibiotics to complete 2 to 3 weeks of therapy. Patients not responding by 48 hours may have a resistant organism, perinephric abscess, nephrolithiasis, or other anatomical abnormalities of the urinary tract; ultrasonography is indicated in these circumstances. Recurrent pyelonephritis is common (up to 20%) and urine cultures should be repeated throughout the pregnancy. Some clinicians use nitrofurantoin suppression (100 mg qhs) after an episode of pyelonephritis throughout the remainder of the pregnancy because of this high recurrence rate.

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PELVIC INFECTIONS Chorioamnionitis Infection of chorioamniotic membranes E. coli, Group B streptococci (GBS), anaerobes Fever, uterine tenderness Sample amniotic fluid if in preterm labor Intravenous (IV) ampicillin, gentamicin, clindamycin Endometritis Infection of uterine wall Increased risk with premature rupture of membranes and cesarean section Fever, uterine tenderness, foul-smelling vaginal discharge Suspected when any woman has postpartum fever IV ampicillin, gentamicin, clindamycin Salpingitis Infection of fallopian tubes Commonly sexually transmitted with Neisseria gonorrhoeae or Chlamydia trachomatis; may be mixed aerobic and anaerobic Fever, low abdominal pain, cervical motion tenderness, mucopurulent cervicitis Cefotetan and erythromycin

4 4.1

CHORIOAMNIONITIS AND ENDOMETRITIS Chorioamnionitis

Chorioamnionitis is an infection of the chorioamniotic membranes and amniotic fluid. Morbid conditions it causes include preterm labor and delivery as well as maternal pelvic infections, and sepsis and pneumonia in the neonate. Chorioamnionitis affects between 0.5% and 2% of term pregnancies and about 25% of women with preterm deliveries. Prolonged rupture of membranes remains the dominant risk factor. Infections are generally polymicrobial, involving both aerobes and anaerobes with GBS and E. coli as the dominant pathogens. Signs and symptoms in the mother almost always include fever, tachycardia, and uterine tenderness, though the latter symptoms may not always be present. Leukocytosis may occur. Amniotic fluid analysis for Gram stain, culture, and glucose concentration is indicated in preterm labor. Management includes parenteral antibiotics and delivery of the fetus. Ampicillin and gentamicin, with or without clindamycin, is a standard treatment regimen. Bacteremia occurs in 2%–3% and postpartum pelvic infections, especially after cesarean delivery, occur in 10%–50%. Maternal mortality rates have declined but this remains a morbid illness. 4.2

Endometritis

Endometritis is infection of the lining of the uterus and/or uterine wall itself. The route of delivery is the most important risk factor. Endometritis rates are <3% for vaginal deliveries but range from 10% to 95% for patients delivered by cesarean section. Highestrisk patients are those who have ruptured membranes for >6 hours, multiple cervical exams, and chorioamnionitis. The bacteriological composition is a mix of aerobic and anaerobic bacteria, including GBS, E. coli, G. vaginalis, enterococci, Bacteroides spp.,

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Prevotella spp., and streptococci. Endometritis should be suspected when any postpartum patient has fever. Other signs and symptoms may include lower abdominal pain or uterine tenderness, foul smelling discharge, or leukocytosis. All patients with suspected endometritis should undergo bimanual examination to assess for uterine tenderness and adnexal mass. Transendometrial culture is not used routinely because of the difficulty of obtaining appropriate specimens; its use is reserved for those not responding to conventional therapy. The differential diagnosis for fever in the postpartum setting includes UTI, wound infection, mastitis, pneumonia, and phlebitis. Use of clindamycin and gentamicin is a classic regimen for the treatment of endometritis. Lack of improvement after 48–72 hours of therapy should prompt further evaluation, including consideration of ovarian vein thrombosis. The risk of endometritis can be reduced for patients delivered electively by cesarean section through the use of prophylactic preoperative antibiotics such as cefazolin. Postpartum ovarian vein thrombophlebitis occurs when one or both of the ovarian veins clot. It usually is associated with postpartum endometritis, though the thrombosis can rarely occur alone. Patients have fever and lower abdominal pain. The thrombosed vessel may be palpated in 50%–75% of patients. Diagnosis can be confirmed with sonography and computed assisted tomography (CT scan). Therapy includes antibiotics for endometritis and full anticoagulation. 4.3

Salpingitis

Salpingitis, or infection of the fallopian tubes, is often sexually transmitted. N. gonorrhoeae and C. trachomatis are the predominant pathogens, though infections can be mixed, including both anaerobic and aerobic GNRs. Patients usually have fever, lower abdominal pain, and cervical motion and adnexal tenderness. Differential diagnosis includes appendicitis, ovarian cyst, endometritis, and chorioamnionitis. Salpingitis can result in infertility, chronic pelvic pain, dyspareunia, ectopic pregnancy, and tubo-ovarian abscess. The pregnant patient who has suspected salpingitis should be admitted to the hospital for intravenous antibiotics. Therapy for the pregnant patient needs to be altered because of the relative contraindications to quinolone and tetracycline use. Cefotetan 2 g IV q12h can be combined with erythromycin 500 mg IV or PO q6h. If the patient is intolerant of erythromycin, the dosage can be decreased to 250 mg q6h or azithromycin IV or PO could be substituted. Amoxicillin orally or ampicillin intravenously can be used as an alternative for erythromycin-intolerant patients, though the risk of late C. trachomatis recurrences is higher. 5

PERINATAL AND CONGENITAL INFECTIONS

A variety of typical and atypical bacteria, viruses, and protozoa can be transmitted from mother to child, causing significant morbidity and mortality. Tables 5 and 6 list the major pathogens associated with disseminated intrauterine infections leading to congenital disease and other pathogens acquired intrapartum. Many of these infections are subclinical in the mother. Originating from practices established during the U.S. syphilis epidemic in the 1940s and expanding to other organisms as data accrued, screening has been used as a way to identify at risk mothers and to target neonates for interventions at delivery. Table 7 summarizes the rationales for screening pregnant women for some of the more common perinatal infections. Pregnant women are routinely screened for GBS colonization, Chlamydia trachomatis, Treponema pallidum, HIV, hepatitis B virus, and rubella. Tuberculosis screening with the purified protein derivative (PPD) test is indicated in some populations because of the prevalence of tuberculosis. Other testing may be indicated by exposures

Usually asymptomatic Urethritis, cervicitis

Often asymptomatic

Majority asymptomatic Primary infection: fever, rash, flulike illness Symptomatic infection, fever, weight loss, thrush, diarrhea, lymphadenopathy Fever, malaise, nausea Many asymptomatic

Fever, lymphadenopathy, arthralgias, transient erythematous rash

Chlamydia trachomatis

Treponema pallidum (Syphilis)

Human Immunodeficiency virus type 1 (HIV-1)

Rubella

a

Antibody or history of vaccination

RPR/VDRL; confirm with FTA-ABS Lesions: dark-field microscopy for spirochetes HIV-1 ELISA with confirmatory Western blot HIV p24 antigen and RNA PCR used in research settings HBsAb and HbsAg HbeAg if HbsAg-positive

Cervical or urine specimen gene probe assay

Rectal and vaginal culture at 35–37 weeks or risk-based screen

Maternal diagnosis

Identification of susceptible women and vaccination 90 days prepartum or immediately postpartum

Determination of need for HBIG for neonate and neonatal HBV vaccination

Identification of silent disease for treatment Partner testing Prevention of congenital infection Identification of need for antiviral therapy for maternal health and prevention of perinatal transmission

Identification of silent disease for treatment Partner testing Prevention of neonatal infection

Identification of colonized women who should receive intrapartum penicillin

Goals

Intrapartum Less common transplacental, postpartum, and with breast-feeding Transplacental

Intrapartum Transplacental Breast-feeding

Transplacental

Intrapartum

Intrapartum

10% Transmission from HbeAg-negative chronic carriers 90% In HbeAg-positive Increased rates during acute HBV 20% For infection in first trimester

⬃100% infected (untreated primary or secondary disease) 50% Congenital syndrome 25% In those untreated Up to 40% in those untreated who breast-feed

1%–2% overall 10%–15% With premature labor or chorioamnionitis 60%–70%

Maternal disease resulting in neonatal or congenital illness, %

Cataracts Patent ductus arteriosis Deafness

Asymptomatic Chronic hepatitis

Asymptomatic Multiorgan illness and growth retardation

Neonatal conjunctivitis (20%– 50%) Pneumonia (10%–20%) Stillbirths Early or late congenital infection

Neonatal sepsis or meningitis

Neonatal or congenital syndrome

HbsAg, hepatitis B virus surface antigen; HbsAb, hepatitis B virus surface antibody; HBsAg, hepatitis B virus surface antigen; HbeAg, hepatitis B virus e antigen; HBIG, hepatitis B immune globulin; RPR, rapid plasma reagin; VDRL, Venereal Disease Research Laboratories; FTA-abs, fluorescent treponemal antibody absorption; ELISA, enzymelinked immunosorbent assay.

Hepatitis B virus (HBV)

Usually asymptomatic

Maternal illness

Group B streptococci

Organism

Major transmission route from mother to child

Table 5 Summary of Major Perinatal and Congenital Infectious Diseases Screened for Routinely During Pregnancya

Vesicular rash Constitutional symptoms Pneumonia (⬃20%) Primary: extensive, painful genital ulcers, fever, lymphadenopathy Asymptomatic ulcers or viral shedding Asymptomatic (50%) Facial rash, polyarthralgias (50%– 80%)

Varicella zoster virus (VZV)

Majority subclinical Acute hepatitis or chronic liver disease

Hepatitis C virus (HCV)

Antibody and HCV RNA

Serum antibody

Acute and convalescent antibody

Antibody if pregnant woman exposed

Acute and convalescent antibody Urine culture Buffy coat culture Blood Ag Antibody if pregnant woman exposed and lacks history of chickenpox Genital culture Antibody tests used in research settings

Maternal diagnosis

Assessment of need for mother or newborn follow-up

Determination of need for fetal testing Spiramycin treatment (maternal infection only) or Pyramethamine-sulfadiazine treatment (maternal and fetal infection) Identification of women with active disease

Identification of women for more frequent ultrasounds to assess for hydrops

Identification of women who would benefit from abdominal delivery or antiviral therapy with acyclovir

Prophylactic VZIG

Prenatal ultrasound Amniocentesis

Goals

Intrapartum or postpartum Possibly transplacental

Transplacental

Transplacental

Transplacental

Intrapartum Rare antepartum and postpartum transmissions

Transplacental

Transplacental

26% Of women with active disease None if women asymptomatic 1.3%–42% In HIV-negative 4%–50% in HIV-positive

15%–60% If mother untreated; rates higher in second and third trimesters

30%–35% Fetal losses highest during second trimester

Primary disease: 50% Nonprimary or asymptomatic disease: 4%

Primary: 30%–50% (Most severe in first or second trimester) Recurrent infection: 0.2%–1.8% 2.3% Rates highest in first and second trimesters

Maternal disease resulting in neonatal or congenital illness, %

LFTs, liver function tests; VZIG, varicella zoster immune globulin; Ag, antigen; CNS, central nervous system; RNA, ribonucleic acid.

Erythema migrans rash Arthritis

Borrelia burgdorferi (Lyme disease)

a

Majority subclinical Mononucleosis-like (10%)

Toxoplasma gondii

Parvovirus B19

Herpes simplex virus (HSV)

Majority subclinical Mononucleosis-like (10%)

Maternal illness

Cytomegalovirus (CMV)

Organism

Major transmission route from mother to child

Majority asymptomatic Higher LFT levels in some

Death, syndactyly, cortical blindness None

In majority no adverse outcome Fetal aplastic crisis and death (20%) Hydrops Asymptomatic (90%) at birth development of chorioretinitis and visual impairment if untreated; multiorgan congenital syndrome (10%)

Asymptomatic (90%) at birth Mental impairment Sensorineural hearing loss Multiorgan involvement Fetal malformations (CNS lesions, limb hypoplasia, skin scarring) Neonatal infections Multiorgan involvement (20%) CNS disease alone (35%) Skin, eye, mucous membrane disease (45%)

Neonatal illness

Table 6 Summary of Major Perinatal and Congenital Infectious Diseases Screened for as Clinically Indicated During Pregnancy or Postpartuma

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Table 7 Rationale for Screening Pregnant Women for Specific Infectious Diseases Identification of need for maternal or neonatal antimicrobial therapy Identification of need for maternal or neonatal immune globulin prophylaxis or vaccination Counseling about exposure risks and prevention of infections during pregnancy Counseling about options for prevention of perinatal transmission Discussion of role for further intrauterine ultrasound imaging or intrauterine testing Discussion of the option to terminate pregnancy

and clinical illness of the mother or birth of a child who has signs suggesting congenital infections (e.g., growth retardation, jaundice, hepatosplenomegaly, hemolytic anemia, intracranial calcifications, petechiae, pneumonitis, myocarditis, cardiac abnormalities, chorioretinitis or keratoconjunctivitis, cataracts, glaucoma, or nonimmune hydrops) (see Table 6). Early-onset GBS neonatal sepsis, acquired through intrapartum contact with the colonized maternal lower genital tract, is the most common bacterial infection of neonates, affecting 1%–2% of births. Twenty percent of women are colonized with the organism in the gastrointestinal or lower genital tract. Colonized women who receive intrapartum antibiotic prophylaxis against the organism have a markedly lower incidence of neonatal disease. Since the 1990s, when national guidelines for screening and prophylactic antibiotics were introduced, the incidence of disease in the United States has been reduced significantly. The current recommendations endorse either a screening-based approach or a risk factor–based approach. In the screening-based approach, rectal and vaginal swabs for GBS are collected at 35–37 weeks of gestation, and those who have positive screening findings are offered intrapartum penicillin. Those who have a previous infant with invasive GBS disease, GBS bacteriuria during the current pregnancy, delivery at less than 37 weeks of gestation, duration of ruptured membranes >18 hours, or intrapartum temperature 38⬚C are recommended to receive intrapartum penicillin G (5-mU IV load, then 2.5-mU IV q4h until delivery). Current practice has been hampered by the relatively poor sensitivity of GBS culture and nonculture screening; these are influenced by timing of testing, collection methods, and specimen handling. Polymerase chain reaction (PCR) assays have promise for improving rapid screening. During pregnancy, there is a slight impairment of cell-mediated immunity, placing the pregnant women at risk for Listeria monocytogenes bacteremia; Listeria sp. meningitis is uncommon. This infection is most common in the third trimester, during the height of immune suppression. Women experience fever, headache, and myalgias. The infection can cause amnionitis and precipitate premature labor and may result in neonatal death in 22% of cases. Treatment is with intravenous ampicillin. 6

HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 AND PREGNANCY

As the human immunodeficiency virus type 1 (HIV-1) epidemic continues, the number of HIV-positive women who become pregnant continues to grow. The effects of HIV on pregnancy are not usually clinically apparent. Similarly, the effects of pregnancy on the course of HIV infection do not appear to be significant in the majority of individuals. In developed countries, antiretroviral therapy during pregnancy is recommended to maintain the mother’s health, as indicated by the CD4 cell count and HIV viral load. The oldest antiretroviral, zidovudine (ZDV) has the best proven track record during pregnancy. How-

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HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND PREGNANCY All pregnant women should be tested for human immunodeficiency virus (HIV) (consent required). HIV infection does not alter the outcome of pregnancy. Pregnancy does not alter HIV infection. Pregnant women with HIV should be treated with antiretroviral agents similarly to nonpregnant women (see Table 4). Antiretroviral therapy markedly decreases perinatal transmission. Goal of therapy is to suppress to undetectable viral load. Those women who are not otherwise candidates for antiretroviral therapy should be treated with at least zidovudine (see Table 8).

ever, most drugs now employed in combination therapy have been used to treat pregnant women. If a woman becomes pregnant while taking an antiretroviral regimen, that combination of medications is usually continued if she has had a good clinical response. Small clinical cohorts and a national registry document the use of many additional antiretroviral agents. Efavirenz, a nonnucleoside reverse transcriptase inhibitor, is a teratogen, however, and is contraindicated in pregnancy. Women should have joint follow-up by their HIV specialists and obstetrical care giver. HIV treatment is reassessed with CD4 cell count and viral load testing each trimester. Mother-to-child transmission of HIV occurs in up to 25% of untreated births in developed country settings and in up to 40% in developing countries where women routinely breast-feed after delivery. A minority of HIV transmissions occur in utero or during breast-feeding. Most perinatal HIV transmission occurs during labor and delivery, when the normal maternal-fetal blood admixture is disrupted. Transmission rates are greater in those with placental inflammation or ulcerative lesions in the genital tract. Transmission rate has a positive correlation with the HIV viral load of the mother. A series of interventions in the United States and Europe have dramatically reduced perinatal HIV transmission rates since 1992. HIV counseling and testing with consent are now recommended for all pregnant women regardless of HIV risk factors. This standard arose from data about the pitfalls of HIV risk assessments in women, as many do not realize they have been exposed to HIV. In addition, identification of maternal HIV infection would justify ZDV to prevent perinatal transmission and other antiretroviral therapy as indicated for maternal health. Although these screening practices have been implemented successfully in many parts of the United States, local practice patterns vary widely and stigmas persist. Because laws about HIV counseling, testing, and reporting are unique to each state, each practitioner needs to be informed about local practice. The AIDS Clinical Trials Group (ACTG) study 076 showed that ZDV given to the mother and child can reduce perinatal transmission from 25% to 8% (67% reduction). ZDV is given during the second and third trimesters, through labor and delivery, and to the neonate during the first 6 weeks of life (see Table 8). In the era of enhanced prenatal testing for HIV and with the use of combinations of highly active antiretroviral agents, the U.S. HIV perinatal transmission rate has fallen to 1%–2%. In response to the findings of several large U.S. and European studies, cesarean delivery is now recommended for HIV-positive women who are not on antiretroviral therapy or who have unsuppressed HIV viral load (>1000 copies/mL.) The risks of cesarean

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Table 8 Zidovudine Perinatal Transmission Prophylaxis Regimen Antepartum

Intrapartum Postpartum

Initiation at 14–34 weeks of gestation and continuation throughout pregnancy 100 mg 5 times daily 200 mg tid 300 mg bid During labor, zidovudine (ZDV) 2 mg/kg IV for 1 hour, followed by continuous infusion of 1 mg/kg/hr until delivery Oral administration of ZDV to newborn (ZDV syrup 2 mg/kg q6h) for first 6 weeks of life, beginning at 8–12 hours after birth

Source: CDC. Recommendations of the Public Health Service Task Force on the use of Zidovudine to reduce perinatal transmissions of HIV. MMWR, 43(No. RR-4):1–20, 1994.

delivery include infection, bleeding, and longer recovery period than in vaginal birth. For women who are successfully taking combination antiretroviral therapy and have suppressed HIV replication in the blood, the added benefit of cesarean delivery is expected to be low. False-positive screening test results during pregnancy are becoming increasingly common as the tests are applied to the broader population of pregnant women. The screening HIV enzyme-linked immunosorbent assay (ELISA) and the HIV Western blot are required to confirm HIV-1 infection. Repeat testing in 1–3 months is indicated to rule out HIV seroconversion if a woman has been exposed to HIV during pregnancy. False-positive test results have been a particular problem with rapid HIV tests now in use in some acute care facilities and sexually transmitted disease clinics in the United States. The benefit of rapid HIV testing in this setting is its ability to target ZDV therapy to HIV-positive women who may not have received prior prenatal care in order to attempt to prevent perinatal HIV transmission.

7

VACCINATIONS

In general, vaccinations during pregnancy should be avoided; however, vaccinations for tetanus, hepatitis B virus, and influenza are acceptable. Live vaccines such as measles, mumps, rubella (MMR); oral poliovirus; oral typhoid; and yellow fever vaccines are contraindicated. The pregnant woman needs immunity to tetanus for prevention of neonatal infection. If she is not immune, vaccination with diphtheria/tetanus should be provided. If she is expected to be in the second or third trimester during the influenza season (October through March), she should be vaccinated against influenza virus (also see Chapter 43).

BIBLIOGRAPHY Centers for Disease Control and Prevention. Sexually transmitted diseases. Treatment Guidelines 2002. Morb Mortal Wkly Rep 51(No. RR-6):1–79, 2002. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: A public health perspective. Morb Mortal Wkly Rep 45(No. RR-7):1–24, 1996. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIVinfected adults and adolescents, February 4, 2002. http://www.hivatis.org. Goldenberg RL, Hauth JC, Andrews WW. Mechanism of disease: Intrauterine infection and preterm delivery. N Engl J Med 324(20):1500–1507, 2000.

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Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIVI-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. August 30, 2002. Available at http://www.hivatis.org. Sweet RL, Gibbs RS, eds. Infectious Diseases of the Female Genital Tract, 3rd ed. Baltimore: Williams & Wilkins, 1995. Tuomala RE, Cox SM, eds. Infections in obstetrics. Infect Dis Clin North Am 11(1):1–239, 1997.

34 The Immune-Compromised Patient Robert W. Lyons University of Connecticut, Farmington, Saint Francis Hospital, Hartford, and Yale University, New Haven, Connecticut, U.S.A.

1

INTRODUCTION

The diagnosis of infection in the immune-compromised adult can be difficult. Both the infecting organisms and their manifestations may be different from those in the normal patient. By considering what sort of immune defect a patient has, however, one can often narrow the infection to a few likely organisms. Certain immune defects render a person particularly susceptible to certain infections while not impairing ability to resist others. In the same way the presence of certain infections may be a clue that the patient has an unsuspected immune defect and help in its diagnosis (see Table 1). The immune system is conventionally divided into the humoral immune system, the phagocytic system, and the cell-mediated immune system. The humoral system comprises circulating antibody, complement, and other circulating substances that serve to coat microorganisms and either destroy them or enable phagocytic cells to engulf them. The phagocytic system consists of circulating phagocytes (polymorphonuclear neutrophils) and tissue macrophages that ingest and kill infecting organisms. The cell-mediated immune system, in which thymus-derived lymphocytes (T lymphocytes) play a major role, recognizes new antigens, especially those within cells, and assists in destroying or containing intracellular pathogens. To these three I would add the ‘‘anatomical immune system,’’ which consists of those anatomical structures that by their presence and adequate function protect the body against infection. Examples of the anatomical system include the spleen, intact skin, gastric acid, the neurological reflexes that control swallowing and the function of the epiglottis, the ciliary cells of the bronchi, and the elaborate architecture of the nasal sinuses. I consider in this chapter the organisms that are usually associated with specific immune defects and the signs and symptoms a patient might present that might lead to a suspicion of an immune defect. An approach to the management of the immune-compromised host (ICH), including prevention and recognition of infection, is summarized. Finally an approach to the patient with staphylococcal furuncles is presented. The acquired immunodeficiency syndrome (AIDS), the major immunodeficiency disease in the world, is discussed in more detail in Chapters 25 and 26. The infected immune-suppressed patient presents a complex diagnostic and therapeutic challenge to the clinician. The potential pathogens may be unusual and the signs 661

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Table 1 Immune Defects and Their Infectionsa Defect

Disease

Organisms/diseases

Splenectomy

Postsurgical Idiopathic Sickle cell disease

Pneumococcal sepsis Severe babesiosis Sepsis after dog bite

Achlorhydria

Postsurgical Medication-induced

Enteric pathogens Salmonella, Shigella spp.

IgG deficiency

Common variable immunodeficiency Acquired hypogammaglobinemia Multiple myeloma CLL

Recurrent sinusitis Recurrent pneumonia Bronchiectasis Pneumococcal infection Chronic diarrhea Relapsing giardiasis Severe enteroviral infection

Hyper-IgE syndrome

Job’s syndrome

Chronic eczema Recurrent pneumonia ‘‘Cold’’ S. aureus abscesses Dental abnormalities

Neutropenia

Leukemia Chemotherapy Cyclic neutropenia

S. aureus bacteremia Gram-negative rod infections Pseudomonas sp. Fungal infections (late) Candida, Aspergillus spp.

Neutrophil dysfunction

Chronic granulomatous disease

S. aureus infections Aspergillus spp. infections Serratia spp. infections, osteomyelitis Burkholderia cepacia infection

Neutrophil dysfunction

Leukocyte adhesion defects

‘‘Cold’’ skin abscesses Poor pus formation, elevated WBC Severe gingivitis, tooth loss

Cell-mediated immunity defects

Lymphoma Steroid therapy HIV/AIDS Organ transplantation Immunosuppressive medications Cyclosporine, OKT3, tacrolimus

Thrush Disseminated herpes zoster Cytomegalovirus Cryptococcal meningitis Pneumocystis carinii pneumonia Listeria spp. meningitis Nocardia spp. infections Mycobacterial infections Strongyloidiasis

a

IgG, immunoglobulin G; CLL, WBC, white blood cell count; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome.

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IMMUNE COMPROMISING CONDITIONS Anatomical defects Asplenia Achlorhydria Humoral defects Common variable immunodeficiency Acquired hypogammaglobulenemia Multiple myeloma Chronic lymphocytic leukemia Hyper–immunoglobulin E (IgE) syndrome (Job’s syndrome) Phagocytic defects Neutropenia with absolute neutrophil count (ANC) <1000 polymorphonuclear lymphocytes (PMNs)/mm3 Chemotherapy-induced defect Acute myelogenous leukemia Neutrophil defects Chronic granulomatous disease Leukocyte adhesion defects Cell-mediated defects Lymphoma Steroids Human immunodeficiency virus (HIV) (see Chapters 25 and 26) Organ transplantation Recurrent staphylococcal skin infections (Figure 1)

and symptoms of infection may be subtle but nonetheless life-threatening. Expert consultation is suggested, and collaboration among specialists is needed. 2

ANATOMICAL DEFECTS

Although there are a number of infections associated with the loss of anatomical barriers to infection, two warrant special consideration. 2.1

The Asplenic Patient

The patient without a spleen has a mechanical defect caused by the loss of the spleen’s filtering capacity and its ability to remove microorganisms from the circulation before the appearance of specific antibody. In addition, the spleen is the major producer of opsonizing antibody required for phagocytosis of organisms. Asplenic patients are particularly susceptible to overwhelming infections with encapsulated organisms, particularly Streptococcus pneumoniae and Haemophilus influenzae; with Capnocytophagia canimorsus (an infection usually caused by a dog bite); and with the blood parasite Babesia microti. The usual syndrome is fever, disseminated intravascular coagulation, and shock, which begin within a few hours and usually progress rapidly to death. Pneumococcal vaccine should be given to all asplenic patients. If a patient is to undergo elective splenectomy, he or she should be given the vaccine at least 2 weeks prior to surgery. If the patient has already had the spleen removed or if the spleen is not

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functional because of disease, as occurs in sickle cell anemia, the vaccine should still be given, but it may be less efficacious. Haemophilus influenzae B vaccine should be given to asplenic children. Its usefulness in adults is unclear. Asplenic patients should be counseled to use pesticides and to wear protective clothing if they are going to an area where ticks may harbor Babesia spp. (see Chapter 30). Fever in any patient who is asplenic should be taken very seriously and hospitalization should be considered. 2.2

Patients with Achlorhydria

The presence of gastric acid is an important barrier against food-borne pathogens, particularly salmonella and, in endemic areas, cholera. Giannella et al. showed years ago that patients who are achlorhydric because of gastric resection are more likely to contract salmonella infection and to have more severe disease than patients with normal amounts of stomach acid. Volunteer studies also showed that increasing the gastric pH of volunteers made them more susceptible to small doses of shigella and Vibrio cholerae. In the modern era of H2 blockers and proton-pump inhibitors, we can make patients more susceptible to enteric infection while protecting them from peptic ulcer disease. There is also anecdotal evidence that patients who lack adequate stomach acid are at higher risk than normal hosts of parasitic diseases such as strongyloidiasis and giardiasis. If a patient who is known to have achlorhydria, as a result of either disease or drug therapy, experiences fever and diarrhea, stool cultures should be obtained. If such a person is to travel to the developing world, he or she should be warned to exercise particular caution about food and water. 3

HUMORAL DEFECTS

There are numerous humoral immune defects that are manifested in infancy and early childhood that are beyond the scope of this chapter. I consider here humoral immune defects and complement deficiencies that may be encountered in adults in an outpatient setting. Patients with humoral defects often have chronic sinusitis or respiratory infections. The occurrence of unusual or repeated infections with S. pneumoniae should always raise the question of acquired hypogammaglobinemia. Many of these patients also have increased susceptibility to gastrointestinal (GI) pathogens, presumably because of immunoglobulin A (IgA) deficiency in the GI tract. Patients who have hypogammaglobinemia usually handle viral infections normally, although adequate immune response may not develop. This lack may lead to recurrent infections. Infection with enteroviruses, however, may be unusually severe, and chronic meningoencephalitis may ensue. This susceptibility to severe enteroviral disease is probably due to deficiency of IgA in the gut. IgA deficiency may also cause an increased susceptibility to Giardia lamblia and bacterial enteropathogens. 3.1

Common Variable Immunodeficiency

Common variable immunodeficiency is a congenital disease due to abnormal B-lymphocyte function. It has a bimodal age distribution with peaks at ages 3–5 and 15–20. Some patients may not be diagnosed well into adult life. The patients have very low levels of both IgG and IgA but may have normal IgM levels. Patients typically report chronic

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sinusitis and mastoiditis and/or recurrent pneumonia. Many have bronchiectasis by the time they are diagnosed. Chronic diarrhea is another manifestation of common variable immunodeficiency. Such patients are prone to infection with Giardia lamblia and with Campylobacter spp. and other bacterial enteropathogens. They also have a high incidence of chronic inflammatory bowel disease. Treatment is directed at restoring the serum IgG levels with replacement ␥ -globulin to a level of >5.0 g/L. This can usually be done with monthly injections of 400 mg/kg of IgG. 3.2

Acquired Hypogammaglobinemia

As noted, a hallmark of acquired hypogammaglobinemia is repeated or unusual infection with encapsulated organisms. In that respect patients with this problem are like asplenic patients, but, unlike asplenic patients, they do not usually have overwhelming sepsis. Acquired hypogammaglobinemia may progress to development of bronchiectasis, as does common variable immunodeficiency, but affected patients usually receive medical attention before the disease becomes chronic. Although acquired hypogammaglobinemia may be idiopathic, two important causes to consider are multiple myeloma and chronic lymphocytic leukemia. Patients with these disorders may need immunoglobulin replacement as well as therapy for their primary disease. Recurrent pneumococcal infection, especially in an elderly patient who has back pain or anemia, should raise the suspicion of multiple myeloma. Immunoglobulin electrophoresis is warranted in such a patient. 3.3

Hyper–Immunoglobulin E Syndrome (Job’s Syndrome)

The first point to be clear about is that Job did not have Job’s syndrome. Job, the biblical figure for whom the syndrome is named, had the acute onset of boils, together with a large number of financial reverses and personal tragedies, that came upon him in middle life. Previously he had apparently been in good health. The syndrome that bears his name is a congenital abnormality that manifests itself in infancy with chronic eczema, pneumonia, and cold skin abscesses due to Staphylococcus aureus. These patients usually have hypereosinophilia and levels of IgE in excess of 2000 IU/mL. Attention has recently been drawn to dental abnormalities and craniofacial and skeletal abnormalities in many patients. The patients do not shed their primary teeth, and the permanent teeth erupt behind or in front of the retained primary teeth. Many patients have hyperextensible joints, abnormalities of midline facial development, and frequent bone fractures. The disease is inherited in an autosomal dominant manner but with variable expressivity. Some patients with Job’s syndrome may survive into adulthood and seek care in an adult medicine office. Most patients with recurrent boils, however, do not have Job’s syndrome, just as he did not. The diagnosis should only be considered when patients report recurrent skin and pulmonary infections since early childhood. 3.4

Complement Deficiency

Deficiencies in complement are relatively rare. They can be inherited (0.03% of the population) or acquired. Acquired defects can occur during acute infection or are related to rheumatological disease. There is an association between deficiencies of the terminal com-

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ponents of the complement cascade (C5, C6, C7, C8) and increased infections due to Neisseria gonorrhoeae and N. meningitidis. Patients who have recurrent neisserial infections may warrant evaluation for complement deficiency. 4

PHAGOCYTIC DEFECTS

Defects in the phagocytic arm of the immune system can be further subdivided into those in which the number of phagocytic cells is decreased and those in which the number is normal, but the cells do not function efficiently. Patients with phagocytic defects are susceptible to a broader variety of bacterial infections than those that infect patients with humoral defects, but they are not particularly susceptible to some of the organisms that may afflict patients with defects in cell-mediated immunity. These distinctions between infecting organisms may become blurred in some patients, such as those on cancer chemotherapy, who may have defects in more than one branch of the immune system. 4.1

Neutropenia

The most common phagocytic defect is a decrease in the absolute number of circulating phagocytes. This is commonly measured as the absolute neutrophil count (ANC). The ANC can be calculated by multiplying the white blood cell count per cubic millimeter by the fraction of the count made up of mature neutrophils and band forms. Thus in a patient receiving systemic chemotherapy who has a white blood cell count of 1000 cells/mm3 of which 25% are mature neutrophils and 5% are band forms, the ANC is 1000 ⫻ (0.25 ⫹ 0.05) = 300 cells/mm3. It is not until the ANC falls below 1000 that problems with infection begin to arise. The problems become both more frequent and more severe when the ANC is less than 500. Patients with severe neutropenia are predominantly at risk for infection, especially bacteremia, with aerobic gram-negative rods (GNRs) from their own GI tract and Staphylococcus aureus. In some reports Pseudomonas aeruginosa has been a major pathogen in such patients, although it is my clinical impression that bacteremia with this organism is not as common as it once was. Bacteremia with anaerobic organisms is remarkably infrequent in such patients. Patients with neutropenia are usually not at increased risk for viral or fungal infections in the early stages of neutropenia. Fungi (Candida spp. and Aspergillus spp.) usually become important pathogens in such patients only after they have been neutropenic for prolonged periods and have received multiple courses of antibiotic therapy that have eliminated their normal microbial flora. The most commonly seen individuals with severe neutropenia are acute myelogenous leukemia patients and cancer patients on chemotherapy. These patients are especially susceptible to infection with bowel organisms, probably because of the deleterious effect of chemotherapy on the bowel mucosa. Patients with severe neutropenia from other causes such as cyclic neutropenia or aplastic anemia seem somewhat less susceptible to infection, but when they become infected, it is usually with the same organisms as other neutropenic patients: aerobic GNRs and S. aureus. Management of the febrile neutropenic patient is reviewed in Chapter 2. In the past, management usually necessitated hospitalization of the febrile patient if the ANC fell below 1000 cells/mm3 (some experts use 500 cells/mm3). With the advent of well-absorbed oral antibiotics with activity against P. aeruginosa (ciprofloxacin) and gram-positive bacteria (amoxicillin-clavulanic acid), outpatient oral therapy is possible for low-risk patients.

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Such patients include those receiving chemotherapy for solid organ tumors who have an expected duration of neutropenia of less than 1 week, are nontoxic, are able to tolerate oral antibiotics, and have close follow-up. 4.2

Neutrophil Dysfunction

There are a variety of defects of phagocytic function in which the patient’s white blood cell (WBC) count is normal or even high, but in which the patient’s neutrophils do not function efficiently enough to protect their host from infection. They are rarely seen in adult practice because most patients so afflicted die of infection in childhood. Two forms of neutrophil dysfunction merit brief consideration: chronic granulomatous disease and leukocyte adhesion defects. 4.2.1

Chronic Granulomatous Disease

The neutrophils of patients with chronic granulomatous disease (CGD) are able to ingest bacteria normally but are unable to kill them because of inability to generate hydrogen peroxide. With some species of bacteria the neutrophil can, however, utilize the hydrogen peroxide made by the bacteria itself to kill it. Bacteria (and fungi) that escape this fate are those that dispose of their own hydrogen peroxide by making the enzyme catalase. Streptococci that are unable to produce catalase are killed normally. Catalase producing bacteria such as S. aureus can cause chronic and severe infections in these patients. There are several genetic forms of CGD. Patients with the X-linked form are most severely infected and usually do not survive into adulthood. There are also several forms of autosomal inheritance, however, that are less severe. Patients who have one of these forms may survive into adulthood. Severe, prolonged, and recurrent infections of soft tissue, bone, and lungs with S. aureus, Burkholderia (Pseudomonas) cepacia, Serratia marcescens, or species of Aspergillus are the hallmark of CGD. The diagnosis should be considered when a patient has recurrent infections of this sort and a history of such infections since childhood. The most widely used test for CGD is the nitroblue tetrazolium (NBT) test. 4.2.2

Leukocyte Adhesion Defects

The neutrophils of leukocyte adhesion defect (LAD) patients adhere poorly to vascular epithelium and have difficulty in migrating to an area of infection. This is due to a defect in the cell wall of the neutrophil. Most patients die in childhood, but some patients with less severe manifestations survive to adulthood. These patients suffer from frequent skin infections in which they have ‘‘cold abscesses’’ or necrotic infections with little or no pus formation. They also experience visceral infections with similar manifestations. Gingivitis is a universal problem, and alveolar bone reabsorption and tooth loss are problems for adults. The patients typically run a high white blood cell count, 20,000 cells/mm3 or more. As in CGD, the diagnosis of LAD should be considered when someone has a history of recurrent bacterial infections from childhood, especially if accompanied by chronic gingivitis and chronic leukocytosis. Unlike in CGD there is no simple test for LAD, and patients suspected of having the disease should be referred to a center specializing in the disorder. 5

CELL-MEDIATED IMMUNE DEFECTS

The major disease in which cell-mediated immune (CMI) dysfunction predisposes to infection is, of course, acqired immunodeficiency syndrome (AIDS), which is discussed in

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Chapters 25 and 26. I would like to consider here the results of the lymphocyte dysfunction seen in lymphoma, that associated with chronic use of adrenocortical steroids and with organ transplantation. 5.1

Lymphoma

Generally speaking, lymphoma patients have a lower risk of severe bacterial infections (with the exception of Listeria, Nocardia, and Legionella spp.) than patients with neutrophil abnormalities, unless they are receiving chemotherapy that renders them neutropenic. The infections seen in these patients are more often mycobacterial, fungal, viral, or, occasionally, parasitic. Listeria monocytogenes is a gram-positive rod usually acquired by ingestion of infected food, often cheese or other milk products. In the normal host it usually causes a mild disease. In a pregnant woman it may cause a devastating infection of the fetus. In patients with lymphoma or in the elderly it can cause a bacteremia and/or severe meningitis. Listeria spp. should always be borne in mind when confronted with a bacterial meningitis in a patient with lymphoma. The organism is sensitive to ampicillin but resistant to the third-generation cephalosporins so often used to treat bacterial meningitis. Nocardia asteroides is a filamentous branching bacterium that resembles a fungus on Gram stain. It causes cavitary lung lesions that may be mistaken for tuberculosis. It may also cause nodular skin lesions and frequently spreads to the brain, where it causes mass lesions and abscesses. It responds to therapy with various sulfa drugs. Legionella spp. (L. pneumophila is most common) are aerobic gram-negative rods transmitted by aerosol commonly related to potable water systems. The most common clinical syndrome is pneumonia with fever, dry cough, and pleuritic chest pain. In the immune-compromised host the cough may be minimal. Diagnosis is by culture on charcoal yeast extract agar or urinary antigen detection (L. pneumophila serogroup 1 only). Therapy employs a macrolide or flouroquinolone. Of the fungal infections the ones most likely to be encountered among outpatient lymphoma patients are oral thrush due to Candida albicans and meningitis due to Cryptococcus neoformans. Such infections may be the first manifestation of lymphoma. Oral thrush in the absence of steroid or preceding antibiotic use always raises the question of a defect in cell-mediated immunity. If there is no obvious cause, its presence should prompt the search for lymphoma, leukemia, or human immunodeficiency virus (HIV) infection. Cryptococcal meningitis can be surprisingly indolent. It may present in an outpatient who reports persistent headache for several weeks with gradual changes in mental acuity or personality changes. A positive blood test result for cryptococcal antigen may suggest the diagnosis, but a negative test result does not exclude it. The only method that makes or excludes the diagnosis with certainty is spinal tap. Although some patients with apparently normal immune systems may acquire cryptococcal meningitis, the finding should prompt a search for an immune defect. Pneumocystis carinii, once thought to be a parasite, is a fungus. It may cause pneumonia in lymphoma patients just as it does in AIDS patients, although not as commonly. The manifestations of the pneumonia—a bilateral interstitial infiltrate with slowly progressive hypoxia—are much the same as those seen in AIDS, although the disease may be even more indolent. Of the viral infections the Herpesviridae family, including herpes simplex virus (HSV 1 and HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes 6, 7, and 8, are of greatest concern. Disseminated herpes zoster

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(more than 10 lesions outside the principal dermatome) may be a first manifestation of a lymphoma, as may severe herpes simplex infection. CMV infections are usually not an early manifestation of lymphoma, but CMV pneumonia may be a problem as the disease progresses. Parasitic infections include Toxoplasma gondii, Cryptosporidium parvum, and Strongyloides stercoralis infections. Of these Strongyloides sp. infection merits special attention. This nematode can persist in its human host for decades, and when cell-mediated immunity declines, it can disseminate to lung, brain, and other organs as the number of worms expands exponentially in what is called the hyperinfection syndrome. If a patient is from the Caribbean, Southeast Asia, or the tropics and has a defect in cell-mediated immunity, it is worth checking the stool for Strongyloides spp. and treating it if found. 5.2

Glucocorticosteroid Therapy

Therapy with glucocorticosteroids can cause a variety of immune defects, including interference with neutrophil migration and impairment of antibody response to new antigens, but the effect on cell-mediated immunity is probably the major one. Significant defects in cell-mediated immunity are not seen with low-dose therapy (ⱕ10 mg. of prednisone per day) or even with high-dose therapy for a few days. It has been shown that cumulative doses of ⱕ700 mg of prednisone are not associated with increase in infection risk. With higher doses and prolonged therapy the risks of infection mimic those seen with lymphoma. Of particular concern are infections with the bacteria Listeria and Nocardia spp.; with fungus, especially Candida species, Cryptococcus neoformans, and Pneumocystis carinii; with the herpesvirus group; and with Strongyloides stercoralis in a host from the appropriate geographical area. Patients who use steroids are probably not particularly susceptible to infection with M. tuberculosis, but they are more susceptible to disease with that organism. They are more likely to experience reactivation of old quiescent tuberculosis lesions and development of active disease after high-dose steroid administration than they would be if they were not receiving that drug. 5.3

Organ Transplantation

With the introduction of effective immune suppressing agents such as glucocorticosteroids, azathioprine, and cyclosporine (Neoral), and more recently tacralimus (Prograf), mycophenolate mofetil (Cellcept), and muromonab/CD3 (Orthoclone OKT3), the number of patients receiving organ transplantation has markedly increased. The primary care provider needs to be vigilant about infections in these patients. The posttransplantation patient is at risk for bacterial infections, Listeria spp., mycobacteria, and Legionella sp.; fungal infections, Pneumocystis carinii, Cryptococcus, Aspergillus, and Candida spp.; and viral infections, HSV, VZV, EBV, and CMV. In addition to causing infectious mononucleosis, EBV can cause a posttransplantation lymphoproliferative disorder, including extranodal lymphoma. Patients who receive lung or heart-lung transplantation are at highest risk for infection and infection-related mortality. Also at very high risk are liver transplantation recipients. At somewhat lesser, though still quite serious, risk are heart and kidney transplantation recipients. The most important pathogen for the transplantation recipient is CMV. As does all herpesviruses, CMV can establish latency and later reactivate. Infections can therefore be

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primary in a nonimmune transplantation recipient, a reactivation of dormant virus in the recipient, or suprainfection with a second strain from the donor into the recipient who has CMV infection. Primary CMV infection occurs when the organ recipient who is CMV antibody– negative receives a CMV-positive organ or blood transfusion. Primary infection can cause fever, leukopenia, thrombocytopenia, atypical lymphocytosis, myalgia, and arthralgia. Other manifestations can include colitis, interstitial pneumonitis (especially in allogeneic bone marrow transplantation), and hepatitis (especially in liver transplantation). In the organ transplantation recipient who has had previous CMV infection, reactivation of CMV or superinfection can cause a febrile mononucleosis-like illness that is generally less severe than the primary infection. Diagnosis can be made by histological demonstration of CMV intranuclear inclusion bodies and by detection of CMV antigen in neutrophils. Reliance on CMV culture is problematic since growth of the virus in urine and sputum does not differentiate active CMV disease from asymptomatic infection. CMV infection may also make the transplantation recipient at greater risk for Pneumocystis carinii, Nocardia spp., and Listeria spp. infections and can contribute to allograft injury, leading to increased rejection. Allograft rejection and drug toxicities can mimic infection, and differential diagnosis can be challenging.

6 6.1

THE IMMUNE-SUPPRESSED PATIENT Presentations Suggestive of Immunodeficiency

The patient at risk for immune suppression and opportunistic infection can be approached from two different directions. One approach involves assessment of the type of immune defect the patient has on the basis of underlying illness. Subsequent infection risk can be judged by the type of immune defect present (see Table 1). The other approach is retrospective when the patient has an infection. Certain infections raise the possibility that a patient has an undiscovered immunodeficiency and may call for further evaluation (see Table 2). Repeated infections with Streptococcus pneumoniae suggest that the patient may have an immunoglobulin G (IgG) deficiency. When these occur in an elderly patient or an elderly patient has an unusual pneumococcal infection such as pneumococcal arthritis, the possibility of a hitherto undiscovered multiple myeloma or chronic lymphocytic leukemia should be considered. Recurrent sinusitis accompanied by recurrent bronchitis since childhood may be a late manifestation of common variable immunodeficiency in an adult and warrants an immunoglobulin electrophoresis. Most recurrent skin infections are not due to an immune defect. Chronic eczema and recurrent Staphylococcal spp. abscesses with little inflammation around them (‘‘cold abscesses’’), however, may suggest either hyper-IgE syndrome or a leukocyte adhesion defect, especially if there is a history of such infections since childhood and the patient also has dental or gingival abnormalities. Recurrent staphylococcal infections are also seen in patients with chronic granulomatous disease. Osteomyelitis caused by Serratia marcescens is seen in this disease and is virtually unheard of in any other situation. The occurrence of oral thrush is a marker for a cell-mediated immune defect. Its occurrence in an adult who is neither on antibiotics or glucocorticoids nor diabetic should raise the question of HIV infection or lymphoma. This is even more true of Pneumocystis

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IMMUNE-COMPROMISED PATIENTS May have unusual pathogens and life-threatening infections; specialty consultation suggested Approach to the patient Prevention of infection Immunizations Pneumovax Hepatitis A, B Influenza (yearly) Trimethoprim & sulfamethoxazole (TMP-SMZ) for Pneumocystis carinii pneumonia (PCP)/Toxoplasma spp. prophylaxis Quinolones and fluconazole for organ transplantation recipient Type of immune defect Immune defect that can be predicted by underlying illness (see Table 1) Immune defect that can predict type of opportunistic infection (see Table 1) Type of infection that may identify immune defect (see Table 2) Degree of immune abnormality Prolonged high-dose steroid use First 6 months post organ transplantation Absolute neutrophil count (ANC) <1000 cells/mm3 CD4 count <200 cells/mm3 Initial evaluation of febrile patient Thorough history and physical examination Minimal signs and symptoms that may presage serious infections Complete blood count, liver function tests, urinalysis, chest radiography Blood and urine cultures Consideration of hospitalization for Temperature >38.5⬚C Fever for >1 week ANC <1000 PMN/mm3 Abnormal chest radiography finding

carinii pneumonia (PCP). Meningitis with Cryptococcus or Listeria spp. may be seen in patients with normal immune function, but its occurrence should also raise the question of a cell-mediated immune defect. Disseminated herpes zoster may be the first clue to an occult lymphoma or leukemia and should be followed up. The same may be said of recurrent herpes zoster, although in my own experience ‘‘recurrent herpes zoster’’ is almost always recurrent herpes simplex occurring in an unusual skin site. Since it is in the nature of herpes simplex to recur again and again in the same area, this phenomenon does not suggest a immunodeficiency. If there is any doubt which virus is involved, culture should be done. 6.2

Degree of Immune Abnormality

Once the type of defect is assessed, the degree of immune suppression should be estimated. This estimate can be made from the type and duration of immunosuppressive therapy, depth of neutropenia, or level of CD4 cells in the HIV-infected person.

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Table 2 Presentations That Suggest Immunodeficiency Presentation

冎

Repeated pneumococcal infections Unusual pneumococcal infections Recurrent sinusitis and bronchitis from childhood Chronic eczema and cold staphylococcal abscesses (especially when associated with dental abnormalities) Serratia spp. osteomyelitis

Immunodeficiency a

再

Acquired IgG deficiency Multiple myeloma, CLL Common variable immunodeficiency Hyper-IgE syndrome Leukocyte adhesion defects Chronic granulomatous disease Chronic granulomatous disease

冎 再

Oral thrush Disseminated herpes zoster Listeria or Nocardia spp. infections Cryptococcal meningitis Pneumocystis carinii pneumonia a

冎再

Cell-mediated immune defect Lymphoma Corticosteroid use HIV infection Organ transplantation Cushing’s syndrome

IgG, immunoglobulin G; CLL, HIV, human immunodeficiency virus.

The patient undergoing systemic chemotherapy with resultant neutropenia is at increased risk when the ANC falls below 1000 cells/mm3. Bacteremia is more frequent when the ANC falls below 200 cells/mm3. The organ transplantation recipient is at highest risk for opportunistic infections during the first 6 months post transplantation, when immune suppression is maximized. Patients who receive additional immune suppression for organ rejection are at higher risk for infection. With the reduction of immune suppressants over time, though, the risk of infection diminishes. The HIV-infected patient who has more than 200 CD4 cells/mm3 is at limited increased risk for bacterial infection but not for the classic opportunistic infections (OI). The risk for Pneumocystis carinii pneumonia and cerebral toxoplasmosis increases once the CD4 falls below 200/mm3. CD4 cell counts <100 cells/mm3 increase the risk for CMV and mycobacterial infections. 6.3

Prevention of Infection

The prevention of many of the infections that the immune-suppressed host is at risk for is possible. Immunizations can avert infections caused by S. pneumoniae, H. influenzae, hepatitis A and B viruses, and influenza virus. (Live vaccines should be avoided.) Trimethoprim & sulfamethoxazole (TMP-SMZ) can prevent PCP and toxoplasmosis in patients who have cell-mediated immune defects in addition to reducing the incidence of urinary tract infections and bronchitis. Quinolone antibiotics can decrease GNR infections in bone marrow transplantation recipients but increase the risk of bacterial resistance and drug reactions. Prophylactic antibiotic therapy, though, is not recommended for asymptomatic neutropenic patients. Similarly, fluconazole can decrease fungal colonization and invasive infection but increases the risk of selection for fluconazole-resistant fungi (Candida krusei and Aspergillus spp.) and does not improve the mortality rate. CMV infection can be

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prevented in the transplantation recipient with intravenous or oral ganciclovir, valacyclovir, or CMV immunoglobulin. Patients with immune globulin deficiencies can be treated with intravenous immune globulin on a monthly basis. There is no role for prophylactic penicillin in the adult asplenic patient. Penicillin has been used successfully in children with functional asplenia caused by hemoglobinopathies to prevent pneumococcal sepsis. The risk of drug toxicities and bacterial resistance outweighs the potential benefits to the adult. 6.4

Initial Assessment of the Febrile Immune-Compromised Patient

Transplantation recipients are at increased risk for infection as a result of not only immune suppression but also operative procedures, disruption of normal anatomical features, allograft ischemia in the transplantation recipient, central venous catheters, and alteration of normal bacterial flora through antimicrobial use. Differentiation of infection from noninfection can be challenging since patients who have relapsing primary leukemia or lymphoma, drug fever, graft-versus-host disease, and allograft rejection can present symptoms similar to those of infections. Differentiation is vital since diagnostic approach and therapeutic intervention are quite different. The immune-compromised patient who has fever or suspected infection requires a detailed history and physical examination. The most common sites of infection include the oral cavity, lung, skin, surgical wounds, and central catheters. Since the inflammatory response may be blunted, awareness of the potential for more serious illness is needed even for minor symptoms or signs. Examples include a persistent dry cough presaging Pneumocystis carinii pneumonia, slight erythema around a central venous catheter representing an early catheter infection, and bacteremia or mild erythema and perirectal pain marking a rectal abscess. Despite the best clinical acumen the clinician is unable to determine whether a febrile patient is bacteremic or not. Initial laboratory assessment should include a complete blood count (CBC), liver function tests (LFTs), urinalysis (u/a), chest radiography (CXR), and cultures of blood and urine. Hospitalization should be considered for patients with temperatures >38.5⬚C, abnormal chest radiographic findings, or temperatures persisting for more than 1 week. 7

THE PATIENT WHO HAS RECURRENT STAPHYLOCOCCAL FURUNCLES

Perhaps the most common office situation in which the question of immunodeficiency arises occurs when a patient has recurrent staphylococcal boils or furuncles. Very, very few of these patients have an immune defect (see Figure 1). In evaluating such a patient it is useful to culture a lesion and to obtain a history of how long the patient has been plagued by such lesions. If the history of the lesions does not extend back to childhood, one can eliminate most major immune defects. If the lesions first appeared in adolescence, they may be a manifestation of cystic acne persisting into adulthood. Acne lesions, however, are not due to S. aureus. If the lesions are recurrent in the axilla or groin, one should consider the diagnosis of hidradenitis suppurativa, a disease of the apocrine glands usually treated surgically. The lesions of hidradenitis suppurativa usually contain a mixture of aerobic and anaerobic organisms and often grow GNRs. If there is a history of skin infections since childhood, then evaluation for immunodeficiency, as noted, may be useful. If there is not, it is worth making some routine blood tests to establish that the patient does not have undiscovered diabetes or leukemia. The usual problem, however, is not a matter of host resistance, but of colonization of the host with an invasive strain of S. aureus.

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Figure 1 The patient who has recurrent staphylococcal skin infections generally does not have an immune defect unless they have occurred since childhood. Immunological evaluation is not otherwise indicated.

If the patient is immunocompetent, as most are, I would proceed with a culture of both nares for S. aureus and start treatment with an oral antistaphylococcal antibiotic and rifampin 600 mg orally each day. If the nares cultures grow S. aureus, I would also treat the nares with mupirocin ointment. I would continue this therapy for 10 to 14 days. The patient should also be encouraged to improve his or her hygiene; it may be useful to advise bathing with a hexachlorophene soap. This course proves satisfactory in many cases, although there are patients who experience relapse. In that case, I would repeat the regimen and also look closely at any factors in the patient’s life such as pets or work or home environment that might expose him or her to recurrent S. aureus infections.

BIBLIOGRAPHY Aucott JN. Glucocorticoids and infection. Endocrinol Metab Clin North Am 23:655–670, 1994. Brigdon ML, Pattullo AL. Prevention and management of overwhelming postsplenectomy infection —an update. Crit Care Med 27:836–842, 1999.

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Cohen JI. Enteroviruses and reoviruses. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. Harrison’s Principles of Internal Medicine, 14th ed. McGraw Hill, 2000. Cooper NM, Lawton AR III. Primary immune deficiency diseases. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. Harrison’s Principles of Internal Medicine, 14th ed. McGraw Hill, 2000. Dahl MV. Strategies for the management of recurrent furunculosis. South Med J 80:352–256, 1987. De Pauw BE, Donnelly JP. Infections in the immunocromprised host: General principles. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingstone, 2000. Dummer JS, Ho M. Risk factors and approaches to infections in transplant recipients. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingstone, 2000. Giannella RA, Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections: A perspective. Ann Intern Med 78:271–276, 1973. Grimsbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O’Connell AC, Dent B, Peck J. Hyper-IgE syndrome with recurrent infections: An autosomal dominant multisystem disorder. N Engl J Med 340:692–702, 1999. Hermaszewski RA, Webster ADB. Primary hypogammaglobulinaemia: A survey of clinical manifestations and complications. Q J Med 86:37–42, 1993. Hoss DM, Feder HM Jr. Addition of rifampin to conventional therapy for recurrent furunculosis. Arch Dermatol 131:647–648, 1995. Johnson RM, Brown EJ. Cell mediated immunity in host defense against infectious diseases. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingstone, 2000. Nauseff WF, Clark RA. Granulocyte phagocytosis. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingstone, 2000. Rubin R, ed. Infections in Transplantation. Infectious Disease Clinics of North America. Philadelphia: WB Saunders, 1995.

35 Infections in the Injection Drug User Audrey L. French Cook County Hospital, and Rush Medical College, Chicago, Illinois, U.S.A.

1

INTRODUCTION

Infection is the most common cause of death in injection drug users (IDUs). Many of these infections are preventable even in the setting of persistent drug use by measures such as use of clean injection equipment, condoms, and vaccination. Thus, every encounter with an IDU should be considered an opportunity for disease prevention and harm reduction for the IDU, his or her sexual partner(s), and their children. Many IDUs are cooperative with care; however, some drug users may behave in a way that makes the relationship with the outpatient clinician challenging. A collaborative and productive relationship with the IDU can be accomplished by providing care in a nonjudgmental fashion and clearly establishing the goals of the relationship. Although cessation of illegal drug use may be the ultimate goal of the clinician, attempts to treat the addiction without the consent of the IDU are counterproductive and harmful to a therapeutic relationship. A therapeutic alliance with clear expectations on each side of the relationship is essential for completing a course of treatment in the outpatient setting. Ultimately the establishment and maintenance of a respectful therapeutic relationship may facilitate treatment of the addiction. Although a number of studies have explored the effects of injection drug use on the immune system, no consistent defect has been identified that can be ascribed to the drug use itself. However, the living conditions of many IDUs do contribute to susceptibility to infectious diseases by factors such as poor hygiene and malnutrition. Efforts to improve living conditions and conditions under which drugs are injected are important to prevention in this group even when the addiction itself is not amenable to treatment.

2

APPROACH TO THE FEBRILE INJECTION DRUG USER

Causes of fever in the IDU are many and include anything from a benign reaction to injected material itself to life-threatening soft tissue, cardiac, or central nervous system infection. Several studies have prospectively evaluated febrile IDUs in urban emergency departments (EDs) to elucidate the spectrum of causes and identify clinical predictors of serious illness. In a study from the Bronx of 87 febrile episodes in 75 IDUs, the authors found that 38% were attributable to pneumonia and 13% to endocarditis; 26% of fevers 677

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were ultimately attributable to less significant illnesses that did not require hospitalization. Clinicians were asked to predict which patients had minor illness. Although diagnostic acumen was good, 29% of patients in whom minor illness had been predicted were ultimately diagnosed with serious illness. The authors found no reliable laboratory or clinical predictor of endocarditis except pyuria. A similar study performed in Boston of 283 IDUs with febrile episodes found clinicians predicted that 103 episodes were due to minor illness. Eleven (11%) of these episodes were actually due to major illness, including 7 of endocarditis. The authors compared those with occult major illness to those with minor illness and found that higher temperature, more recent injection drug use, and proteinuria were associated with more significant illness. The authors of both of these studies concluded that all febrile IDUs require hospital admission unless follow-up can be assured. The authors caution that clinicians consider the selection bias of self-referral to an ED. It is possible that the patients studied had more severe conditions than those in an outpatient office. However, unless follow-up is certain, as in the setting of residential drug treatment or a methadone maintenance program, consideration should be given to hospitalization of all febrile injection drug users at least until blood culture findings are negative. 3

SKIN AND SOFT TISSUE INFECTIONS

Skin and soft tissue infections are the most common infection of IDUs. These may be simple infections amenable to outpatient treatment, but care must be taken to rule out serious complications that are common in the IDU. 3.1

Cellulitis

The reason for the high incidence of soft tissue infection in IDUs is the repeated subcutaneous and intravenous self-inoculation with nonsterile equipment. Often the injected

SOFT TISSUE INFECTIONS Cellulitis Mostly Staphylococcus and Streptococcus spp. Less commonly gram-negative rods (GNRs), anaerobes Therapy: first-generation cephalosporin, dicloxacillin, clindamycin, ampicillin-clavulanate Hospitalization for large abscesses, involvement of hand or neck Ulceration Tissue necrosis from injected material and chronic venous stasis Local wound care and antibiotics if assocated with cellulitis Culture results not reliable May be necessary to rule out underlying osteomyelitis Fasciitis Medical emergency Excessive pain, bullae, anesthetic skin, crepitance Group A ␤-hemolytic Streptococcus spp. or mixed aerobic/anaerobic Pyomyositis Deep muscle abscess Most often S. aureus Drainage necessary

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substances themselves can cause vasoconstriction and ischemia, leading to devitalized tissues. It is because of the varied organisms injected and the presence of devitalized tissue that skin and soft tissue infections in the IDU can be more complex than in the non-IDU. Skin pathogens such as Staphylococcus and Streptococcus spp. are the most common organisms found in cellulitis in IDUs. It is important to note that methicillin-resistant Staphylococcus aureus (MRSA) is more prevalent in soft tissue infections in IDUs than in the general outpatient population. In some series MRSA is the most common organism isolated, probably engendered by the widespread use of nonprescribed antibiotics to selftreat or prevent infections. Some, but not all, of these infections may be treatable by clindamycin. Other organisms are more rarely seen. Oral organisms such as Eikenella corrodens, Haemophilus spp., and pneumococcus may be found when IDUs lick their needles prior to use. Anaerobes, such as Fusobacterium nucleatum and Prevotella, Peptostreptococcus, and Veillonella spp. (predominantly mouth organisms), are prominent in some series. Enteric gram-negative rods (GNRs) are found in a substantial minority of patients. Polymicrobial infections are common, representing the majority of infections in series in which good anaerobic technique is used for culture. Before deciding to treat cellulitis on an outpatient basis, the clinician must rule out conditions that require major surgical intervention such as large abscesses or soft tissue necrosis requiring de´bridement. Necrotizing fasciitis, a medical emergency, requires a high level of suspicion for rapid recognition (see later discussion). Skin abscess is exceedingly common and may not be obvious on physical exam. Imaging studies such as ultrasound may be necessary to delineate fully the anatomical features and the extent of the abscess, but small abscesses may be incised and drained in the outpatient setting. Soft tissue infection in certain anatomical locations requires an inpatient approach in most cases. Infections of the neck may spread to adjacent sites, including the carotid sheath. Many hand infections require specialty consultation. If outpatient therapy is chosen, an agent with activity against S. aureus, Streptococcus spp., and mouth anaerobes should be chosen. A first-generation cephalosporin or penicillinase-resistant penicillin such as dicloxicillin may suffice. Clindamycin or amoxicillinclavulanate may be used if there is a concern that anaerobic organisms are prominent. The role of the recently approved drug linezolid, which has excellent oral bioavailability and activity against gram-positive organisms including MRSA, has yet to be clarified. Oral linezolid should not be used when intravenous therapy is indicated, as in S. aureus bacteremia. Because of the cost of the drug, it should be used only when organisms sensitive to no other oral agent have been isolated. 3.2

Ulcers

Soft tissue ulcers are common in the injection drug user and may be caused by acute necrosis and tissue damage that result from injecting vasoconstricting substances or from chronic venous stasis as a consequence of long-term IDU. Ulcer management is primarily an issue of local wound care with de´bridement as necessary. Antibiotics are clearly indicated when there is concomitant cellulitis and some experts recommend using them until the wound is completely covered with granulation tissue. Cultures from ulcers are notoriously poor predictors of offending pathogen(s), and antibiotic choice should be based on the likely organisms, which are S. aureus, Streptococcus spp., and GNRs. Underlying osteomyelitis is important to recognize but difficult to diagnose. Plain films may reveal a periosteal reaction and therefore do not yield conclusive results. A triple-phase bone scan may be helpful, and a positive result supports the diagnosis. Bone biopsy with culture is

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the definitive test but may require traversing infected tissue and therefore may be contraindicated. 3.3

Necrotizing Fasciitis

The combination of devitalized tissue and recurrent introduction of bacterial pathogens puts IDUs at high risk for necrotizing fasciitis. Necrotizing fasciitis with or without myositis is caused by group A streptococcus in about half of the cases and mixed infection in half. The patient may first show signs of a simple cellulitis. Clinical clues to necrotizing fasciitis are rapid progression of symptoms, pain out of proportion to physical findings, and hypoesthesia in the skin overlying the area of involvement. As the syndrome progresses, the classic physical findings of cutaneous bullae, crepitance, and skin necrosis may occur. Abnormal vital signs may be present, and signs of sepsis may be out of proportion to the physical findings. Surgical de´bridement is imperative in cases of necrotizing fasciitis, and a high level of suspicion is necessary to assure rapid admission and appropriate surgical referral. Broad-spectrum parenteral antibiotic therapy that includes coverage of gram-positive, gram-negative, and anaerobic organisms should be started as soon as possible. 3.4

Pyomyositis

Pyomyositis is a primary muscle abscess in the absence of a contiguous site of infection. More common in the tropics (hence the term tropical pyomyositis), pyomyositis is seen in injection drug users in the United States, particularly those who have human immunodeficiency virus (HIV) infection. S. aureus is the classic causative organism, but in IDUs other gram-positive organisms, GNRs, and anaerobes are found in a substantial minority of cases. The presentation is usually of localized muscle pain and tenderness. The muscle is swollen, but the overlying skin is often normal. Treatment involves open or percutaneous drainage and antistaphylococcal antibiotic therapy. If the patient is systemically ill, it is reasonable to use a broader-spectrum agent that is active against GNRs and anaerobes until culture results are available. Because of the association with human immunodeficiency virus (HIV) infection, patients with pyomyositis should be offered HIV counseling and testing. 4

ENDOVASCULAR INFECTIONS

One of the most important challenges facing the clinician confronted with a febrile IDU is ruling out endovascular infection, either endocarditis or more peripheral vascular infection. 4.1

Endocarditis

The incidence of infective endocarditis (IE) in IDUs is very high, 1.5–2 per 1000 patientyears by some estimates (also see Chapter 18). In series looking at the cause of fever in the IDU, endocarditis was found in 6%–13% of febrile IDUs in the ED. In a large series from Detroit, IE was the cause of 41% (74/180) of episodes of bacteremia in IDUs. Because of the high incidence, the clinician’s suspicion must remain high. Unfortunately IE is difficult to predict in the IDU so blood cultures should routinely be obtained for any febrile episode. The clinical presentation of IE is usually acute; most patients seek medical attention after less than 1 week of fever, body aches, and malaise. The classic signs of

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ENDOVASCULAR INFECTIONS Endocarditis Blood cultures for all febrile injection drug users (IDUs) S. aureus (including methicillin-resistant Staphylococcus aureus [MRSA]); gram-negative rods (GNRs), including Pseudomonas spp., less common Mostly tricuspid valve Cough, hemoptysis, pleuritic pain Empirical vancomycin/ceftazidime and hospitalization Mycotic aneurysm Femoral or neck vessels Tender, enlarging pulsatile mass Diagnosis by blood culture, computed tomography (CT) imaging, or angiography Same bacteriological features and empirical antibiotics as in infective endocarditis (IE) Septic thrombophlebitis Localized pain, swelling Septic pulmonary emboli Same bacteriological features and empirical antibiotics as in IE Splenic abscess Fever, abdominal pain, pleuritic chest pain, left shoulder pain Diagnosis by blood culture, CT imaging Same bacteriological features and empirical antibiotics as in IE

endocarditis such as Osler’s nodes and Janeway lesions are rarely found, and a cardiac murmur may not be present. In 40%–69% of episodes of IE in IDUs the tricuspid valve is involved. Patients with right-sided IE often have respiratory symptoms such as cough, hemoptysis, or pleuritic pain. With tricuspid valve involvement, murmur is heard in the minority of patients. The offending organism in IE is most often S. aureus, including MRSA; streptococci are the second most common. Gram-negative organisms are seen with various frequencies. Several epidemics of Pseudomonas spp. endocarditis have been reported in Detroit and Chicago. Serratia marcescens caused a prolonged epidemic of IE in Oakland, California. Fungi are seen in approximately 5% of endocarditis cases in IDUs. Myriad other organisms have been reported, and polymicrobial infections may be seen. The outpatient clinician’s role in IE in the IDU is primarily to suspect the disease, obtain blood cultures, and refer the patient for hospital admission. Empirical therapy after blood cultures are obtained is appropriate if the patient is very ill and hospital admission will be delayed. Empirical therapy should include antistaphylococcal therapy: vancomycin if the local incidence of MRSA is significant or a penicillinase-resistant penicillin. It should be noted that vancomycin is inferior to ␤-lactam therapy when the organism is sensitive to both, so prolonged vancomycin therapy should be used only for resistant organisms or ␤-lactam allergy. Whether to include gram-negative coverage depends on the prevalence of these organisms in the geographical area. If gram-negative therapy is begun, a ␤-lactam (ceftazidime, piperacillin, imipenem-cilastatin) with activity against Pseudomonas spp. should be chosen. An aminoglycoside is indicated for synergy with many organisms and may be started empirically or later when the syndrome is fully elucidated. Outpatient therapy of IE is rarely appropriate in the IDU. If circumstances demand outpatient therapy,

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there are some data supporting the use of oral ciprofloxacin and rifampin in right-sided staphylococcal endocarditis. 4.2

Noncardiac Vascular Infections

Although less common than endocarditis as a cause of bacteremia, noncardiac vascular infections may be life- or limb-threatening and should be considered as a cause of fever in the IDU. The major syndromes are mycotic aneurysm and septic thrombophlebitis. 4.2.1

Mycotic Aneurysms

Mycotic aneurysms were so named originally by Sir William Osler to describe a mushroom-shaped arterial aneurysm in a patient with endocarditis. Despite the name, mycotic aneurysms are primarily caused by the same bacteria (not fungi) implicated in endocarditis in the IDU. These aneurysms, caused by repetitive trauma, most frequently involve the femoral vessels in IDUs, less commonly vessels of the neck or other locations. The patient is usually febrile and has a tender, enlarging, and frequently pulsatile mass. Distal ischemia or nerve root compression may also occur. Bacteremia is usually present and should be sought. At times the pulsatile mass is obscured by overlying cellulitis or chronic skin changes and a high index of suspicion should be maintained. Early diagnosis is imperative because rupture may cause exsanguination or loss of limb. Diagnosis is ideally made by conventional or digital subtraction angiography, although computed tomography (CT) with contrast may be adequate to make the diagnosis. Empirical antibiotic therapy is similar to that described for endocarditis. Treatment must include surgical excision of the infected portion of the vessel and 4 to 6 weeks of parenteral antibiotics. IDUs rarely have classic mycotic aneurysms, which are caused by hematogenous seeding of a previously damaged vessel. These are primarily cerebral aneurysms, which are manifested by neurological signs and symptoms as a consequence of enlargement or rupture. 4.2.2

Septic Thrombophlebitis

Septic thrombophlebitis is usually seen in the femoral veins and less commonly in neck or axillary veins. These infections may cause local pain and swelling or symptoms of septic pulmonary emboli. Fever is common and blood cultures are usually positive. Therapy includes parenteral antibiotics, so referral for admission is indicated. The use of anticoagulation remains controversial, although some experts advocate short-term use of anticoagulants. 4.2.3

Splenic Abscess

Common risk factors for splenic abscess formation include trauma, bacteremia, and endocarditis. Therefore, injection drug users are at particular risk for these infections. The clinical presentation of splenic abscess may be nonspecific with fever and abdominal pain. Pleuritic chest pain or left shoulder pain may also be present. Physical exam may reveal signs of pleural effusion and abdominal tenderness. Splenomegaly may not always be present, and a splenic rub is found in the minority of cases. CT scan or ultrasound is likely to be diagnostic and blood culture results are often positive. The most common organism is S. aureus, followed by Streptococcus spp., but any organism that causes bacteremia or endocarditis may be seen. When a splenic abscess is suspected, the patient should be referred for imaging and hospital admission, as splenectomy, in combination with parenteral antibiotics, is usually necessary. Percutaneous drainage has been used successfully in some cases.

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PNEUMONIA AND TUBERCULOSIS Pneumonia Bacterial pneumonia, tuberculosis, septic pulmonary emboli, drug-induced pulmonary edema, and foreign body granuloma potentially have similar clinical presentations S. pneumoniae, H. influenzae most common bacterial pathogens Vaccination (see Table 1) Tuberculosis Skin testing and treatment of latent infection (see Table 2) Directly observed therapy (DOT) Initial therapy with four drugs (see Chapter 13)

5 5.1

PULMONARY INFECTIONS Pneumonia

The IDU commonly seeks medical care for pulmonary signs and symptoms. Although bacterial pulmonary infections are extremely common in IDUs (the most common cause of fever in some series), consideration of several other important causes of pulmonary syndromes is important before attributing the syndrome to a routine bacterial infection. First, as detailed later, tuberculosis is common in IDUs and should be included in the differential of any pulmonary syndrome. Primary tuberculosis (as is especially common in HIV-infected patients) can present a radiographic picture indistinguishable from that of bacterial pneumonia. Second, right-sided endocarditis often first causes pulmonary symptoms from septic pulmonary emboli. Third, noninfectious processes may exactly mimic pulmonary infections. For example, heroin overdose may cause unilateral or bilateral pulmonary edema, fever, and leukocytosis. Talc and starch found in drugs prepared for injection may cause pulmonary granulomas. Fourth, as for all infectious syndromes of IDUs, unrecognized HIV infection and resulting pulmonary opportunistic infections must always be considered. Primary bacterial pneumonia is extremely common in the IDU, even in the absence of HIV infection, as a result of a number of factors, including impaired clearance of secretions, aspiration, poor nutrition, and concomitant alcohol and tobacco abuse. Bacterial pneumonia in the IDU presents routinely, and the offending organisms are those seen in most series of community-acquired pneumonia. S. pneumoniae and H. influenzae are most commonly described. Oral anaerobes may be implicated when aspiration has occurred. S. aureus and P. aeruginosa, when seen, usually arise from hematogenous seeding of the lungs and should prompt an investigation for endovascular infection. Because of the broad differential diagnosis, including endovascular infection and tuberculosis, and the unreliability of follow-up, treatment of the febrile IDU with more than minor pulmonary symptoms is best initiated in an inpatient setting. If the patient is not seriously ill and follow-up can be assured, outpatient therapy of uncomplicated pneumonia may be possible. Blood cultures should be obtained before starting therapy if possible, and a tuberculin skin test should be performed. Antibiotic therapy should include coverage of pneumococcus and H. influenzae (also see Chapter 12). Atypical agents such as C. pneumoniae and Legionella spp. are not commonly reported in IDUs. Quinolones should be used with caution because of their activity against M. tuberculosis and the danger of promoting resistance if they are used as single agents in occult tuberculosis.

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Table 1 Recommended Vaccinations in the Injection Drug User Pneumococcal

Hepatitis A

Hepatitis B

Tetanus (dT)

Influenza

HIV-infected

Yes

Yes b

Yes b

Yearly

HIV-uninfected

No a

Yes b

Yes b

Yes (every 10 years) Yes (every 10 years)

No a

a

Vaccination not indicated for injection drug users (IDUs) unless they meet other criteria for vaccination such as cirrhosis or chronic alcoholism for pneumococcal vaccination, or age >50 for influenza. HIV, human immunodeficiency virus. b Screen for immunity before administering.

Although injection drug use itself is not an indication for pneumococcal vaccination, IDUs who have HIV infection, cirrhosis, or chronic alcoholism should be immunized (Table 1). 5.2

Tuberculosis

IDUs are at high risk for exposure to tuberculosis as a result of their life-style. Once tuberculosis infection has occurred, IDUs are also at high risk of development of active tuberculosis regardless of HIV status. The incidence of active tuberculosis among IDUs with positive tuberculin skin test results is presented in Table 2. These high rates even among HIV-uninfected IDUs may reflect increased transmission or more recent infection. Screening for tuberculosis infection and disease is an important aspect of routine care of IDUs. Screening for tuberculosis (TB) infection is covered in Chapter 13, and aspects of tuberculin screening in the IDU are summarized in Table 2. Because of the high risk of active disease, treatment of latent infection is indicated for all IDUs regardless of age or HIV status. The most recent CDC guidelines for treatment of latent TB infection advocate short course therapy with 2 months of rifampin and pyrazinamide. Unfortunately there have been cases of severe liver toxicity, including several fatalities with this regimen. Therefore 9 months of isoniazid is the preferred regimen unless close (biweekly) monitoring of clinical and laboratory status can be assured. Short course therapy may be appropriated in settings such as jails, prisons, or methadone maintenance programs where follow-up is certain. It is important to note that rifampin has significant interactions with many antiretroviral drugs and may be contraindicated. Rifabutin may be substituted when antiretroviral therapy is used, but adjustments of rifabutin and antiretroviral therapy dosages may be required. TB preventive therapy may be given as directly observed preventive

Table 2 The Tuberculin Skin Test in the Injection Drug User

HIV-uninfected HIV-infected a

Positive TST result

Risk of active TB with positive TST result

Latent infection regimen a

10-mm Induration 5-mm Induration

10/1000 patient-years 76/1000 patient-years

INH 300 mg/day ⫻ 9 mo Same

INH may be administered twice weekly in the setting of directly observed preventive therapy. TST, tuberculin skin test; TB, tuberculosis; HIV, human immunodeficiency virus; INH, isoniazid.

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therapy (DOPT). Isoniazid or rifampin and pyrazinamide may all be administered twice weekly if DOPT is planned. DOPT is especially appropriate in the setting of methadone maintenance and can be required as a condition of continued participation. Several studies in the early 1990s reported that anergic HIV-infected IDUs had a risk of TB high enough to warrant preventive therapy. Subsequent studies have not supported this and routine anergy testing is not recommended for any population. The IDU with active tuberculosis should be considered a public health hazard, and the clinician should inform the local health department as soon as the diagnosis is made. The patient should be started on at least four antituberculous drugs, usually isoniazid, rifampin, pyrazinamide, and ethambutol. In some communities the incidence of drug resistance among IDUs is high enough to necessitate inclusion of more drugs in the initial regimen, although this is becoming rare as tuberculosis control has improved nationally. Drug treatment of the IDU who has active tuberculosis presents numerous challenges. To improve adherence, directly observed therapy is imperative, and the clinician should always enlist the help of experts in administration of antituberculosis therapy. Enablers and incentives such as access to drug treatment, housing, food vouchers, or even cash should be used to improve compliance. Therapy should be administered in conjunction with methadone treatment if possible. 6

HEPATITIS

Injection drug use is the classic risk factor for acquisition of the blood-borne viral hepatitides. IDUs tend to acquire hepatitis B and C early in their drug-using history, when needle sharing is more common. An important goal of the physician caring for an injection drug user is prevention of acquisition and further spread of these infections. 6.1

Hepatitis C Virus

The seroprevalence of hepatitis C virus (HCV) infection in IDUs in the United States ranges from 64%–90%. IDUs rarely have clinical manifestations of acute HCV infection. HCV is more likely to be diagnosed serologically in asymptomatic persons or when liver disease becomes clinically significant. Therapeutic options for hepatitis C are covered in Chapter 23. The decision to initiate hepatitis C therapy should be made in consultation with an expert in HCV treatment. The likelihood of development of liver disease with HCV infection is increased with use of alcohol and other hepatotoxic substances; thus the patient should be advised to limit exposure. 6.2

Hepatitis B and D Viruses

Some series report the prevalence of serological markers of hepatitis B virus (HBV) exposure to be as high as 60%–80% in IDUs who share needles. The clinical manifestations, diagnosis, and treatment of HBV are covered in Chapter 23. Vaccination against HBV is indicated for all IDUs who share needles. Because of the high seroprevalence of hepatitis B, IDUs should be tested for antibody to HBV prior to immunization. There is no specific recommendation for which antibody test to administer. Testing for hepatitis B core antibody (HBcAb) identifies all previously infected persons but does not distinguish between carriers and noncarriers. Testing for hepatitis B surface antibody (HBsAb) identifies previously infected persons; however, levels of HBsAb may wane over time. Any IDU who does not have HBsAb or HBcAb should be vaccinated with the three-dose series. Exact adherence to the recommended dosage schedule may be difficult in IDUs, and immunity

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HEPATITIS, HUMAN IMMUNODEFICIENCY VIRUS, HUMAN T-LYMPHOTROPIC VIRUS, AND SEXUALLY TRANSMITTED DISEASE Hepatitis Hepatitis C virus (HCV), HBV High incidence in injection drug users (IDUs) Transmitted parenterally HBV vaccine for those at risk: HBsAb < 10 IU/mL Avoidance of other hepatotoxins such as alcohol Therapy for HBV, HCV (see Chapter 23) HAV Fecal-oral spread Vaccination of all IDUs Human immunodeficiency virus (HIV) Testing all IDUs for HIV Methadone drug interactions with antiretrovirals Role of postexposure prophylaxis unclear (see Chapter 41) Human T-lymphotropic virus (HTLV) Low overall incidence HTLV-I T-cell leukemia HTLV-associated myelopathy tropical spastic paraparesis HTLV-II Up to 10% Of IDUs No clear disease associations Sexually transmitted disease (STD) See Chapters 16 and 17 Increased risk of HIV transmission Risk of false-positive rapid plasma reagin (RPR) result Screening for asymptomatic chlamydia and gonorrhea in female IDU

may be conferred by other dosage schedules. Immunization Practices Advisory Committee (ACIP) publications (CDC 1991, 1999) should be consulted for specific questions. HIVinfected IDUs should have postimmunization testing for HBsAb, and revaccination should be provided if levels are <10 mIU/mL. Sexual partners of IDUs should be tested for immunity to HBV and, if not immune, vaccinated if the IDU is HBsAg-positive. Screening and vaccination of IDU’s sexual partners are especially important if the IDU is hepatitis B envelope antigen–(HBeAg)-positive. Hepatitis D is a defective hepatotrophic ribonucleic acid (RNA) virus that depends upon coexisting hepatitis B for expression and replication. Coinfection is seen in 10%–15% of IDUs with HBV and is particularly associated with chronic HBsAg carriage. Hepatitis D infection can be prevented by HBV vaccination. 6.3

Hepatitis A Virus

Although hepatitis A (HAV) infection is primarily transmitted through the fecal-oral route, IDUs have been found to be at higher risk of infection than the general population. The modes of transmission for HAV outbreaks among IDUs have not fully been elucidated, but the high incidence likely reflects poor hygiene. Blood-borne transmission, although

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theoretically possible, is quite rare. HAV causes acute hepatitis with nausea, vomiting, and jaundice. Laboratory test result abnormalities include elevated hepatic transaminase levels. Because of the increased risk of infection, vaccination against hepatitis A is indicated for all IDUs. Vaccination is especially important in IDUs who have chronic liver disease such as HCV or chronic HBV as these conditions increase the risk of fulminant hepatitis and hepatic failure once HAV has been acquired. Screening for immunity before vaccination is clearly indicated for older IDUs. Younger IDUs are less likely to have been previously exposed. HAV vaccine is administered in two doses 1 month apart. 7 7.1

RETROVIRUS INFECTIONS Human Immunodeficiency Virus

More new cases of HIV infection have been predicted among injection drug users than among any other risk group in the United States, and injection drug users are responsible for transmitting a significant number of the heterosexual and perinatally acquired HIV infections. Thus every encounter with an IDU should be considered an opportunity for HIV counseling and testing, education about safer sex and safer injection practices, and provision of condoms, if appropriate. Some clinicians may have a nihilistic attitude about HIV prevention in the actively using IDU, but counseling provided in a respectful fashion may be remarkably effective. The immunological characteristics and therapy of HIV do not differ between IDUs and other risk groups. As the reader can easily deduce from the current chapter, bacterial infections and tuberculosis are more common in IDUs than in other risk groups. IDUs with HIV have a higher rate of death before development of acquired immunodeficiency syndrome (AIDS) than other risk groups, mostly because of the high incidence of serious bacterial infection. IDUs may have significant barriers to adherence to antiretrovirals and other medications, and some investigators have explored providing directly observed HIV therapy in the context of methadone treatment programs. The efficacy and cost-effectiveness of this approach are still being investigated. Methadone has significant drug interactions with antiretrovirals. Nevirapine and efavirenz increase the clearance of methadone, thus decreasing its effect. A complex interaction between ritonavir and methadone causes methadone’s clearance to be initially increased then decreased. Postexposure prophylaxis (PEP), which is commonly provided when health care workers are parenterally exposed to HIV, has been advocated by some as a potential consideration in selected cases of HIV exposure in the IDU. No doubt, the provision of PEP to the IDU will be the subject of much debate. If the clinician decides to provide PEP to the IDU in a particular situation, the regimen should be similar to that for health care workers, outlined in Chapter 42. 7.2

Human T-Lymphotropic Virus Types I and II

Human T-lymphotropic virus types I and II (HTLV-I and II) can be acquired through injection drug use. Screening for these viruses is done routinely by blood banks. Former and current injection drug users may learn of a positive test result and require counseling about the significance of the infection. Although these infections are not prevalent in the United States (seroprevalence among volunteer blood donors is approximately 0.025%), a significant proportion of those infected, especially with HTLV-II, are injection drug users. In fact, the incidence of HTLV-II among drug users in some series exceeds 10%. HTLV-

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I is associated with adult T-cell leukemia/lymphoma and a chronic degenerative neurological disease, referred to as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, the incidence of these syndromes in HTLV-I-infected persons is quite low (estimates range from 2% to 4% of carriers). HTLV-II has not been clearly associated with any diseases, although a few cases of hematological malignancy and a HAM/TSP-like neurological syndrome and other nonspecific neurological syndromes have been described. Counseling of individuals infected with these viruses is difficult because of the uncertainty regarding their clinical significance but should include avoidance of: breast-feeding; donation of blood, semen, or tissue; and sharing of drug injection equipment. Serodiscordant couples are counseled to use latex condoms.

8

BONE AND JOINT INFECTIONS

Skeletal infections are common in IDUs (see Chapters 27 and 28). Besides contiguous spread from a soft tissue ulcer, as previously described, hematogenous seeding of bones and joints by bacteria and fungi occurs. Joint infections largely affect the extremities. Left-sided infections predominate probably because of the tendency of the right-handed IDU to inject in the left side. Unusual

BONE, JOINT, CENTRAL NERVOUS SYSTEM, AND EYE INFECTIONS AND TOXINS Bone and joint Contiguous spread or hematogenous Staphylococcus and Streptococcus spp. and gram-negative rods (GNRs) Mostly large joints of extremities Lumbar spine, sternoclavicular joint, also pubic symphysis Diagnosis by joint/bone aspirate Central nervous system (CNS) infections Meningitis potentially confused with drug overdose, intoxication, and encephalitis due to endocarditis Most commonly caused by bacteremia Neuroimaging required before lumbar puncture (LP) Endophthalmitis Hematogenous origin: Staphylococcus, Streptococcus spp. Prompt referral for blurred vision and eye pain imperative Toxin-mediated Tetanus Painful generalized spasm, trismus Of U.S. cases 40% injection drug users (IDUs) Associated with skin popping Importance of tetanus vaccination Wound botulism Black tar heroin Blurred vision, cranial nerve palsies Symmetrical descending paralysis

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joints may be infected, such as the sternoclavicular joint, the sacroiliac joint, and the pubic symphysis. Pain in any joint should lead to consideration of septic arthritis and a diagnostic tap should be performed. As in skin and soft tissue infections, gram-positive organisms predominate, but GNRs, including P. aeruginosa, are seen. Therapy should consist of repeated arthrocentesis or open drainage and antibiotic therapy aimed at the isolated organism. Prolonged courses of 4 to 6 weeks of antibiotics are usually necessary. Antibiotics are usually administered parenterally; however, there are cases, when the organism and its susceptibility are known, highly active oral drugs are available, and compliance can be assured, in which a portion of therapy can be given orally. Such a decision should be made in consultation with an infectious disease specialist on a case by case basis. The axial skeleton is often involved in hematogenous osteomyelitis in the IDU, most commonly the lumbar spine; cervical spine infection is less common. The extremities and unusual sites such as the chest wall may be involved as well, depending upon sites of repeated injection. Skeletal pain and tenderness are the most common features. Fever and leukocytosis may be absent. Pathogens that cause joint infections also cause osteomyelitis: S. aureus, groups A and G Streptococcus spp., and GNRs, including P. aeruginosa. In addition, Candida spp. may cause osteomyelitis in IDUs. The possibility of tuberculous spondylitis, which usually affects the thoracic spine, should always be considered. Clues to tuberculous infection are lack of improvement with routine antibacterials, a positive tuberculin skin test result, and concomitant pulmonary disease; however, the latter two may be absent, especially in the setting of HIV infection. Spinal epidural abscess (discussed in detail later) may complicate vertebral osteomyelitis and should be considered, as urgent surgical intervention is often required. Empirical therapy is rarely indicated in osteomyelitis. Because of the broad range of bacterial, fungal, and mycobacterial pathogens that may cause osteomyelitis in the IDU, bone biopsy with culture is imperative to establish an etiological agent. As with joint infections, prolonged antibiotic therapy of 6 weeks or more is indicated, usually parenteral. There are rare instance in which the IDU is in a controlled outpatient environment where a portion of therapy can be completed on an outpatient basis.

9

SEXUALLY TRANSMITTED DISEASE

IDUs are at high risk for sexually transmitted diseases (STDs) because of the common practice of trading sex for drugs or money and the disinhibition produced by drug and alcohol use, which leads to unsafe sexual practices. The diagnosis and treatment of STDs are covered in Chapters 16 and 17. Because of the prevalence of these infections, STD should be included in the differential diagnosis for many febrile syndromes of the IDU. Disseminated gonococcal infection, secondary syphilis, and Fitz-Hugh–Curtis syndrome (infectious perihepatitis caused by chlamydia or gonorrhea) are prevalent and should be considered when a febrile IDU has appropriate signs and symptoms. Identification and treatment of STDs are vital to the IDU, given the importance of STDs, especially ulcerative diseases, in facilitating the sexual transmission of HIV. Screening for syphilis should be part of routine care for IDUs. A resurgence of syphilis in certain communities has been linked to injection drug and crack cocaine use. The diagnosis of syphilis is complicated by the prevalence of biologically false-positive rapid plasma reagin (RPR) results among injection drug users, and confirmation of the diagnosis with a treponemal test such as MHA-TP (Microtiter hemagglutination assay-Treponema pallidum) or FTA (fluorescent treponemal antibody) is needed. Routine screening for chlamydia and

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gonorrhea may be indicated, especially for female IDUs, since these infections may by asymptomatic. 10

CENTRAL NERVOUS SYSTEM INFECTIOUS

The evaluation of central nervous system (CNS) signs and symptoms in the IDU is difficult because the infectious and noninfectious diagnostic differentials are broad and complicated by the ever-present possibility of unrecognized HIV infection. Although noninfectious causes of CNS syndromes are common and include drug overdose or intoxication, drug withdrawal, and cerebrovascular accidents, it is of paramount importance not to ascribe CNS signs and symptoms to complications of drug ingestion itself without thorough evaluation for all treatable causes. The most common focal and diffuse CNS infections in the IDU occur as a complication of bacteremia, usually associated with endocarditis. It is important to emphasize that the bacteriological characteristics of CNS infections in the IDU may differ from the more usual classic CNS infections that arise from invasion by oropharyngeal organisms. Diffuse CNS infections include meningitis and cerebritis. The differential diagnosis and therapy of meningitis are covered in Chapter 2. Although meningitis in the IDU may be caused by the high-grade bacteremia associated with endocarditis, routine pathogens that cause community-acquired meningitis, such as meningococcus or pneumococcus, can also be present. In addition, tuberculosis and fungal pathogens such as cryptococcus are included in the differential diagnosis, especially in the setting of HIV infection. Diagnosis of meningitis is made by the lumbar puncture (LP). Given the high incidence of occult HIV and the possibility of concurrent brain abscess in the IDU, many experts would advocate neuroimaging studies before LP in these patients. Blood cultures are imperative. The measurement of opening pressure is particularly important in the IDU because of its therapeutic significance in cryptococcal meningitis. Diagnostic studies beyond the routine should include cryptococcal antigen, Venereal Disease Research Laboratories (VDRL) testing, and cultures and stains for acid-fast bacilli. Empirical therapy of meningitis in the IDU may be appropriate in the outpatient setting if LP is delayed. After blood cultures are obtained, empirical therapy including coverage for routine meningitis pathogens and S. aureus (including MRSA) may be started. Patients who have endocarditis or high-grade bacteremia can also experience a ‘‘toxic’’ encephalitis characterized by confusion, headache, and stiff neck. It is distinguished from meningitis by sterile spinal fluid with minimal pleocytosis, but clinically distinguishing the two is difficult, especially when the patient first presents. Although IDUs are susceptible to the same causes of viral encephalitis as the general population, an acute confusional state with fever is likely secondary to endocarditis in this population. Diagnostic evaluation like that recommended for meningitis should be undertaken, and empirical therapy while awaiting the results of LP should include antistaphylococcal agents as well as therapy for community-acquired meningitis pathogens if the syndrome cannot be distinguished from meningitis. Focal neurological findings in IDUs should lead to prompt neuroimaging. Common infectious syndromes that cause focal neurological findings include brain abscess, mycotic aneurysm, and HIV-associated mass lesions. The pathogenesis of the former two occurs through hematogenous dissemination of organisms during transient or sustained bloodstream infection. As are diffuse syndromes, most brain abscesses are bacterial; S. aureus is the most common organism. Fungal brain abscesses also occur in IDUs. The classic association is with cerebral mucormycosis, but infections with Aspergillus spp. and other

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fungi have been reported. Cerebral mucormycosis in the IDU is clinically distinct from rhinocerebral mucormycosis associated with uncontrolled diabetes and portends a better prognosis. When an IDU has focal neurological findings, little can be done in the outpatient setting. Emergent antibiotic therapy is rarely indicated except when the neurological syndrome accompanies systemic sepsis. In those cases, empirical therapy after obtaining blood cultures should include therapy aimed at S. aureus, including MRSA and GNRs. Spinal epidural abscess must be recognized and treated promptly as it may cause rapid loss of neurological function if untreated. These abscesses are caused by direct infection of the epidural space or extension from a vertebral osteomyelitis. The outpatient clinician is likely to see the patient during an early stage of illness when the signs and symptoms are not obvious. The disease is first manifested by focal vertebral pain, followed by pain that begins to radiate along the course of the involved nerve roots. This stage may be followed rapidly by evidence of spinal cord compression (long-tract findings) and finally paralysis below the level of the lesion. Thus any IDU who has back pain and fever or back pain and neurological findings is a candidate for neuroimaging. 11 11.1

TOXIN-MEDIATED ILLNESS Tetanus

Injection drug users account for approximately 40% of tetanus cases reported in the United States. Skin popping is a particular risk factor. Hispanic ethnicity is also a risk factor, most likely because of lack of protective antibody. Tetanus has a number of forms, the most common of which is generalized tetanus, which is associated with trismus (masseter muscle spasm) and risus sardonicus (spasm of the orbicularis oris muscle) and progresses to generalized spasm that resembles decorticate posturing and is severely painful. Localized tetanus may be more difficult to recognize as it is manifested as lower motor neuron dysfunction at the site of spore inoculation. It is important to consider tetanus and not to ascribe symptoms to drug toxicity or withdrawal. When tetanus is suspected the patient should be immediately referred for admission. Vaccination of IDUs against tetanus is of paramount importance. Any clinician interaction with an IDU should be considered an opportunity to administer tetanus booster (dT) unless the patient has recently been vaccinated. 11.2

Botulism

Wound botulism has also been reported among IDUs, particularly among Californian IDUs who use ‘‘black tar’’ heroin. The neurological symptoms of wound botulism are identical to those of food-borne botulism. The illness begins with bilateral cranial nerve palsies, which are followed by a symmetrical descending paralysis. The outpatient clinician is likely to see the disease in its early stages, when blurred vision and extraocular muscle dysfunction are the most prominent features. Prompt referral for admission is essential when botulism is suspected as mechanical ventilation and antitoxin administration may be required. 12

ENDOPHTHALMITIS

Endogenous endophthalmitis is most often a complication of bloodstream infection and thus occurs relatively frequently in injection drug users. Whenever an IDU reports blurred vision, eye pain, or decreased visual acuity, endophthalmitis should be considered. Physical

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findings may include lid edema, conjunctival injection, corneal haze, and cells in the anterior chamber. Hypopyn (layering of cells in the anterior chamber) is variably seen, and its absence does not rule out endophthalmitis. The onset of symptoms varies according to the organism; fungal ocular infection may have an insidious onset, whereas bacterial infection may appear within a day of the inciting event. The most common infecting organism in IDUs is S. aureus; Streptococcus spp. and GNRs may be seen. Several unusual causes of endophthalmitis are particularly common in IDUs. A fulminant form of bacterial endophthalmitis caused by Bacillus cereus occurs almost exclusively in IDUs. Fungal endophthalmitis is caused most often by Candida or Aspergillus species. Endogenous endophthalmitis carries a poor visual prognosis especially when treatment is delayed, so prompt referral to an ophthalmologist or ED is imperative. Diagnosis is made by culture of vitreous and aqueous humors. Treatment involves vancomycin and either amikacin or ceftazidime, administered parenterally and via ophthalmological instillation. 13

PROMOTION OF SAFER INJECTION PRACTICES

The promotion of clean needle use is an important responsibility of the clinician caring for the IDU. IDUs should be taught how to clean injection equipment (‘‘works’’) (see Table 3). Some clinicians or agencies provide bleach to facilitate such cleaning. The provision of sterile injection equipment to IDUs is a controversial topic. However, it is increasingly being advocated as an ethical and effective method of disease prevention. A number of governmental and mainstream medical organizations, including the American Medical Association, support the option for physicians to prescribe injection equipment to IDUs. Criticisms of this practice are based on the notion that it encourages continued illegal drug use. Scientific evidence does not support this criticism. The majority of epidemiological studies have shown that among IDUs who are provided sterile needles, the level of drug use has not increased. The majority of studies also demonstrate the efficacy of providing sterile needles for decreasing transmission of HIV and viral hepatitis. Organized needle exchange programs (NEPs) are the most desirable venue for distributing sterile equipment. The benefits of NEPs have been demonstrated by numerous

Table 3 Safer Injection Techniques Ideally new sterile equipment (needle, syringe, cotton, water, and cookers) should be used for each injection. Never share injection equipment, including needles, syringes, cotton, cookers, and water. If equipment must be reused, clean needles and syringes with bleach: Step 1. Rinse works with water to remove any blood: Using sterile or boiled water, draw up water to fill syringe completely, shake 30 seconds to break up clots, flush, and repeat three times. Discard water. Step 2. Using full-strength bleach, fill syringe completely, shake 30 seconds, tap syringe, flush, and repeat three times. Step 3. Rinse works with water to remove bleach. Repeat step 1 completely, rinsing fully four times. Pull plunger completely out of syringe and rinse with water. Cleaning with bleach is more effective in preventing HIV transmission than HBV and HCV transmission.a Wash hands and injection site with soap and warm water and use alcohol pad to clean injection site before injection. a

HIV, human immunodeficiency virus; HBV, hepatitis B virus; HCV, hepatitis C virus.

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studies. In most communities in which NEPs have been studied, risk-taking behavior has been reduced and HIV and hepatitis incidence has been stabilized or reduced. NEPs can serve as a focal point for other prevention and health promotion activities such as condom distribution, STD treatment, testing for HIV, referral to drug treatment programs, and, in some cases, access to routine health care. Unfortunately the capacity of needle exchange programs in the United States does not meet the need of all IDUs. Many experts advocate the provision of sterile equipment by individual clinicians. A recent legal review of this topic reports that physician prescribing of sterile injection equipment is consistent with the ethical principles governing the practice of medicine and is legally defensible in most states in the United States. BIBLIOGRAPHY Burris S, Lurie P, Abrahamson D, Rich JD. Physician prescribing of sterile injection equipment to prevent HIV infection: Time for action. Ann Intern Med 133:218–226, 2000. CDC. Hepatitis B virus: Comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 40 (RR-13):1–19, 1991. CDC. Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 48 (RR12):1–37, 1999. CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 49 (RR-6):1–51, 2000. Lerner PI. Neurologic complication of infective endocarditis. Med Clin North Am 69:385–398, 1985. Levine DP, Brown PB. Infections in injection drug users. In: Mandell GL, Bennett JE, Dolan R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone, 2000, pp 3112–3125. Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical Center. II. A prospective comparative study. Rev Infect Dis 8:374–396, 1986. Marantz PR, Linzer M, Feiner CJ, Feinstein SA, Kozin AM, Friedland GH. Inability to predict diagnosis in febrile intravenous drug abusers. Ann Intern Med 106:823–828, 1987. Samet JH, Shevitz A, Fowle J, Singer DE. Hospitalization decision in febrile intravenous drug users. Am J Med 98:53–57, 1990. USPHS, CDC. Guidelines for counseling persons infected with human T-lymphotropic virus type I and type II. Ann Intern Med 118:448–454, 1993.

36 Infections in the Dialysis Patient Michael Berkoben Duke University Medical Center, Durham, and Gambro Healthcare, Henderson, North Carolina, U.S.A.

1

INTRODUCTION

Not only may infectious agents contribute greatly to the morbidity and mortality of patients on dialysis, but several agents (hepatitis B and C viruses and human immunodeficiency virus) can directly lead to end-stage renal disease (ESRD). Infection is the second leading cause of death, following cardiovascular disease, of chronic dialysis patients. The risk of death of infection is higher for peritoneal dialysis patients than for hemodialysis patients and increases in older age groups. The increased susceptibility to infection in dialysis patients is due to four factors: impaired host defense from renal failure, impaired host defense from the dialysis treatment itself, underlying diseases that suppress immunity or require immunosuppression (e.g., diabetes mellitus or systemic lupus erythematosus), and presence of vascular or peritoneal access. Many of the infectious diseases that afflict dialysis patients, such as pneumonia, are treated in a manner similar to that for nondialysis patients. This chapter focuses on access-related infections and on other infectious diseases that, although not unique to dialysis patients, deserve special consideration in this patient population. 2

VASCULAR ACCESS INFECTIONS

Table 1 lists the advantages and disadvantages of the three forms of permanent vascular access. The primary arteriovenous fistula is the preferred form of vascular access for chronic hemodialysis. 2.1

Primary Arteriovenous Fistula Infections

Primary arteriovenous fistulas are typically created by anastomosis of the cephalic vein and radial artery at the wrist or the cephalic vein and brachial artery at the elbow. Primary fistulas have higher patency rates and lower infection rates than synthetic fistulas. Primary fistula infections are uncommon, are usually localized, and can usually be successfully treated with antibiotic therapy and without surgical intervention. 2.2

Synthetic Graft Infections

Synthetic grafts are composed of polytetrafluoroethylene (PTFE). These grafts typically bridge the brachial artery and basilic vein in either the forearm or the upper arm. Synthetic 695

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VASCULAR ACCESS INFECTIONS Types of access devices (see Table 1) Highest infection rates in synthetic grafts and silastic catheters Most commonly due to S. aureus and S. epidermidis; also gram-negative rods (GNRs) and enterococci Fever, commonly during or after hemodialysis Potential for inflamed appearance of access (2) sets of blood cultures and culture of access if applicable Empirical antibiotics that include vancomycin and an aminoglycoside (see Table 2) Removal of synthetic grafts and silastic catheters often necessary

graft infections are common. They are the second leading cause of graft loss and, together with catheter-related bacteremia, the leading cause of bacteremia in hemodialysis patients. Gram-positive organisms—Staphylococcus aureus and, less commonly, Staphylococcus epidermidis—are responsible for most cases. Enterococci and gram-negative bacilli account for most of the remaining infections. Fever, chills, and rigors are the typical presenting symptoms of the hemodialysis patient who has graft-related bacteremia. Chills and rigors typically precede fever. These phenomena often occur during the hemodialysis treatment or shortly thereafter. Physical evidence of graft infection is often absent. Indeed, bacteria may have been introduced into the bloodstream by the dialysis needles during graft cannulation. The febrile hemodialysis

Table 1 Types of Permanent Vascular Access Devices Type of access

Patency rates

Advantages

Disadvantages

60%–70% At 1 year Low thrombosis and infec- May require 6 months or more to mature 50%–65% At 2 to 4 tion rates years May provide complication- 24%–27% maturity failure rate free access for many years (few interventions required to maintain patency) Synthetic (PTFE) 62%–83% At 1 year Require only 3 weeks to Thrombosis and infection rates graftsa 50%–77% At 2 mature higher than those for primary years fistulas (many interventions necessary to maintain patency) Double-lumen 30%–74% At 1 year May be used immediately With chronically low blood cuffed catheters No risk of arterial steal flow rates potential for inadeMorbidity rate of insertion quate dialytic therapy and removal low High rate of catheter-related No needle puncture rebacteremia and metastatic inquired for hemodialysis fection Primary arteriovenous fistula

a

PTFE, polytetrafluoroethylene. Source: Berkoben M and Schwab SJ 1999.

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patient with a synthetic graft should be presumed to have graft-related bacteremia unless the history, physical examination, or initial investigations provide convincing evidence to the contrary. Blood cultures should be obtained. Empirical antibiotic therapy consists of loading doses of vancomycin (20 mg/kg) and either gentamicin (2 mg/kg) or tobramycin (2 mg/kg). Because methicillin-resistant S. aureus (MRSA) and coagulase-negative staphylococci are common pathogens, a ␤-lactam antibiotic is not an appropriate empirical agent. Continued antibiotic therapy should be guided by the blood culture isolate findings. If enterococci or ␤-lactam-resistant staphylococci are isolated, continued vancomycin therapy is appropriate. If staphylococci that are susceptible to ␤-lactam antibiotics are isolated, a ␤-lactam should be substituted for vancomycin unless the patient has a ␤-lactam allergy. If gram-negative bacilli are isolated, the aminoglycoside antibiotic may be continued. If there is no evidence of metastatic infection, the author’s practice is to administer a 3-week course of antibiotic therapy. Dosage regimens are described late. Blood cultures should be obtained after completion of antibiotic therapy to confirm that bacteremia has been eradicated. It must be emphasized that extensive graft infection may be present even when the physical examination findings are unremarkable. If bacteremia or fever is persistent or recurrent in spite of appropriate antibiotic therapy, surgical exploration is mandatory. Detection of a pustule, abscess, or erythema overlying the graft mandates surgical consultation. In addition, bleeding through an erosion overlying the graft may be the initial manifestation of synthetic graft infection. This ‘‘herald bleeding’’ mandates surgical evaluation. Localized infection of the graft may be treated by simple incision and drainage or by partial graft excision and bypass grafting. Extensive graft infection mandates complete graft excision. 2.3

Catheter-Related Infections

Double-lumen silastic catheters with felt cuffs are inserted into a central vein, typically the internal jugular vein, and tunneled through subcutaneous tissue. These catheters are much more likely to lead to bacteremia than are primary fistulas and synthetic grafts. It is for this reason that their use should be restricted to those patients whose primary fistulas or synthetic grafts have not yet matured and to those patients for whom all sites for primary fistula or synthetic graft placement have been exhausted. Despite these restrictions, cuffed tunneled catheters have assumed an increasingly important role in chronic hemodialysis. In 1996, cuffed tunneled catheters were used in 18.9% of new hemodialysis patients and in 12.9% of patients who had been undergoing hemodialysis for 60 days. To reduce the risk of infection, povidone-iodine ointment and a dry gauze dressing or mupirocin ointment and a dry gauze dressing should be applied to the exit site at each hemodialysis treatment. Occlusive dressings should be avoided as they trap drainage and create a moist environment at the exit site. Exit site infections are characterized by erythema and tenderness and perhaps by scant purulent exudate at the exit site. Blood cultures should be drawn. If systemic symptoms are absent and if blood cultures yield no growth, topical and/or parenteral antibiotic therapy should suffice. If there is purulent drainage from the tunnel, blood cultures should be drawn, an exit site culture obtained, and parenteral antibiotic therapy administered. Copious purulent drainage or positive blood culture findings necessitate catheter removal. Chills, rigors, and fever are the typical presenting problems of the hemodialysis patient who has catheter-related bacteremia. Blood cultures should be drawn and empirical antibiotic therapy (vancomycin and either gentamicin or tobramycin) administered. Continued antibiotic therapy should be guided by the blood culture results. S. aureus is the most common isolate.

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In cases of catheter-related bacteremia, the catheter should be removed whenever possible. Blood cultures should be obtained once the patient defervesces. If these blood cultures yield no growth, a new cuffed, tunneled catheter may be inserted into another central vein. Because a period of 48 to 72 hours is generally required to demonstrate that blood culture results are negative, one hemodialysis treatment via a noncuffed catheter in the femoral vein may be necessary. Unless there is evidence of metastatic infection, a 3week course of antibiotic therapy should be administered. Because this practice may involve multiple procedures, requires a several-day hospital stay, and leads to use (and perhaps eventual loss) of another central venous access site, alternative practices have been proposed. Treatment of catheter-related bacteremia with the catheter in place is not recommended. Even with prolonged antibiotic therapy, this practice appears to be successful in only 25% to 32% of cases. In the remainder, recurrent bacteremia necessitates catheter removal. Another approach, however, has been more effective. If there is no evidence of tunnel infection and if the patient defervesces within 48 hours of initiation of antibiotic therapy, the catheter may be exchanged over a guidewire. A 3-week course of antibiotic therapy should suffice. This approach is successful in more than 80% of cases. If there is any indication of tunnel infection or if defervescence does not occur in response to empirical antibiotic therapy, however, the catheter must be removed and a new one placed after defervescence and eradication of bacteremia. 2.4

Metastatic Infections

S. aureus bacteremia has a propensity to lead to metastatic complications including endocarditis, septic arthritis, septic pulmonary emboli, osteomyelitis, empyema, and meningitis. Patients should be questioned for symptoms and examined for signs of metastatic infection. Infective endocarditis may occur in up to 14% of cases of S. aureus bacteremia in hemodialysis patients. A new murmur or persistent fever or persistent bacteremia should prompt the physician to request echocardiography. If transthoracic echocardiography is performed and demonstrates no valvular vegetations, transesophageal echocardiography (TEE) should be requested (see Chapter 18, Figure 1). Detection of vegetations mandates a longer course of antibiotic therapy. Indeed, some have proposed that TEE be performed for all hemodialysis patients with S. aureus bacteremia in order to determine proper duration of therapy. Epidural abscess and vertebral osteomyelitis are also complications of staphylococcal bacteremia in hemodialysis patients (see Chapter 28, Figure 4). Most patients have had recent bacteremia or have ongoing bacteremia. The most consistent initial symptom is excruciating back pain. Laboratory evidence of persistent inflammation (low serum albumin concentration, anemia resistant to erythropoietin therapy) is often impressive. The absence of fever, neurological signs, or leukocytosis should not dissuade one from making the diagnosis. Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in the evaluation of spinal infection. Indeed, severe back pain in a hemodialysis patient with previous or concurrent bacteremia should prompt magnetic resonance imaging of the spine. Neurological deficits may indicate posterior extension of the infection (epidural abscess) and mandate surgical evaluation. Indications for surgical intervention include extensive destruction of the vertebral bodies, signs of spinal cord compression, epidural abscess, and paravertebral abscess. If the culprit organism is in doubt, CT-guided needle aspiration may be useful. If this procedure does not identify the causative organism, surgical exploration is necessary. Duration of antibiotic therapy is 6 to 8 weeks.

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Prevention of Staphylococcal Infections

Two randomized trials have demonstrated that topical preparations applied to hemodialysis catheter exit sites reduce the risk of S. aureus exit site infections and S. aureus bacteremia. In one study, povidone-iodine ointment plus a sterile dressing applied to the exit site at each hemodialysis treatment was superior to a sterile dressing alone (Levin et al., 1991). In the second study disinfection of the exit site with povidine-iodine followed by application of mupirocin ointment was superior to povidone-iodine alone (Sesso et al., 1998). S. aureus nasal carriage significantly increases the risk of S. aureus bacteremia in chronic dialysis patients. Indeed, most patients are infected with their own strains. It has been postulated that the anterior nares serve as a reservoir from which the hands and skin become colonized. By touching their vascular access sites, hemodialysis patients may contaminate them with S. aureus. Intranasal mupirocin is effective in reducing S. aureus nasal and hand carriage, and weekly application of intranasal mupirocin appears to reduce the risk of S. aureus infection in hemodialysis patients. 2.6

Antibiotic Dosage Strategies for Hemodialysis Patients

As described empirical antibiotic therapy of suspected bacteremia in the hemodialysis patient consists of vancomycin 20 mg/kg and gentamicin 2 mg/kg or tobramycin 2 mg/ kg (Table 2). If blood cultures yield enterococci or staphylococci resistant to ␤-lactam antibiotics, vancomycin therapy should be continued. Subsequent vancomycin dosage depends on the permeability characteristics of the dialyzer membrane being used. Vancomycin is eliminated almost entirely by glomerular filtration, and its elimination half-life is markedly prolonged in patients with end-stage renal disease. However, hemodialysis with high-flux (high-permeability) dialysis membranes results in substantial removal of vancomycin. After the initial loading dose, subsequent doses of 500 mg after each hemodialysis treatment result in prehemodialysis serum vancomycin levels above 10 ␮g/ml in the great majority of patients who have high-flux hemodialysis. For patients undergoing low-flux hemodialysis, no firm recommendations can be made. Whether vancomycin is administered after each hemodialysis treatment or as a single weekly dose, prehemodialysis

Table 2 Antibiotic Dosage for Hemodialysis Patients Antibiotic

Loading dose

Vancomycin

20 mg/kg IV

Cefazolin Gentamicin Tobramycin Amikacin

20 mg/kga 1.7–2 mg/kg 1.7–2 mg/kg 7.5 mg

a

Maintenance dose 500 mg After each HD treatment if HD with high-flux membranes Maintenance dose guided by serum vancomycin levels if HD with low-flux membranes 20 mg/kg after each HD treatmenta 1 mg/kg After each HD treatment 1 mg/kg After each HD treatment 4–5 mg/kg After each HD

An alternative dosing regimen is 2 g after each of the first two HD treatments of the week and 3 g after the third HD treatment of the week. HD, hemodialysis. Sources: Aronoff et al. 1999, Barth and DeVincenzo 1996, Fogel et al. 1998, and Marx et al. 1998.

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levels should be monitored and the dose adjusted as necessary to maintain therapeutic levels while avoiding drug accumulation. If gentamicin or tobramycin therapy is to be continued, subsequent doses of 1 mg/ kg should be administered after each hemodialysis. Prolonged use of an aminoglycoside in combination with vancomycin is strongly discouraged because of the risk of otovestibulotoxicity. If the blood culture isolate is susceptible to cefazolin, a first-generation cephalosporin should be substituted for both vancomycin and the aminoglycoside (unless the patient is allergic to ␤-lactams). Cefazolin 20 mg/kg (rounded to the nearest 500-mg increment) administered after each hemodialysis treatment is a reasonable alternative. Substitution of cefazolin for vancomycin for susceptible strains of S. aureus should help limit the emergence of vancomycin resistance. In 1999, strains of S. aureus with intermediate resistance to vancomycin were reported (Sieradzki et al., 1999; Smith et al., 1999). Two of the patients from whom these strains were isolated were undergoing chronic dialysis. One patient had a peritoneal catheter and the other had a central venous catheter and a synthetic graft. Both had MRSA infections for which they received a prolonged course of vancomycin therapy. It is thought that prolonged exposure to vancomycin and the presence of prosthetic material acted in concert to produce vancomycin resistance. 3 3.1

INFECTIONS IN PERITONEAL DIALYSIS PATIENTS Peritonitis

Peritonitis is the most common cause of peritoneal catheter loss and the most common cause for the discontinuation of peritoneal dialysis. Many factors conspire to make the peritoneal dialysis patient susceptible to peritonitis. The peritoneal catheter tunnels through the abdominal wall and provides a portal of entry into the peritoneum. Biofilms that harbor and protect bacteria, especially S. aureus and S. epidermidis, may form on the catheter. Continuous ambulatory peritoneal dialysis (CAPD) requires four manual exchanges of dialysate per day at a volume of 2–3 L per exchange. This totals 1460 exchanges per year that require sterile technique. Contamination of the catheter lumen would seem to be inevitable even if expert technique were employed. The risk of intraluminal contamination may be reduced by two means. First, the number of connections and disconnections may be reduced. Continuous cyclic peritoneal dialysis (CCPD) involves three to five automated exchanges performed by a peritoneal dialysis cycler over 10 hours at night followed by a 14-hour daytime exchange. This technique requires one connection to the peritoneal di-

PERITONITIS IN CONTINUOUS AMBULATORY PERITONEAL DIALYSIS Abdominal pain and cloudy effluent dialysis fluid Fluid with >100 white blood cells (WBCs)/mm3 Culture and Gram stain of fluid Most commonly due to S. aureus and S. epidermidis; less commonly gram-negative rods (GNRs) and yeast Polymicrobic infection suggestive of viscus perforation Empirical antibiotics that include cefazolin and an aminoglycoside delivered intraperitoneally (see Table 3) Catheter removal sometimes necessary

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alysis (PD) cycler at night and one disconnection in the morning. As a result, the peritonitis rate for CCPD is lower than that for CAPD. Second, the likelihood of intraluminal contamination during each exchange may be reduced. Advances in ‘‘connection technology,’’ especially the introduction of the Y system in the 1980s, have led to a reduction in peritonitis rates. A discussion of connection technology is beyond the scope of this chapter. The peritoneal dialysis procedure itself may predispose to peritonitis. Peritoneal dialysis fluid is not physiological. In order to achieve ultrafiltration (fluid removal) across the peritoneum, dialysis fluid is hyperosmolar with glucose concentrations of 1500, 2500, or 4250 mg/dL. Dialysis fluid pH is low. The presence of large volumes of dialysis fluid in the peritoneal cavity dilutes peritoneal macrophages and cytokines. In addition, activated macrophages and cytokines are removed with each exchange. Patients classically have abdominal pain accompanied by cloudy effluent dialysis fluid. Fever (often low-grade) is present in about one-half of cases and diffuse abdominal tenderness is detected in the majority. The white blood cell count in the peritoneal fluid typically exceeds 100/mm3. Most of these cells are neutrophils. Gram stain of the peritoneal fluid is usually nondiagnostic, but culture of the peritoneal fluid yields a positive result in 80% to 90% of patients. The method for culturing the peritoneal fluid varies among institutions. At some institutions, 10 mL of spent dialysis fluid is placed into each of two blood culture bottles. At the author’s institution, up to 50 mL of spent dialysis fluid is transported to the laboratory in a sterile container. The fluid is centrifuged and the sediment is planted onto culture medium and inoculated into thioglycolate broth. Blood cultures should be obtained in severely ill patients but usually have a negative result. Although the diagnosis of peritonitis is straightforward in most cases, four important points must be made. First, abdominal pain may be accompanied by clear effluent dialysis fluid. In these cases, the dialysis fluid often turns cloudy within a day. Repeated peritoneal fluid cell counts may be necessary when a peritoneal dialysis patient has abdominal pain. Second, the peritoneal fluid differential cell count is important. Not all cloudy dialysate is due to infection. Eosinophilic peritonitis usually occurs soon after peritoneal catheter placement and is thought to result from chemicals leached from the catheter, dialysate containers, or tubing. Peritoneal fluid cultures typically yield no growth (although fungal and parasitic peritonitis may cause peritoneal fluid eosinophilia) and peritoneal fluid eosinophilia typically resolves within 2 to 6 weeks. Third, not all abdominal pain in peritoneal dialysis patients is due to peritonitis. The increased intra-abdominal pressure that results from peritoneal dialysis leads to formation of hernias. In addition, a perforated viscus (as from diverticulitis) may be responsible for peritonitis and should be strongly suspected if peritoneal fluid culture indicates a polymicrobic infection with enteric organisms or anaerobes. Free intraperitoneal air is often present in peritoneal dialysis patients and is presumably due to leakage of air through the catheter insertion site. Thus detection of free air under the diaphragm by an upright film of the abdomen is not diagnostic of a ruptured viscus in a peritoneal dialysis patient. Finally, the peritoneal fluid culture may yield no growth if the culture is obtained early in the course of the illness (before organisms are present in high numbers) or if too little peritoneal fluid is cultured. Staphylococcus epidermidis and Staphylococcus aureus are the most pathogens. About 15% of cases are due to gram-negative bacilli. Polymicrobial infection and fungal infection are much less common. Cases of peritonitis caused by vancomycin-resistant enterococci (VRE) appear to be on the rise. In 10% to 20% of cases, the peritoneal fluid culture yields no growth. Drug is transported across the peritoneum from dialysate to blood. Therefore, antibiotics may be administered through the peritoneum. Patients with peritonitis may be

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treated as outpatients. Admission to a hospital is indicated for patients who are severely ill or who do not improve within the first 24 to 48 hours of therapy. Intraperitoneal antibiotic therapy should be initiated after the peritoneal fluid culture has been obtained (Table 3). If the Gram stain result is negative, a first-generation cephalosporin (cefazolin or cephalothin) and an aminoglycoside should be administered in the same dialysate bag. The loading dose for the cephalosporin is 1000 mg and the maintenance dose 125 mg/L in each bag. The loading dose for gentamicin and tobramycin is 1.7–2 mg/kg in the dialysate bag and the maintenance dose is 4–6 mg/L. In order to reduce the risk of otovestibulotoxicity, the maintenance dose of the aminoglycoside may be administered as a single daily dose. For gentamicin and tobramycin, the dose is 20 mg/ L in one bag each day. If one chooses to add gentamicin or tobramycin to each dwell at a concentration of 4–6 mg/L, care must be taken to prevent otovestibulotoxicity. It is the author’s practice to administer this regimen for 5 days, hold aminoglycoside therapy for 2 days, obtain an aminoglycoside blood level, and administer, if necessary, another loading dose. It is hoped that this practice will prevent severe otovestibulotoxicity. If the patient appears very ill, the loading doses of the cephalosporin and aminoglycoside should be administered intravenously rather than intraperitoneally. Because of the emergence of VRE, vancomycin is no longer recommended as initial empirical therapy for peritonitis. Its use should be limited to cases due to MRSA, ␤lactam-resistant S. epidermidis, and gram-positive organisms for patients allergic to ␤lactam antibiotics. In some dialysis centers, however, vancomycin should be part of the

Table 3 Antibiotic Dosage for Peritoneal Dialysis Patients Antibiotic Cephalosporins Cefazolin Cephalothin Ceftazidime Vancomycin Penicillins Ampicillin Quinolones Ciprofloxacin Aminoglycosides Gentamicin

Maintenance dose

1000 mg 1000 mg 1000 mg 1000–2000 mg

125 mg/L In each bag 125 mg/L In each bag 125 mg/L In each bag 15–25 mg/L In each bag or 1000–2000 mg/week

1000–2000 mg IV

125 mg/L In each bag

400 mg IV

25 mg/L In each bag

1.7–2 mg/kg

4–6 mg/L In each bag or 20 mg/L in one bag each dayb,c 4–6 mg/L In each bag or 20 mg/L in one bag each dayb,c 6–7.5 mg/L In each bag or 60 mg/L in one bag each dayb

Tobramycin

1.7–2 mg/kg

Amikacin

5.0–7.5 mg/kg

Antifungals Fluconazole Flucytosine a

Loading dosea

2000 mg PO

150 mg IP every other day 1000 mg PO/day

Unless otherwise specified, loading doses are given as milligrams per bag of dialysis solution. The volume of dialysis solution is not important. b See text for details of dosage if aminoglycoside is to be administered in each bag. c Consider maintenance dose of 6–8 mg/L in each bag if culprit organism is Pseudomonas or Xanthomonas sp. Source: Keane et al. 1996.

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initial empirical regimen. All peritoneal dialysis centers should monitor the susceptibilities of the isolates from cases of peritonitis and devise an empirical regimen that will be effective in the great majority of cases. In cases of gram-positive pathogen peritonitis, the cephalosporin may be administered for 3 weeks in S. aureus infections and for 2 weeks in S. epidermidis infections. In cases of ␤-lactam resistance, vancomycin should be administered. The loading dose of vancomycin is 1000–2000 mg and the maintenance dose 15–25 mg/L of dialysate. Alternatively, 1000–2000 mg may be administered every 7 days. In patients who have significant residual renal function, however, serum vancomycin levels may become subtherapeutic (<15 ␮g/mL) in less than 7 days. Serum vancomycin levels should be monitored every 3 to 5 days in these patients and vancomycin administered more frequently if indicated. In cases of S. aureus peritonitis that are slow to respond to therapy, addition of rifampin 600 mg orally per day may be helpful. Enterococcal peritonitis should be treated with ampicillin and an aminoglycoside for 2 weeks. Gram-negative peritonitis may be treated with an aminoglycoside, ceftazidime, or ciprofloxacin, depending on susceptibilities. A 2-week course of therapy should suffice except in cases of Pseudomonas sp. or Xanthomonas sp. peritonitis. Pseudomonas sp. peritonitis and Xanthomonas sp. peritonitis are often difficult to eradicate without catheter removal (especially if there is coexisting exit site infection) and should be treated with two antibiotics to which the organism is susceptible. The aminoglycoside should be administered at a dose of 6–8 mg/L dialysate. Duration of therapy is 3 to 4 weeks. Catheter removal may be necessary if there is no improvement by 5 days. Patients who have culture-negative peritonitis that responds to empirical antibiotic therapy may complete a 2-week course of such therapy. If there is no clinical improvement, however, catheter removal must be considered. Fungal peritonitis is typically caused by Candida species. Oral flucytosine and intraperitoneal fluconazole should be administered. The dosage of flucytocine should be reduced in those with impaired renal function. Peak and trough levels should be monitored. Treatment duration is 4 weeks. Catheter removal is necessary if there is no clinical improvement within a few days. Many nephrologists believe that the catheter should be removed in all cases of fungal peritonitis. Amphotericin B is indicated for severe illness and for fungi resistant to fluconazole. It must be emphasized that bacterial and fungal peritonitis can be deadly. Peritoneal catheter removal is indicated if there is clinical deterioration despite appropriate therapy or if there is no clinical improvement after a few days of appropriate therapy. Catheter removal is also indicated in cases of frequently relapsing peritonitis. Consultation with a nephrologist and infectious disease specialist is suggested. 3.2

Peritoneal Catheter Exit Site and Tunnel Infections

Exit site infections are manifested by erythema, induration, and/or discharge from the exit site. If there is erythema at the exit site but no drainage, topical antibiotic therapy (povidone iodine, chlorhexidine, mupirocin, or dilute hydrogen peroxide) may be administered. Occlusive dressings should not be used. If there is drainage from the exit site, intraperitoneal or oral antibiotic therapy is indicated. The drainage should be cultured. Because Staphylococcus species are responsible for most cases of exit site infection, intraperitoneal vancomycin is an appropriate empirical agent. If the drainage culture yields a gram-positive organism, vancomycin may be continued or a first-generation cephalosporin substituted. Addition of oral rifampin 600 mg/day may be helpful in cases of staphylococcal

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exit site infections in which clinical improvement is slow. If a gram-negative organism is isolated, intraperitoneal or oral ciprofloxacin 500 mg/day should be prescribed. In cases of Pseudomonas sp. exit site infection, ciprofloxacin 500 mg twice daily for 3 to 4 weeks should be prescribed, but catheter removal is often necessary. Regardless of the organism, catheter removal is indicated in cases of refractory exit site infection and should be considered in cases of coexisting peritonitis caused by the same organism. Tunnel infection is manifested by erythema and tenderness over the catheter tunnel. Ultrasonography may reveal a fluid collection or abscess within the tunnel. These infections are difficult to treat with antibiotic therapy alone. The catheter should certainly be removed if there is coexisting peritonitis. Nasal carriers of S. aureus are much more likely to have S. aureus exit site infections than are noncarriers. Intranasal mupirocin therapy (twice daily for 5 consecutive days every 4 weeks) for nasal carriers of S. aureus has been shown to reduce the risk of exit site infection due to S. aureus but has not been shown to reduce the risk of peritonitis or catheter loss. Mupirocin ointment applied daily to the peritoneal catheter exit site (regardless of carrier state) has been advocated in order to prevent S. aureus exit site infections, S. aureus peritonitis, and catheter loss due to S. aureus infection. Unfortunately resistance to mupirocin has developed and may interfere with the efficacy of widespread use.

4 4.1

VIRAL HEPATITIS Hepatitis B Virus

Three major forms of renal disease may be seen in association with hepatitis B virus (HBV) infection: membranous nephropathy, membranoproliferative glomerulonephritis, and polyarteritis nodosa. All three may lead to ESRD. Dialysis patients are at risk of acquiring HBV infection. About 10% of patients who have an intact immune system will become chronic carriers after infection with the HBV. Because of impaired immunity, dialysis patients are more likely to have chronic HBV infection. Hepatitis B virus infection is transmitted by exposure to blood or other body fluids. In the hemodialysis center, HBV infection may be transmitted to staff by accidental needle sticks or accidental splashes of blood and may be transmitted to patients by accidental splashes of blood. One can imagine transmission of HBV infection by staff to patients by contaminated gloves or by exposure of patients to nicks or abrasions on the staff members’ hands. Contact with contaminated equipment or with contaminated environmental surfaces is undoubtedly responsible for some cases of HBV infection. Fortunately, both the incidence and the prevalence of HBV infection decreased dramatically in the 1980s. The Centers for Disease Control and Prevention (CDC) reported that the prevalence of hepatitis B surface antigenemia (HBsAg) in hemodialysis patients fell from 7.8% to 1.2% from 1976 to 1990 (Tokars et al., 2000). During that same period the incidence of HBsAg fell from 3% to 0.2%. Decreases in the prevalence and incidence of HBsAg in hemodialysis staff were reported as well. Many factors are likely responsible for these dramatic declines. Screening of potential blood donors for HBsAg and antibodies to hepatitis B core antigen was initiated. The advent of erythropoietin therapy led to a dramatic decline in the need for blood transfusion. Patients were routinely screened for HBsAg and for hepatitis B surface antibody (HBsAb). Susceptible patients (and staff) were vaccinated, and chronic carriers were dialyzed in separate rooms with dedicated machines. The reuse of dialyzers in chronic carriers was prohibited. Finally, adherence to standard barrier precautions (use of gloves, gowns, and face shields) by dialysis staff has undoubtedly played a role. In spite of these phenomena, outbreaks of

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HBV infection in hemodialysis units continue to occur and administration of the hepatitis B vaccine is recommended for dialysis patients. Administration of recombinant hepatitis B vaccine produces an immune response (HbsAb titer >10 IU/L) in 95% of normal adults but in only 50%–60% of chronic hemodialysis patients. Nevertheless, administration of the hepatitis B vaccine substantially reduces the risk of hepatitis B infection in chronic hemodialysis patients. The CDC has recommended that all susceptible dialysis patients receive the hepatitis B vaccine. In order to increase the likelihood of an immune response, a higher dose is given to dialysis patients than to healthy adults. Engerix-B (SmithKline Beecham) is given as an intramuscular injection of 40 ␮g at 0, 1, and 6 months. Recombivax HB (recombinant hepatitis B virus vaccine) is given as an intramuscular injection of 40 ␮g at 0, 1, and 6 months. HBsAb should be tested 1 to 2 months after the series of injections. If there is an inadequate immune response (HBsAb <10 IU/L), revaccination with three additional doses is recommended. If a protective antibody level (HBsAb >10 IU/L) is achieved, HBsAb level should be monitored yearly. If HBsAb subsequently falls below 10 IU/L, a single booster dose of 40 ␮g should be administered. If HBsAb level remains below 10 IU/L in spite of revaccination or booster administration, HBsAg level should be tested monthly. The presentation, diagnosis, and treatment of HBV infection are reviewed in Chapter 23. 4.2

Hepatitis C Virus

Three forms of renal disease may be seen in association with hepatitis C virus (HCV) infection: mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and membranous nephropathy. All three may lead to ESRD. HCV is transmitted by exposure to blood or other body fluids. Hemodialysis patients are at risk for nosocomial infection. The prevalence of anti–hepatitis C virus antibody among dialysis patients in the United States is about 19% but varies widely among dialysis centers. The incidence and prevalence of HCV infection among dialysis patients are falling. Three major factors are responsible. Screening of blood donors for anti-HCV antibody and the use of erythropoietin therapy have reduced the risk of posttransfusion hepatitis. Implementation of infection control measures has reduced nosocomial transmission of HCV infection within dialysis centers. The CDC does not recommend patient isolation and dedicated machines and does not prohibit dialyzer reuse for patients with HCV infection. There are two major reasons. HCV is less infective than is HBV since it circulates in low levels in serum and is rapidly degraded at room temperature. In addition, a positive test result for anti–hepatitis C virus antibody does not distinguish between past and present infection, and a negative test result does not exclude infection. Detection of HCV ribonucleic acid (RNA) by polymerase chain reaction would be helpful in this regard but is not practical. Nosocomial transmission of HCV infection in dialysis centers is best prevented by strict adherence to universal precautions and by careful sterilization of dialysis machines. HCV infection in dialysis patients can be overlooked. Symptoms of ESRD may mask or mimic those of HCV. Additionally, the alanine aminotransferase (ALT) level may be normal even when liver disease is advanced. Use of second- or third-generation enzyme immunoassays for hepatitis C virus RNA testing will enhance diagnostic abilities. Interferon-␣ appears to be effective for dialysis patients with chronic active hepatitis. Interferon ␣-2b at a dose of 3 million units subcutaneously three times per week for 6 to 12 months has been effective in reducing ALT levels and in inducing clearance of HCV RNA from serum. Improvement in liver histological features has been reported as well (Huraib et al., 1999). However, discontinuation of therapy due to side effects appears to

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be more likely in patients who have ESRD. In addition, recurrence of viremia is frequent after discontinuation of therapy, and long-term benefits of therapy have not been established. Nevertheless, interferon-␣ therapy should be considered for selected dialysis patients, especially those who have chronic active hepatitis indicated by liver biopsy or those who are candidates for renal transplantation. The posttransplantation course in these patients depends largely on the pretransplantation severity of liver disease. Liver biopsy is mandatory for kidney transplant candidates. Ribavirin therapy is not recommended for patients who have ESRD as clearance of the drug is reduced and drug is not removed by hemodialysis. The presentation, diagnosis, and treatment of HCV are further reviewed in Chapter 23. 5

HUMAN IMMUNODEFICIENCY VIRUS

Several forms of renal disease are associated with human immunodeficiency virus (HIV) infection. The most common form is collapsing focal glomerulosclerosis. This form of HIV-associated nephropathy is much more common in blacks and in males. Heavy proteinuria or the nephrotic syndrome is typically present at the onset. Rapid progression to ESRD has been the rule, but preliminary evidence indicates that combined highly active antiretroviral therapy may improve the prognosis of this disorder. Prolonged survival on maintenance dialysis is possible. Combined highly active antiretroviral therapy should be administered to HIV-infected patients with ESRD. However, the dosages of didanosine (give one-fourth of the total daily dose for normal renal function once a day) and zidovudine (100 mg q8h) must be adjusted. The risk of patient-to-patient transmission of HIV infection in a hemodialysis center is extremely low. Neither dedicated hemodialysis machines nor patient isolation is necessary. 6

VACCINATIONS

Recommendations for administration of the hepatitis B virus vaccine have been given. The Advisory Committee on Immunization Practices (ACIP) recommends that the 23valent pneumococcal polysaccharide vaccine be administered to all adult dialysis patients. More than 75% of dialysis patients mount an adequate immune response to the pneumococcal vaccine, but antibody levels often decline within 5 years. Revaccination is recommended in 5 years. The immune response to the influenza vaccine of chronic dialysis patients is similar to that of controls. Yearly influenza vaccination is recommended for all chronic dialysis patients. 7

URINARY TRACT INFECTIONS

Pyuria in the absence of infection is common in patients with ESRD. Nevertheless, urinalysis is frequently requested during the evaluation of the febrile dialysis patient. In the absence of symptoms of urinary tract infection (dysuria, flank pain, abdominal pain), pyuria should not lead one to conclude that a urinary tract infection (UTI) is the cause of the fever. Antibiotic therapy for UTI should be limited to patients with symptoms of UTI or a positive urine culture finding. Pyocystis denotes pus in the bladder and may cause fever in anuric dialysis patients. Symptoms include suprapubic pain and purulent urethral discharge. Bladder catheterization

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yields pus, and urine culture frequently yields multiple organisms. Treatment consists of catheter drainage of the bladder and irrigation of the bladder with antibiotic solutions. If systemic symptoms or signs are present, parenteral antibiotic therapy should be administered. Urological consultation and cystoscopy are recommended. Cystoscopy may reveal a structural lesion of the bladder for which surgical intervention or even cystectomy is indicated. Autosomal dominant polycystic kidney disease accounts for 2.5% of cases of ESRD in the United States. Renal cyst infections are characterized by fever, flank pain, and flank tenderness. Pyuria may be absent and urine culture may yield no growth. Ciprofloxacin and trimethoprim-sulfamethoxazole are able to penetrate cysts and are the antibiotics of choice for cyst infections. Chloramphenicol is also able to penetrate cysts.

BIBLIOGRAPHY Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I, Swan SK, Bennett WM. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th ed. Philadelphia: American College of Physicians, 1999. Barth RH, DeVincenzo N. Use of vancomycin in high-flux hemodialysis: Experience with 130 courses of therapy. Kidney Int 50:929–936, 1996. Berkoben M, Provenzale J. A hemodialysis patient with excruciating back pain. Semin Dial 9:286– 288, 1996. Berkoben M, Schwab SJ. Hemodialysis vascular access. In: Henrich WL, ed. Principles and Practice of Dialysis, 2nd ed. Baltimore: Williams & Wilkins, 1999, pp 41–59. Fogel MA, Nussbaum PB, Feintzeig ID, Hunt WA, Gavin JP, Kim RC. Cefazolin in chronic hemodialysis patients: A safe, effective alternative to vancomycin. Am J Kidney Dis 32:401– 409, 1998. Herwaldt LA. Reduction of Staphylococcus aureus nasal carriage and infection in dialysis patients. J Hosp Infect 40:S13–S23, 1998. Huraib S, Tanimu D, Romeh SA, Quadri K, Al Ghandi G, Iqbal A, Abdulla A. Interferon-alpha in chronic hepatitis C infection in dialysis patients. Am J Kidney Dis 34:55–60, 1999. Keane WF, Alexander SR, Bailie GR, Boeschoten E, Gokal R, Golper TA, Holmes CJ, Huang CC, Kawaguchi Y, Piraino B, Riella M, Schaefer F, Vas S. Peritoneal dialysis-related peritonitis treatment recommendations: 1996 update. Perit Dial Int 16:557–573, 1996. Levin A, Mason AJ, Jindal KK, Fong IW, Goldstein MB. Prevention of hemodialysis subclavian vein catheter infection by topical povidone-iodine. Kidney Int 40:934–938, 1991. Marr KA, Kong LK, Fowler VG, Gopal A, Sexton DJ, Conlon PJ, Corey GR. Incidence and outcome of Staphylococcus aureus bacteremia in hemodialysis patients. Kidney Int 54:1684–1689, 1998. Marx MA, Frye RF, Matzke GR, Golper TA. Cefazolin as empiric therapy in hemodialysis-related infections: Efficacy and blood concentrations. Am J Kidney Dis 32:410–414, 1998. Miller ER, Alter MJ, Tokars JI. Protective effect of hepatitis B vaccine in chronic hemodialysis patients. Am J Kidney Dis 33:356–360, 1999. Murphy BVR, Pereira BJG. Hepatitis and human immunodeficiency virus infections in end-stage renal disease patients. In: Henrich WL, ed. Principles and Practice of Dialysis. 2nd ed. Baltimore: Williams & Wilkins, 1999, pp 285–304. NKF-DOQI Clinical Practice Guidelines for Vascular Access. New York: National Kidney Foundation, 1997, pp 62–65. Rangel MC, Coronado VG, Euler GL, Strikas RA. Vaccine recommendations for patients on chronic dialysis. Semin Dial 13:101–107, 2000. Schwab SJ, Beathard G. The hemodialysis conundrum: Hate living with them, but can’t live without them. Kidney Int 56:1–17, 1999.

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Sesso R, Barbosa D, Leme IL, Sader H, Canziani ME, Marfredi S, Draibe S, Pignatari AC. Staphylococcus aureus prophylaxis in hemodialysis patients using central venous catheter: effect of mupirocin ointment. J Am Soc Nephrol 9:1085–1092, 1998. Sieradzki K, Roberts RB, Haber SW, Tomasz A. The development of vancomycin resistance in a patient with methicillin-resistant Staphylococcus aureus infection. N Engl J Med 340:517– 523, 1999. Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson-Dunn B, Tenover FC, Zervos MJ, Band JD, White E, Jarvis WR for the Glycopeptide-Intermediate Staphylococcus aureus Working Group. Emergence at vancomycin resistance in Staphylococcus aureus. N Engl J Med 340:493–501, 1999. Tokars JI, Miller ER, Alter MJ, Arduino MJ. National surveillance of diaylsis-associated diseases in the United States, 1997. Semin Dial 13:75–85, 2000.

37 Infections in the Patient with Animal Contact Anthony L. Esposito and George Abraham Saint Vincent Hospital at Worcester Medical Center, and University of Massachusetts, Worcester, Massachusetts, U.S.A.

1

INTRODUCTION

The remarkable spectrum of human infections acquired from animals continues to expand and to capture the attention of medical professionals and the general public. For example, innumerable news reports and public health announcements accompanied the New York City outbreak of West Nile viral disease, a mosquito-transmitted infection, which initially appeared in North America in the summer of 1999. It produced deaths in birds, horses, and humans and rapidly spread into the neighboring states of New Jersey, Maryland, Connecticut, and Massachusetts. Obviously, the number and complexity of animal-associated illnesses preclude a comprehensive review of the entire subject in a single chapter. Moreover, most of these conditions remain uncommon, even for the infectious disease consultant, and many produce such catastrophic manifestations that afflicted patients require immediate hospitalization. Accordingly, this chapter focuses on conditions potentially encountered by a primary care physician treating adults in an ambulatory setting in the United States. Of note, some prevalent infections, such as Lyme disease and Rocky Mountain spotted fever, are addressed in detail in Chapter 30 along with ehrlichiosis, tick-borne relapsing fever, tularemia, and babesiosis. Additional information on animal-acquired diseases associated with life-threatening syndromes, such as arbovirus encephalitis and hantavirus pulmonary syndrome, is reviewed in Chapter 31. An awareness of the mechanisms through which microbes can be transmitted from vertebrate animals to humans provides insight into the clinical syndromes with which patients present. In brief, infections derived from vertebrates (or zoonotic diseases) can be acquired through direct contact, the inhalation of infectious aerosols, the ingestion of contaminated products, or the bite of an arthropod vector. Consequently, the ensuing clinical syndromes include soft tissue infections (e.g., cellulitis due to Pasteurella multocida after a cat bite), lymphadenopathy (e.g., cat-scratch disease resulting from contact with a kitten), lower respiratory tract infections (e.g., pneumonia due to Chlamydia psittaci in a bird fancier), gastrointestinal disorders (e.g., diarrhea caused by Salmonella spp. acquired from contaminated poultry products), and cutaneosystemic disorders (e.g., Lyme disease or Rocky Mountain spotted fever transmitted by a tick bite). 709

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ZOONOSIS History Animal contact Hunting Occupation Water exposure Travel Consumption of raw milk Presentations with pneumonia, lymphadenopathy, diarrhea, and fever (see Table 1) Animal bite wounds (see Figure 1) Increased concern with cat bites, wounds involving bones and joints, and immune compromised hosts Cleaning and de´bridement Assessment of need for antibiotic prophylaxis or therapy Assess need for tetanus and rabies immunotherapy Reassessment in 24–48 hours Rabies vaccination (see Figure 2 and Table 3) Cat scratch disease (see Figures 3 and 4) Regional lymphadenopathy associated with kitten scratch Diagnosis with antibodies to Bartonella henselae Generally self-limited

2

EPIDEMIOLOGICAL CLUES TO ZOONOTIC INFECTIONS

The possibility that a patient who has pneumonia, diarrhea, lymphadenopathy, or fever has an animal-associated problem is raised by the nature and course of the illness. Accordingly, in those circumstances in which the cause of the problem remains enigmatic or in which simple diagnostic tests are unrevealing, an epidemiological or ‘‘exposure’’ history should be secured. In short, is the patient at risk for a zoonotic illness through exposure to the necessary source or vector? Important diagnostic clues in the epidemiological histories of patients with specific clinical syndromes are outlined in Table 1. Details concerning these disorders, including antimicrobial therapies, can be found in standard texts of medicine or infectious diseases. The discussion that follows centers on the clinical problems of animal bites and catscratch disease. The authors recognize that in some geographical regions of the country, other animal-associated conditions may be more common or more nettlesome to practitioners than the topics selected. Nevertheless, limitations of space and the importance of a detailed discussion on the more prevalent zoonotic illnesses demand a narrow focus. 3

ANIMAL BITES

Epidemiologists estimate that 1–2 million Americans experience an animal bite annually. Dogs or cats are involved in the vast majority of these episodes; however, the spectrum of animal bite–associated human infections is broad; it is illustrated in Table 2. Thus, although the following discussion is devoted to the management of dog and cat bites and addresses the more common soft tissue infections complicating these insults, the clinician

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should be aware that any vertebrate bite can lead to human disease. Consequently, every bite wound requires thoughtful and thorough attention. The management of the patient who has an animal bite is guided by the presence or absence of frank infection at the time of presentation, the nature and location of the wound, the risk of rabies, and a few other factors. Of note, the traditional medical reasons for recording a detailed history and physical examination are augmented in the setting of an animal bite, since the injury can lead to litigation. Accordingly, sketches or even photographs may be necessary in order to provide the most accurate description of the wound. Patients may seek medical care immediately after an animal bite because of pain, blood loss, crush injury, or the need for suturing, prophylactic antibiotics, or rabies vaccination. An approach to the uninfected bite wound is outlined in Figure 1. Later presentations (after 8 hours) are usually due to the onset of infections. The patient may experience pain, erythema, swelling, fever, and/or purulent wound discharge. The risk of infection can be 10-fold greater in cat versus dog bites. The higher infection rate is related, in part, to the fact that cats more commonly produce puncture wounds and that cats more frequently harbor Pasteurella multocida in their oropharynx. Accordingly, except in cosmetically important areas such as the face, cat bites should not be primarily closed with sutures. Equally importantly, since cellulitis caused by Pasteurella spp. typically begins 24–48 hours after the injury, an assessment of the patient’s status should be made soon after the initial visit, regardless of whether or not antimicrobial chemoprophylaxis has been administered. Persons immunologically impaired by splenectomy, lymphoproliferative disease, corticosteroid use, or alcoholism are at risk of experiencing serious infection due to Capnocytophaga canimorsus (formerly termed dysgonic fermenter, type 2 [DF-2]). This is a gram-negative bacillus that is carried in the oropharynx of some dogs and cats. In normal hosts, C. canimorsus rarely causes disease, although in immunosuppressed patients, the bacterium can cause a fulminant illness characterized by bacteremia, sepsis, disseminated intravascular coagulation, adrenal and renal failure, and peripheral gangrene. Of note, about a quarter of patients infected with C. canimorsus report an antecedent exposure to a dog but no actual bite. Obviously, once the full sepsis syndrome evolves, these patients require admission to an intensive care unit. Penicillin represents the antimicrobial treatment of choice. Infected dog or cat bites should be managed similarly to uninfected wounds (Figure 1). Infected wounds should never be closed and therapeutic antimicrobials are indicated. In general, wound cultures should be obtained, especially for patients who require admission to a hospital. By employing appropriate techniques, three to five bacteria can be isolated. The microbes most commonly recovered include P. multocida or P. canis, aerobic streptococci, staphylococci, Moraxella spp., and a variety of anaerobes, such as Fusobacterium spp. and Bacteroides spp. Although the antimicrobial therapy of infected wounds is be guided by the results of deep wound cultures, the initial regimen should have activity against the most common pathogens, especially Pasteurella spp., which is usually resistant to semisynthetic penicillins (i.e., dicloxacillin), first-generation cephalosporins (i.e., cephalexin), and clindamycin. Amoxicillin-clavulanate possesses sufficient in vitro activity against the pathogens usually associated with these infections and is often recommended. Penicillin in combination with a first-generation cephalosporin (e.g., cephalothin) or with penicillinase-resistant penicillin (e.g., dicloxacillin) may also be considered. For the patient with disease requiring parenteral therapy in an inpatient or ambulatory setting, ampicillinsulbactam or penicillin plus oxacillin provides the necessary coverage. Treatment can be modified as microbiological information becomes available. In the penicillin-allergic pa-

Fever

Diarrhea

Pneumonia

Clinical syndrome

Q fever

Tularemia

Pneumonic plague

Cattle, sheep, goats

Wild rabbits, beaver, squirrels, muskrats

Wild rodents or fleas in Western states

Murine typhus

Giardiasis

Water potentially contaminated with animal excreta

Fleas

Campylobacteriosis, salmonellosis

Poultry products

Calves and other neo- Cryptosporidiosis natal ruminants

Psittacosis

Possible diagnosis

Birds

Exposure history

Both psittacine (i.e., parrots, parakeets) and other birds (i.e., canaries, ducks, geese, pigeons) potential sources of infection Shedding of microbe in milk, urine, and birth products by infected domesticated ungulates (hoofed animals) Landscapers, hunters, farmers, laboratory workers, and veterinarians at risk

Comment

Usually secondary to septicemic plague, pneumonia fatal if therapy delayed; condition a public health emergency Examination of stool for oocysts of Crypto- Household pets (dogs, cats) also sources of infecsporidium spp. tion; farmers, veterinarians, and abattoir workers at risk Culture of stool for Campylobacter, Salmo- Young dogs and cats (Campylobacter spp.) and nella spp. turtles and snakes (Salmonella spp.), household sources of disease Examination of stool for cysts and trophozo- Individuals who consume water from streams or ponds contaminated by beaver, cattle, or sheep ites of Giardia intestinalis, or antigen deat risk tection assays, or rarely sampling of duodenal fluid Serological tests for Rickettsia typhi Disease largely confined to southern California or south Texas; thrombocytopenia, leukopenia, and elevated hepatic transaminase level clues to diagnosis; maculopapular, truncal rash present in most cases

Serological tests for Francisella tularensis; isolation in laboratory possible but risky to personnel Smear and culture of bubo aspirate; culture of blood and sputum for Yersinia pestis

Serological tests for Coxiella burnetti

Serological tests for Chlamydia psittaci

Laboratory tests

Table 1 Elements of an Epidemiological History That Raise the Possibility of a Zoonotic Disease a

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Serological tests for Ehrlichia; review of blood smears for intraleukocytic inclusions (morulae) although test insensitive; PCR of peripheral blood Serological tests for Francisella tularensis

Ehrlichiosis

Tularemia

Serological tests for Coxiella burnetti

Sheep, goats, cattle

Q fever

Serological tests for Brucella spp.; blood cultures with selective media

Serological tests for Leptospira spp.

Serological tests for Colorado tick fever virus; immunofluorescent staining for intraerythrocytic viral antigen

Colorado tick fever

Leptospirosis

Microscopic exam of blood smears for Babesia microti; serological tests also available

Babesiosis

Cattle, sheep, goats; Brucellosis unpasteurized milk or cheese

Animal urine

Ticks

Elderly and splenectomized patients at risk of severe disease; most prevalent on islands and along coast of Massachusetts, Rhode Island, and New York; hemolytic anemia and hemoglobinuria possible Self-limited illness endemic in mountainous regions of Colorado, Montana, Wyoming, Utah and Idaho; hunters, hikers, and campers at risk; headache, photophobia, abdominal pain; rash present in 10% of cases More common in southern and south-central states; clues to diagnosis include leukopenia, thrombocytopenia, and abnormal hepatic transaminase results; maculopapular rash present in about 30% of cases Tick transmission less common than direct contact; high-risk groups similar (as above) Microbe carried by wide range of domesticated and wild animals, especially rodents; laboratory mice implicated in many outbreaks; cough, diarrhea and conjunctival suffusion; rash present during late stage; hepatic and renal involvement in severe illness Although reported in all states, incidence highest in Texas, California, Florida, and Virginia; farmers, veterinarians, and abattoir workers at risk; consumption of contaminated fresh dairy products are also a risk Parturient sheep implicated in many cases (as above)

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Fever and lymphadenopathy

Clinical syndrome

Smear and culture of bubo aspirate for Yersina pestis

Bubonic plague

Wild rodents or fleas in western states

Serological tests for Toxoplasma gondii

Toxoplasmosis

Serological tests for Francisella tularensis

Serological tests for Bartonella henselae

Culture of blood for Yersina pestis; smear and culture of bubo aspirate

Laboratory tests

Cat-scratch disease

Septicemic plague

Possible diagnosis

Wild rabbits, beaver, Ulceroglandular squirrels, muskrats; tularemia ticks

Cats

Wild rodents or fleas in western states

Exposure history

Table 1 Continued

Septicemic plague that may be primary or secondary to progression of untreated bubonic disease; hunters, trappers at risk Disease also associated with noncontact cat exposure; adenopathy regional, tender and persistent for months; fever low-grade and transient Cats as the definitive host able to shed oocysts in feces; oocyst sporulation in a few days, producing infectious forms that can persist for weeks in soil, poorly maintained litter boxes, etc.; protozoan parasite potentially acquired through fecal-oral route Inoculation of skin through contact (i.e., skinning) that produces ulcer on hand or forearm and regional tender adenopathy; inoculation via tick, which produces ulcer at bite site and local node enlargement Buboes (enlarged, painful lymph nodes) usually present in groin or axilla; lesions extremely tender; course fulminant without appropriate therapy

Comment

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Anthrax

Rat bite fever

Rats

Cattle, sheep, donkeys, goats

Rickettsial pox Recovery of Streptobacillus moniliformis or Spirillium minor from blood or synovial fluid Culture for Bacillus anthracis from vesicle

Serological tests for Rickettsia akari

Direct immunofluorescence of skin biopsy; serological tests for Rickettsia rickettsii

Rocky Mountain spotted fever

Mice or mouse mites

(As above) (As above) Serological tests for Borrelia burgdorferi

Colorado tick fever Ehrlichosis Lyme disease

Ticks

(As above)

Murine typhus

Fleas

PCR, polymerase chain reaction.

Papules

Fever and Rash — — Most cases reported in Connecticut, New York, Massachusetts, Rhode Island, Pennsylvania, Wisconsin, Minnesota, and California; present in 75% of cases, rash (erythema migrans) typically expanding red lesion with central clearing found in axilla, groin, or thigh; secondary lesions possible over chest and trunk Disease reported in every state; rash present in 90% of cases; initially maculopapular and appearing on wrists and ankles; cutaneous lesion that spread to trunk and become petechial as disease progresses Disease in urban areas; chickenpox suggested by generalized papulovesicular rash Myalgias and migratory polyarthritis suggestive; maculopapular or morbilliform rash present over palms, soles, and extremities Painless, prurutic papule with vesicles, generally on extremities or face; agent that can be used in biological warfare. Inhalation of spores manifested by pneumonia.

—

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Table 2 Spectrum of Pathogens Recovered from Humans Infected Through Uncommon Animal Bites Source Alligator Dolphin Ferret Hamster Horse Lion Monkey Pig Piranha Rat Shark Tiger Wolf

Microbe Aeromonas hydrophila, Pseudomonas aeurginosa a Mycobacterium marinum a Mycobacterium bovis a Acinetobacter sp.b Pasteurella sp., Actinobacillus sp.a Pasteurella multocida a Herpesvirus simiae c Pasteurella sp., Actinobacillis suis a Aeromonas hydrophila a Streptobacillus moniliformis,d Leptospira sp.d Vibrio carchariae a Pasteurella multocida a Pasteurella multocida a

a

Soft tissue infection. Osteomyelitis. c Nervous system infection. d Systemic infection. b

tient, clindamycin plus a tetracycline or quinolone, which are agents possessing appropriate in vitro activity against P. multocida, provides acceptable therapy. Of course, the potential toxicities of tetracyclines and quinolones limit their use for pregnant or lactating women. Erythromycin, clarithromycin, and azithromycin exhibit variable activity against Pasteurella spp. and should not be used. Prophylactic antimicrobial therapy for the noninfected wound may be administered for 3–5 days, whereas for infected wounds, treatment should be continued for 10–14 days. 4

RABIES PROPHYLAXIS

Few discussions produce greater frustration than do those initiated by distraught patients concerning the need for rabies prophylaxis after animal contact. Fear of a universally fatal disease usually sweeps aside thoughtful consideration of the actual risks and the scientifically based recommendations. In fact, the decision concerning the need for antirabies immunoprophylaxis for an animal bite should be guided by a number of simple factors including the presence or absence of rabies in the region where the injury occurred, the circumstances of the bite, and the availability of the animal for observation or for sacrifice and brain harvesting (Figure 2). The following are considered to indicate a ‘‘provoked’’ bite: trespassing through an animal’s territory; playing with, petting, or feeding an animal; intervening in a fight; caring for an injured animal; handling an animal in a veterinary facility; and running, riding, or walking past an animal. Although the animal’s vaccination status should be determined, a history of rabies immunization does not exclude the possibility of the disease. Deaths due to rabies have occurred in travelers bitten outside the United States by dogs believed to have been immunized. In addition, the patient should

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Figure 1 Management of the adult with an uninfected animal bite. PCN, penicillin; Td, tetanus and diphtheria toxoid; TIG, tetanus immunoglobulin.

be assessed for tetanus immunization (intramuscular, tetanus and diphtheria toxoid [Td], 0.5 mL) and tetanus immune globulin ([TIG], 250–500 IU intramuscularly) (see Figure 1; also see Chapter 42). Bats and carnivorous animals (raccoons, skunks, foxes, and coyotes) are most likely to be infected with the virus. Any person who has the bite wound of a wild carnivorous mammal should be considered at risk for rabies unless immunofluorescent staining of the animal’s brain tissue yields a negative finding for the virus. As for all bite wounds, these lesions must be cleaned thoroughly with soap and water, a simple procedure that in experimental circumstances is extremely effective in reducing the transmission of the rabies virus. Previously unvaccinated patients should be given passive and active immunization (Table 3). Local reactions such as pain, swelling, and redness occur in up to 70% of vaccine recipients. Systemic reactions are less common and tend to be mild. Human rabies

Figure 2 Guidelines concerning rabies immunoprophylaxis for patients with animal bites.

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Table 3 Postexposure Rabies Immunoprophylaxis Protocol a Component Human rabies immune globulin (HRIG) Human diploid cell vaccine (HDCV)b

Dosage

Comment

20 IU/kg

Infiltrate as much of dose as possible around wound; give the balance IM into gluteal region Give IM into deltoid, the only acceptable sitec; doses administered on days 0, 3, 7, 14, and 28

1.0 mL

a

Previously immunized individuals should receive a dose of the human diploid cell vaccine on days 0 and 3. HRIG and HDCV should never be mixed in the same syringe. c HDCV must never be administered in the gluteal region. In young children, HDCV can be given in the outer aspect of the thigh. b

acquired in the United States is usually attributed to nonbite contact with bats. Thus patients who have a history of close contact with bats but no bite injury may nevertheless be candidates for rabies prophylaxis. Additional details concerning postexposure rabies prophylaxis can be obtained from state public health departments. 5

ZOONOSES MANIFESTING WITH LYMPHADENOPATHY

The causes of lymphadenopathy are myriad; the documentation of antecedent animal exposure can limit the list of potential causes (Figure 3). Thus, a history of outdoor activities or of recent catching or skinning a rabbit or other wild animal, especially in the late winter, raises the possibility of tularemia (Table 1). A history of travel to the Southwest and fleabites brings into focus the diagnosis of bubonic plague. Manifested 2–8 days after the bite of a rat flea, the syndrome is one of febrile lymphadenopathy (Table 1). Of note, with increasing intercontinental travel, diseases associated with enlarged lymph nodes can be acquired abroad. Thus, travelers to the African continent bitten by the tsetse fly can experience West or East African trypanosomiasis (caused by Trypanosoma rhodesiense and T. gambiense, respectively). Voyagers to Central or South America bitten by a reduviid insect (kissing bug) can contract Chagas disease (caused by T. cruzi). 6

CAT-SCRATCH DISEASE

With an estimated 25,000 cases annually in the United States, cat-scratch disease represents the most common animal-associated cause of lymphadenopathy likely to be encountered by a primary care physician (Figure 4). The incidence of the problem is greater in warm, humid regions of the country, where the prevalence of cats infected with Bartonella henselae, the etiological agent, is greatest. Remarkably, in some regions, about 50% of normal cats less than 1 year of age have been shown to be bacteremic with Bartonella sp. and 90% have antibodies against the microbe. Fleas have been implicated in the dissemination of Bartonella sp. among cats but do not appear to transmit the bacterium to humans. The symptoms of cat-scratch disease develop 2–3 weeks after exposure, typically to a recently acquired kitten. In more than 90% of cases in immunocompetent hosts, lymphadenopathy represents the cardinal manifestation of the disease. Fever and other constitutional symptoms tend to be mild. In about a third of patients, a local reaction in the form of a red or brown papule is noted. The course of the papule tends to parallel that of the adenopathy. Anatomically related to the inoculation site, the lymphadenopathy is usually unilateral and localized. The most commonly involved regions include the axillary

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Figure 3 Diagnostic clues to zoonotic diseases in the patient with lymphadenopathy. HIV, human immunodeficiency virus; EBV, Epstein-Barr virus; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

and epitrochlear nodes (⬃50%), the cervical and submandibular nodes (⬃25%), and the femoral and inguinal nodes (⬃20%). Rarely, the adenopathy may be generalized and associated with severe constitutional symptoms and with hepatic, splenic, or abdominal node involvement. Atypical cat-scratch disease manifestations include Parinaud’s oculoglandular syndrome (preauricular adenopathy with an ipsilateral conjunctivitis), encephalopathy with seizures, and endocarditis. Individuals infected with the human immunodeficiency virus (HIV) and other immunosuppressed patients are at risk of experiencing a disseminated Bartonella sp. infection that is characterized by cutaneous, subcutaneous, and visceral proliferative vascular lesions (bacillary angiomatosis) and that can be fatal without antimicrobial therapy. The available diagnostic tests for cat-scratch disease include the in vitro cultivation of the microbe on synthetic medium, the identification of the organism in tissues or other

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Figure 4 Management of the patient with suspected cat-scratch disease.

clinical specimens by polymerase chain reaction (PCR), and the detection of serum immunoglobulin G (IgG) and IgM antibodies by immunofluorescent or enzyme-linked immunosorbent assay (ELISA) techniques. In general, the diagnosis of cat-scratch disease is suggested by the clinical picture and usually confirmed by the indirect immunofluorescent antibody (IFA) assay for Bartonella henselae. Of note, since serological test results may be negative in 15%–20% of cases if specimens are secured within the first two 2 weeks of the onset of symptoms, repeated testing at 4–8 weeks may be necessary to detect antibodies to confirm the diagnosis. Uncomplicated cases of cat-scratch disease do not warrant antimicrobial therapy. The adenopathy can be expected to persist 3–4 months (range, 1–12 months) and resolve spontaneously. Serial assessments to document regression are essential, and if the diagnosis remains uncertain, a biopsy should be performed to exclude the presence of other problems, especially lymphoma. On occasion, massive suppuration and the threat of rupture

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necessitate needle aspiration to decompress the lesions. On the basis of one controlled trial, administration of azithromycin appears to be the treatment of choice. Other agents possessing in vitro activity and occasionally utilized include erythromycin, clarithromycin, doxycycline, rifampin, and ciprofloxacin. The prognosis is good and most patients recover without sequelae. BIBLIOGRAPHY Bass JW, Vincent JM, Person DA. The expanding spectrum of Bartonella infections. II. Cat scratch disease. Pediatr Infect Dis J 16:193–179, 1997. Bass JW, Freitas BC, Freitas AD, Sisler CL, Chan DS, Vincent JM, Person DA, Claybaugh JR, Wittler RR, Weisse ME, Regnery RL, Slater LN. Prospective randomized double blind placebo-controlled evaluation of azithromycin for the treatment of cat-scratch disease. Pediatr Infect Dis J 17:447–452, 1998. Centers for Disease Control and Prevention. Human rabies prevention—United States, 1999: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 48(RR-1):1–21, 1999. Goldstein EJC. Household pets and human infections. Infect Dis Clin North Am 5:117–130, 1991. Hicklin H, Verghese A, Alvarez S. Dysgonic fermenter-2 septicemia. Rev Infect Dis 9:884–890, 1987. Noah DL, Drenzek CL, Smith JS, Krebs JW, Orciari L, Shaddock J, Sanderlin D, Whitfield S, Fekadu M, Olson JG, Rupprecht CE, Childs JE. Epidemiology of rabies in the United States, 1980 to 1996. Ann Intern Med 128:922–930, 1998. Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJ. Bacteriologic analysis of infected dog and cat bites. N Engl J Med 340:85–92, 1999. Tan JS. Human zoonotic diseases transmitted by dogs and cats. Arch Intern Med 157:1933–1943, 1997. Weber DJ, Rutala WA. Zoonotic infections. Occup Med 14:247–284, 1999. Weber DJ, Wolfson JS, Swartz MN, Hooper DC. Pasteurella multocida infections: Report of 34 cases and review of the literature. Medicine 63:133–154, 1984. Weinberg AN. Ecology and epidemiology of zoonotic pathogens. Infect Dis Clin North Am 5:1– 17, 1991.

38 The Patient with Fatigue Irving E. Salit Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada

1

INTRODUCTION

In clinical practice, patients may present with the following common symptoms: fatigue, insomnia, dizziness, constipation, or pain. These symptoms are often considered to be ‘‘soft,’’ difficult to quantify, and may have no obvious underlying organic cause. Etiologically these symptoms are usually more often associated with psychosocial factors than organic ones. Because of that association there is a perception that these presentations represent more minor problems that may even be an irritant to some physicians. This irritation arises from the fact that these patients are often the ‘‘worried well’’ who may ‘‘medicalize’’ symptoms; the diagnosis is obscure and attempts at treatment are unsuccessful. Medical training is geared to ruling out organic diagnoses, so medical textbooks usually focus on ‘‘interesting’’ organic illnesses and may outline long, exotic differential diagnoses for such problems, but these are rarely the causes. The symptoms described, in particular fatigue, are in fact not minor and may be associated with functional impairment comparable to or greater than caused by many organic conditions. Patients with chronic fatigue can be helped, but the process is often a frustrating one for the doctor, the patient, the loved ones, and insurance companies.

2

BACKGROUND

Fatigue is a very common symptom in the community as well as among those who seek medical attention. Large community surveys have found that 20% of men and 25% of women ‘‘always feel tired,’’ yet only a fraction of these people perceive the fatigue as a medical problem and seek medical attention. Approximately 20% of primary care patients report that they suffer from fatigue, and about 15% report fatigue as either their chief complaint or a secondary complaint. Self-limited fatigue, which generally lasts up to 4 to 6 weeks, very commonly occurs after acute medical illnesses and after surgical operations. For example, follow-up studies of patients who have had lower respiratory tract infections indicate that persisting cough and fatigue last a median of 2 weeks and longer in those with more severe infections. Similarly, fatigue is well known to occur after influenza, infectious mononucleosis, aseptic meningitis, myocardial infarction, and cardiovascular surgery. Other, more clearly psycho723

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FATIGUE Common, often incapacitating symptom Can be acute or chronic, including chronic fatigue syndrome (CFS) (Table 1) CFS True clinical syndrome, of unknown cause Centers for Disease Control (CDC) definition (see Table 2) Unrefreshing sleep, postexertional fatigue Cognitive dysfunction Myalgia Patient characteristics (see Table 4) Female Aged 20–45 years Normal physical and laboratory results Management (see Table 5) Guarded prognosis (see Table 6)

social stressors, such as motor vehicle accidents (in the absence of physical injury), major job changes, serious family illness, moving to a new house, and major changes in a relationship, can all be associated with fatigue. It is important for the physician to help provide the necessary insight and reassurance in order to help prevent these subacute forms of fatigue from developing into chronic fatigue. Community studies have found a prevalence of chronic fatigue of almost 40/100,000 population with a female-to-male ratio of 1.3:1 and a mean age of 34 years. Other studies have found little variation with age. Those with chronic medical illness and those with psychiatric illness were more likely to have had fatigue. Conversely those with fatigue have a higher prevalence of lifetime and current psychiatric disorders such as major depression, somatization disorder, and dysthymia. Those in the community with fatigue also have a greater number of medically unexplained symptoms and more health care visits, especially if there is an associated psychiatric diagnosis. Similarly, patients who report fatigue in the primary care setting have a significantly higher lifetime prevalence of depressive or anxiety disorders and perceive that they have undergone significantly more stress over the preceding 3 months than have control subjects (Figures 1 and 2). Most patients who report fatigue in the primary care setting do acknowledge a psychosocial contribution to their fatigue and an association with self-perceived emotional vulnerability. Women are more likely to report fatigue even after adjusting for psychosocial distress. Those patients with more than 6 months of fatigue have experienced more somatic symptoms, greater worry about their illness and have lower recovery rates. Although fatigue is common in the primary care setting, very few patients with fatigue actually mention the chronic fatigue syndrome (CFS) as the cause. Many studies in patients who were examined in tertiary care centres further document the high rates of current major depression as well as a lifetime history of depression in patients with chronic fatigue. Chronic fatigue is not a new condition but has been described in many forms over the centuries. In 1750, febricula, or little fever, was described as ‘‘listlessness with great lassitude and weariness all over the body.’’ These patients also had myalgias, arthralgias,

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Figure 1 Etiological diagnoses of 200 patients with chronic fatigue (Demitrack and Abbey, 1996).

and forgetfulness. In 1869, George Beard, an American neurologist, described ‘‘neurasthenia,’’ which had all of the features of chronic fatigue syndrome: it was a condition of ‘‘nervous exhaustion . . . undue fatigue on slightest exertion, both physical and mental . . . headache, . . . and subjective sensations of all kinds.’’ Later, chronic fatigue was described as occurring after brucellosis, influenza, and infectious mononucleosis, but the association was controversial. In the 1950s, there was mounting evidence that prolonged morbidity after infections was often due to psychological disorders and not due to a continuing infection. For example, in a prospective evaluation of male employees at Fort Detrick in whom Asian flu developed, premorbid psychological vulnerability predicted influenza illness and a longer recovery time. More recently a prospective cohort study of primary care demonstrated that prolonged fatigue after flulike illnesses was related to premorbid psychological distress. Furthermore, in carefully controlled cold virus challenge studies there was an increase in the rates of both documented infection and clinical illness caused by these viruses with increases in the degree of psychological stress. For many patients seen in the office it may be difficult to determine whether fatigue has led to

Figure 2 Psychiatric diagnoses of 200 patients with chronic fatigue (Demitrack and Abbey, 1996).

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psychological distress or psychological factors have led to fatigue (or both). It is, however, clear that in prospective studies psychological factors can predispose to infection and especially persisting ill health. Thus chronic fatigue syndrome (CFS) can be viewed as a classical association involving the mind, body, and environment; in traditional Chinese medicine this is conceptualized as yin and yang. In addition to the more sporadic forms of CFS noted, outbreaks of CFS-like illness have also been described. Epidemics of a fatiguing illness in association with other symptoms came to be known as epidemic neuromyasthenia, and outbreaks came to be known by different designations based on the location (e.g., Royal-Free disease, Iceland disease, Lake Tahoe epidemic). Twenty-three such epidemics were reported from 1934 to 1958. The origin of these outbreaks is uncertain, but it was alleged that there was a strong element of mass hysteria in many of these outbreaks. These apparent outbreaks seem to be much less frequent in recent decades and attention has turned to sporadic cases. Sporadic forms of chronic fatigue bear some resemblance to the cases in these epidemics, but the relationship between sporadic and epidemic fatigue is uncertain. Our focus in this chapter is on sporadic fatigue, especially chronic fatigue that lasts more than 6 months. 3

DEFINITIONS AND CRITERIA

The main presentations to be delineated are subacute fatigue, chronic fatigue, and chronic fatigue syndrome (CFS) (see Table 1). Short-lived or subacute fatigue generally lasts up to several weeks but can last for months and is associated with acute precipitating causes. These causes may be related to organic illness, psychosocial stressors, psychiatric disorders, surgery, or trauma. Chronic fatigue is fatigue lasting more than 6 months that can be explained on the basis of a medical or psychiatric diagnosis. Alternatively, it is fatigue that is chronic but not extremely debilitating. For example, from a large group of patients suffering from chronic fatigue, one can make a psychiatric diagnosis in about 75%, a

Table 1 Forms of Fatigue Acute/subacute Up to 4–6 weeks Very common in community After acute medical illness (e.g., post pneumonia) Posttraumatic Chronic Variable severity Very common in community May or may not have associated symptoms Several to many months High prevalence of psychiatric disorders Chronic fatigue syndrome Much less frequent form of fatigue >6 Months Very severe fatigue Myalgia Sleep disorder Cognitive dysfunction Depressive symptoms

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medical diagnosis in 2%, and a medical and psychiatric diagnosis in 3% (see Figure 2). We are then left with a subset of patients (perhaps up to 20%) who have idiopathic chronic fatigue; many of those patients have chronic fatigue syndrome. In 1994 a case definition was developed by the Centers for Disease Control and Prevention (CDC) to encompass the syndrome known as chronic fatigue syndrome (CFS) (Fukuda et al., 1994). The value of this noncommittal label is that it did not attribute the fatigue to any particular cause or pathological condition, unlike the terms chronic EpsteinBarr virus (EBV) and myalgic encephalomyelitis (see Tables 2 and 3). CFS overlaps with other conditions. It is likely that CFS is identical to the conditions known as chronic Epstein-Barr virus syndrome, postviral fatigue, chronic fatigue and immunodeficiency syndrome (CFIDS), and myalgic encephalomyelitis. There is also considerable overlap of CFS with fibromyalgia. Furthermore, many subjects with CFS also have other medically unexplained illnesses such as temporomandibular joint pain, irritable bowel syndrome, and chronic headaches. The role of a case definition for CFS is to assist in proper diagnosis and appropriate investigations to rule out other conditions. CFS is defined solely on the basis of patientreported symptoms, so other causes of such symptoms have to be excluded. Although chronic fatigue and chronic fatigue syndrome are differentiated, it really is not clear that these two patient groups differ substantially. 4

THE CHRONIC FATIGUE SYNDROME PATIENT

Characteristically the CFS patient is a female between the ages of 20 and 45. The patient enters your office in a very characteristic fashion. Especially if the patient is unfamiliar to you there may be several phone calls to your office before the appointment because the patient often has concerns about the appointment related to location of the office, the duration of the visit, and what the visit entails. The patient usually arrives with a friend or family member who may have driven him or her to the appointment and who may wish to participate in the interview. It is generally preferable to interview the patient alone in order to assess better his or her ability to tell the history and to observe the patient’s cognitive functioning. Any gaps in the story can subsequently be filled in with the help of the accompanying person. The patients usually state that they have cognitive problems and require a friend or family problem to help them. It is actually rare, though, for the patient to encounter any difficulties with the ability to recount his or her history in considerable detail. Patients with CFS may arrive with a binder that includes detailed documentation of symptoms, medical history, and day-to-day functional ability that they themselves have catalogued. They may also have information from the Internet, newspapers, or magazines that alleges a new cause or cure for CFS. The patient may indicate that the main complaint is ‘‘tiredness’’ but you must determine exactly what the patient means by this term; you should differentiate between sleepiness, fatigue, lack of muscle power, depression, and other causes. All patients with CFS have very profound mental and physical fatigue that exceeds anything they have ever experienced and in fact often defies description. The hallmark of the fatigue is worsening after simple activities that the patient could have done quite easily in the past. It is made worse by stress, exertion, or mental functioning and is not very much improved by prolonged rest. The other predominant symptoms include problems with sleep, achiness, headaches, depression, and irritability. For the first few months of the illness the patients may be sleeping excessively (‘‘all day long’’), but later in the illness there may be frequent reawakenings and even when sleep does improve somewhat, patients are still unrefreshed in the morning.

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Table 2 Chronic Fatigue Syndrome: Centers for Disease Control Case Definition Clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that Is new or has a definite onset (that is, has not been lifelong) Is not the result of ongoing exertion Is not substantially relieved by rest Results in a substantial reduction in previous levels of occupational, educational, social, and/or personal activities Concurrent presence of four or more of the following symptoms that have persisted or recurred during 6 or more consecutive months of illness and did not predate the fatigue Self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of activity Sore throat Tender cervical or axillary lymph nodes Muscle pain Multijoint pain in absence of arthritis Headaches of new type, pattern, or severity Unrefreshing sleep Postexertional malaise lasting more than 24 hours

Attention should be paid to the circumstances under which the illness started or the precipitating factors (Figure 3). As noted in Figure 3, there may be one or more apparent precipitants that act on a background of psychosocial factors and result in the symptoms of CFS. Poor coping, misinformation, and abnormal illness behavior amplify and prolong the symptoms; it is the severity and chronicity of the illness that lead to a diagnosis of CFS. The debilitating illness may again lead to flulike symptoms and worsening; this stage completes the cycle. Patients often indicate that they were feeling perfectly well until they

Table 3 Chronic Fatigue Syndrome: Exclusionary Conditions Any active medical condition that explains the fatigue Any prior chronic medical condition whose resolution has not been documented (e.g., chronic hepatitis C) Past or current major depression with psychotic or melancholic features, bipolar affective disorders, schizophrenia, delusional disorders, dementias, anorexia nervosa, or bulimia Substance abuse within 2 years before onset Severe obesity

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Figure 3 A hypothesis of the generation and perpetuation of chronic fatigue syndrome (CFS).

had the initial or precipitating flulike illness, which seemed unremarkable. Indeed, they have usually been very active in exercise, social life, and family life and may have been working very long hours. However, after the acute, usually respiratory symptoms disappear in a week or so, they are left with overwhelming fatigue. Attempts to return to school or the workplace are unsuccessful because of the fatigue and cognitive dysfunction. Their boss or coworker may tell them to go home and not return until they are feeling much better. The clinician should inquire whether there were major changes in the workplace before the onset of the illness. A determination should be made as to prior coping strategies. Many patients in fact relate that in the year or so preceding the onset of the illness there were a number of psychosocial stressors, they were finding it increasingly difficult to cope, and they had to cut back on other activities. During the first year of the illness many patients are extremely incapacitated and may only be able to lie in bed or lie on the couch, or they may have great difficulty in even going to the washroom (some have to crawl on their hands and knees to do so). The physical examination findings are generally normal. There may be some redness of the throat, which is of uncertain significance. Although patients may describe tender, swollen lymph glands there is rarely palpable lymphadenopathy. It is more likely that any cervical tenderness relates to some tenderness of the sternomastoid muscles. Generalized muscle tenderness and tenderness of the tendon insertions are not infrequent, and there may be classical fibromyalgia tender points. Anxiousness during the examination is common and may be associated with tachycardia, moist palms, and jumpiness. There is no muscle weakness and no neurological abnormalities are found in CFS. Simple tests of cognitive functioning such as the mini–mental test yield normal findings. As a further assessment of cognition you should make note of the patient’s ability to relate the medical history in a careful and chronological fashion with attention to detail; there is usually no impairment at all in this regard.

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Patients should be observed for any signs of fatigue during the comprehensive history taking and examination. It is perplexing that patients rarely have any signs of overt fatigue during this process but indicate that they will be wiped out for a day or two after the office visit (see Table 4).

5

INVESTIGATIONS

Only a very small minority of patients who have typical CFS have evidence of an underlying organic disorder that can be uncovered by investigations. One has to reach a balance between doing too few tests and missing a rare organic cause and doing too many tests that may increase the patient’s concerns about a nonexistent underlying disorder; furthermore, doing more testing increases the likelihood that one will uncover some irrelevant abnormalities by chance alone. One useful approach is to do a minimal battery of laboratory screening tests to include a complete blood count; liver function tests; calcium, phosphorus, glucose, creatinine, thyrotropin (TSH) levels; and a urinalysis. It also may be useful to pursue more detailed targeted investigations when patients have a predominant symptom or sign that points to a possible underlying organic disorder; for example, if there has been abdominal pain, then perhaps a screening ultrasound would be of use. Many other kinds of tests have been reported to yield abnormal findings in CFS, and patients may be aware of these test abnormalities from their reading. Some of the reported immunological changes involve every aspect of lymphoid cell function, yet the changes are small and inconsistent, and it is uncertain whether they are truly different from normal. For example, expansion of CD45RO with adhesion markers suggests that immunologically mediated processes and cytokine production may be responsible for the clinical picture of CFS. One of the most documented and reproducible findings is a defect in natural killer (NK) cell function. A neuroendocrine explanation for CFS is suggested by low basal evening cortisol levels, which appear to be caused by a central nervous system– (CNS)-mediated failure to activate the hypothalamic-pituitary-adrenal axis. These changes can be induced by stress, infections, and/or psychiatric disorders. The neuroendocrine and immune findings may be central to the causation of CFS or may be epiphenomena resulting from fatigue, prolonged physical activity, and other symptoms such as psychological problems. By and large, these are research tests, which have no place in the general evaluation of such patients. Other tests that are not recommended include a computed tomography (CT) scan, single photon emission CT (SPECT) brain scanning, magnetic resonance imaging (MRI), antibodies to Candida spp., red blood cell magnesium, sleep studies, and the tilt table test.

6

MANAGEMENT

Optimal management of CFS lies primarily in the areas of empathy, education, and counseling. The CFS patient is very frustrated. Such a patient would definitely like to get better and return to his or her previous life-style but is confused by different messages as to how to do so. These patients are not malingering. They have an illness that needs attention and they need validation of their illness. It is not helpful to tell them that there is ‘‘nothing wrong’’ with them or that ‘‘it is all in their head.’’ It should be explained that this is not an infectious disease. There is no evidence for a continuing infection despite the way they feel. This illness is multifactorial in origin, so all possible contributory causes (e.g., psychosocial stressors) and solutions have to be explored.

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Table 4 The Chronic Fatigue Syndrome Patient Female Aged 20–45 years Normal physical examination findings Unrefreshing sleep, postexertional fatigue, cognitive dysfunction, achiness, headaches Normal routine blood test results

Patients may well have unfounded concerns that they have a terminal illness, a dementing illness, or an illness that is progressive and will not show any improvement. They must be educated that this is not the case at all. It should be emphasized that there has not been and will not be any permanent damage to any part of the body since their activities are often restricted by a fear that they will harm themselves. One should emphasize that this is an illness in which function is impaired without destruction of any organs or tissues. The doctor, however, should acknowledge the very severe impact that this condition has had on the patient’s life and emphasize that it is a real illness with real symptoms even though blood test results may be normal. It is important to review the process through which this illness has likely occurred so that the patient can gain some insight. This can be done by reviewing the history and pointing out how typical their illness is when compared to other cases of CFS and demonstrating the role for precipitating factors that may be obvious to you. Patients often want to know whether they actually have CFS. If they have had severe fatigue continuing for months, then the answer is virtually always, Yes, you do have chronic fatigue, but the issue now is how the illness occurred and how best to manage it. The actual label itself is less important than proper education and management. Although some with chronic fatigue may not actually fulfill the Centers for Disease Control (CDC) criteria for CFS, management is the same. The patients should be encouraged to regularize their life-style by getting out of bed at a reasonable hour every morning and getting dressed. Even though they may have to rest before and after activities, they should plan to do some activities in the morning and afternoon even though these may be very simple tasks. Furthermore, patients should be encouraged to leave the house for even brief walks, the duration of which can be built up in a very gradual fashion. They should be encouraged to continue to work or attend school although they may not be able to function on a full-time basis. If there are significant abnormalities in sleep and especially if depressive symptoms are present, they should be encouraged to take very small doses of antidepressants. Patients with CFS may tell you that they are hypersensitive to medication, and they are usually philosophically opposed to any antidepressant therapy. The low-dose antidepressants should be offered as medication that may benefit sleep and achiness. Start with the smallest possible dosage and then try to build up to therapeutic dosage, but this will be a challenge. Many patients who do accept such an approach show considerable improvement. If nonprescription medication is more acceptable to them, then they can start on St. John’s wort, which in some studies has been shown to be equivalent in efficacy to tricyclic antidepressants. Some patients also benefit from a sedative-hypnotic to help their sleep. The patients should be discouraged from seeking many medical opinions and seeing many specialists. Detailed, exotic, and expensive testing should also be discouraged. Out of desperation and perhaps because of philosophical differences with traditional medicine, most patients with CFS have tried alternative treatments such as anti–Candida therapy,

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echinacea, or evening primrose oil. Although these do not appear to be of any consistent benefit, one should support the patients in trying some of these remedies for a brief period if only to show them that there will be no benefit and to discourage them from spending excessive time, money, and energy on researching alternative therapies. It should be emphasized to patients that they can and will very likely improve over time by using some of the approaches advocated and by avoiding the harmful approaches. The role of formal exercise is uncertain in altering outcomes in CFS, but simple stretching exercises and perhaps exercising in a warm therapeutic pool may be of some symptomatic benefit for the muscle aching; the exercise also gives the patients some confidence that they are indeed able to exercise without having a setback. These activities may help their sleep and may improve their social interactions if these activities are done outside the home. Overall, patients should be encouraged to take increasing responsibility and not allow well-meaning family members to do too much for them. The approaches outlined are also aimed at moving patients out of the sick role and reducing illness behavior. It is also helpful for some patients to have more formal counseling by a psychologist, psychiatrist, occupational therapist, or social worker to give them support in their attempts at recovery. Some studies have shown that cognitive behavioral therapy is effective in improving outcomes. Many different therapies have been reported to be beneficial in CFS, but these either have not been confirmed or have been refuted. Some reportedly beneficial therapies of the past have included efamol, magnesium, and immunoglobulin injections. Because of this long history of allegedly beneficial therapies one has to be quite skeptical about the most recent ‘‘cures’’ that you may read about or that patients draw to your attention (see Table 5).

7

OUTCOME

The most favorable prognosis in chronic fatigue occurs in those for whom an organic cause is found, those with symptoms of less than 4 months in duration, and those who have only one or two symptoms and an absence of a lifetime history of dysthymia. Unfortunately, in CFS none of these conditions commonly applies so the prognosis is fairly poor. The worst outcomes occur among those who have a fixed belief in a physical or viral cause of the CFS and those who deny that psychosocial factors may be playing a role. Furthermore, there is a poor prognosis for those who are members of a CFS support

Table 5 Management of Chronic Fatigue Syndrome Validate the illness (the symptoms are real and severely limiting) Educate about causation (not a virus) Alleviate concerns (nonfatal, will not worsen) Increase activities slowly Regulate daily schedule Encourage antidepressants, hypnotics as needed Provide cognitive-behavioral therapy Discourage excessive reliance on alternative therapies

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group. Recovery is also independent of virological and immunological results and more related to psychosocial morbidity. Avoidance of physical activity plays a part in perpetuating symptoms. If some of the appropriate management strategies are applied within the first few months of the fatiguing illness, it is possible that chronic fatigue can be averted. There is, however, no confirmation that this is the case. Fully developed CFS (by definition, it has been present >6 months) is a severely disabling and generally very chronic condition that commonly lasts for years. If there was an acute onset of fatigue, patients are generally at their worst in the first 3 months or so, after which there may be some improvement. With the proper approach and a committed patient there may be a 50% improvement in the functional ability during the first 1 to 2 years. After 2 to 3 years only 5% or so of subjects have fully recovered. Only 2% of subjects have another medical diagnosis that can explain the fatigue, whereas in about 20% an alternative psychiatric diagnosis becomes likely. On a positive note, patients rarely worsen over time. Patients should be made aware of the likely outcomes (without undue pessimism) because this knowledge will allow more realistic planning and will actually prevent frustration caused by unexpectedly slow improvement. When improvement does occur, patients should be encouraged to increase their activities and possibly return to school or the workplace on at least a part-time basis. Many patients may be reluctant to increase their activities because they may believe that their improvement has been due to major life-style changes and severe limitation of activities. They may be afraid to go back to some of their previous activities and therefore maintain a stagnant low level of activity (see Table 6).

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ASSESSMENT FOR INSURANCE PURPOSES

Because of severe disabling fatigue, many subjects who have CFS are unable to work on a full-time basis. The insurance assessment should be considered an integral part of the management of patients with CFS. The overall aim should be for the patients to remain in the workplace or return to the workplace whenever possible. Assessments should be based on the symptoms and the degree of disability and not necessarily on the fulfillment of any diagnostic criteria for CFS. The difficulty for insurance companies is that the manifestations of CFS are based on subjective criteria only; there are no specific laboratory test result abnormalities or other objective criteria. Patients state that any difficulties with insurance companies and involvement of attorneys increase their stress and makes their illness worse. What may compound their uncertainty is that after years of illness patients often do not have the same job or any job to return to.

Table 6 Outcome of Chronic Fatigue Syndrome after Several Years Improvement Full recovery Worsening Another medical diagnosis Psychiatric diagnosis

50% 5% 2% 2% 20%

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SUMMARY

CFS is a form of chronic fatigue associated with cognitive impairment, myalgias, arthralgias, headaches, unrefreshing sleep, and postexertional malaise. CFS likely has a multifactorial cause, and it requires a multifaceted approach to management. Improvement is very slow, but most patients have the capability of improving considerably over a period of 2 to 3 years. BIBLIOGRAPHY Beard GM. Neurasthenia or nervous exhaustion. Boston Med Surg J 3:217–220, 1869. Demitrack MA, Abbey SE, eds. Chronic Fatigue Syndrome. New York: The Guilford Press, 1996. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 121:953–959, 1994. Imboden J, Canter A, Cluff L. Convalescence from influenza: A study of the psychological and clinical determinants. Arch Intern Med 108:393–399, 1961. Kruesi MJP, Dale JK, Straus SE. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry 50:53–56, 1989. Manu P, Matthews DA, Lane TJ, Tennen H, Hesselbrock V, Mendola R, Affleck G. Depression among patients with a chief complaint of chronic fatigue. J Affect Dis 17:165–172, 1989. Pawlikowska T, Chalder T, Hirsch S, Wallace P, Wright D, Wessely S. A population based study of fatigue and psychological distress. Br Med J 308:763–766, 1994. Salit IE. Sporadic postinfective neuromyasthenia: Persistent illness after acute infections. Can Med Assoc J 133:659–663, 1985. Salit IE. The chronic fatigue syndrome: An overview of important issues. J Musculoskeletal Pain 3:17–24, 1995. Salit IE. Precipitating factors for the chronic fatigue syndrome. J Psych Res 31:59–65, 1997. Sharpe MC, Hawton KE, Simkin S, Surawy C, Klimes I, Peto TEA, Warrell D, Seagroatt V. Cognitive therapy for chronic fatigue syndrome: A randomized controlled clinical trial. Br Med J 312:22–26, 1996. Taerk GS, Toner BA, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int J Psychiatry Med 17:49–56, 1987. Wessely S, Chalder T, Hirsch S, Pawlikowska T, Wallace P, Wright DJ. Postinfectious fatigue: Prospective cohort study in primary care. Lancet 345:1333–1338, 1995.

39 Epstein-Barr Virus Infection and Infectious Mononucleosis–Like Illnesses Irving E. Salit Toronto General Hospital and University of Toronto, Toronto, Ontario, Canada

1

INTRODUCTION

In the strict sense, mononucleosis refers to a marked increase in the peripheral blood mononuclear cells (monocytes and lymphocytes) usually accompanied by atypical lymphocytes. This in turn can be caused by a variety of infections and other conditions. However, the term has come to be synonymous with acute infectious mononucleosis (IM), or ‘‘mono,’’ which is caused by the Epstein-Barr virus (EBV). The focus in this chapter is on EBV-induced acute infectious mononucleosis, also called glandular fever in the United Kingdom. The differential diagnosis of EBV mononucleosis is also reviewed. There were clinical descriptions of infectious mononucleosis in the 1880s. The recognition of the atypical lymphocyte as a hematological marker for the disease led to more specific diagnostic criteria. In the 1930s it was noted that heterophile antibodies (human antibodies that react to cells from other animals) developed during the course of infectious mononucleosis, and a diagnostic test that was the forerunner of the current rapid diagnostic tests was developed. The Epstein-Barr virus was described in 1964, and in the 1960s and 1970s large-scale epidemiological studies demonstrated that heterophile-positive IM occurred in patients who did not have preexisting EBV antibody but who later acquired antibody to EBV. These epidemiological studies allowed the recognition of subclinical EBV infections. It became apparent that 10%–20% of the cases of heterophile-negative mononucleosis were caused by other conditions, including cytomegalovirus infection. It is now recognized that EBV is also associated with nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s disease, and B-cell lymphoma in immune-compromised patients. 2

EPSTEIN-BARR VIRUS

The name Epstein-Barr virus reflects the work of Epstein, Barr, and Achong, who discovered a herpesvirus in the tissues of African patients who had Burkitt’s lymphoma. EBV has the characteristic features of other members of the Herpesviridae. It is an enveloped virus containing an icosohedral nucleocapsid enclosing double-stranded deoxyribonucleic acid (DNA). The EBV genome codes for more than 100 proteins. The viral capsid antigen (VCA) and early antigen (EA) are expressed during the lytic phase of infection; the nuclear 735

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EPSTEIN-BARR VIRUS INFECTIONS Most infections asymptomatic in childhood (see Figure 1) Clinical illness more often seen in teenagers and adults By adulthood 95% of population immune No association with chronic fatigue syndrome Clinical illness (see Table 1) Sore throat, malaise, headache, fever (see Table 2) Lymphadenopathy, pharyngitis, splenomegaly (see Table 3) Laboratory diagnosis Leukocytosis and atypical lymphocytes (>10%) Elevated liver function test (LFT) results Thrombocytopenia Positive heterophile antibody (monospot test) finding in 80%–90% Antibodies to Epstein-Barr virus (EBV) antigens (see Table 5) Positve IGM to viral capsid antigen (VCA) Older patients Less pharyngitis, lymphadenopathy May have <10% atypical lymphocytes Complications Hemolytic anemia, thrombocytopenia, splenic rupture, encephalitis Treatment Supportive Steroids for severe complications

antigen (NA) is expressed in latently infected B cells. Antibody formation to these viral proteins forms the basis of specific EBV testing. After a primary infection, EBV can persist in a latent form that can reactivate with viral shedding but without clinical symptoms. The virus persists in the oropharynx of patients with infectious mononucleosis for up to 18 months after clinical recovery. It can also be cultured from throat washings of 10%–20% of normal healthy adults but from much higher proportions of subjects who are immunocompromised such as organ transplantation recipients and those who are human immunodeficiency virus– (HIV)-infected. EBV initially infects nasopharyngeal cells and then proceeds to infect B lymphocytes. T cells (morphologically atypical lymphocytes) react to and help limit the spread of this infection. EBV probably persists for life in lymphocytes, but other cells such as oropharyngeal cells may also be chronically infected. After infecting B cells the linear EBV genome becomes circular to form an episome. The genome usually remains latent in these B cells. Viral replication is spontaneously activated in only a small percentage of the latently infected B cells. The virus replicates in cells in the oropharynx in nearly all seropositive persons, and infection of humans with EBV usually occurs through contact with oral secretions in which the virus is being shed.

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EPIDEMIOLOGICAL CHARACTERISTICS

The epidemiological features of EBV infection vary geographically. Antibodies are acquired earlier in life in developing countries than in industrialized countries, and antibodies are also acquired earlier in lower socioeconomic groups within industrialized countries.

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By adulthood, 90%–95% of most populations demonstrate EBV antibodies. It should be emphasized that detection of such antibodies is of little diagnostic value and does not necessarily indicate the presence of any active disease. EBV is acquired before the age of 5 years in about 50% of the children in the United States. A second wave of seroconversion occurs in the mid- to late teens, and 30%–50% of persons entering college remain susceptible. Only 3%–10% of adults older than 40 years of age remain susceptible. There is a difference between the rates of development of clinically apparent infectious mononucleosis and the rates of acquisition of EBV. Even though there are high rates of acquisition of EBV before the age of 5, these children rarely become clinically ill. In contrast, clinical illness is much more frequent in the 15- to 24-year-old age group (Figure 1). The overall incidence of IM in a large epidemiological study in the United States was about 45 cases/ 100,000/year. The incidence of IM was highest in the 15- to 24-year-old age group and was the same for women and men, although women acquire IM 2 years earlier than men. The incidence of infection in this age group was 30 times higher for whites than for blacks as a result of the earlier acquisition of EBV in black children when subclinical infections generally occur. There is no clear-cut seasonal incidence. Most transmission is from chronically infected asymptomatic persons to nonimmune hosts, rather than from those who are acutely infected. EBV does not survive outside the body, so the environment is not a source of transmission. Most cases are, however, probably contracted by intimate contact, for example, by transfer of saliva with kissing. Spread may also occur within families and very uncommonly as a blood-borne infection (for example, by transfusion). Epidemics of IM probably do not occur. EBV is shed in low titers even from those who have acute IM, and their susceptible roommates do not have EBV infection any more frequently than the general susceptible population. Only 6% of

Figure 1 Clinical manifestations of infection with Epstein-Barr virus. Neurological diseases include encephalitis, myelitis, cerebellitis, neuropathy, and cranial nerve palsies. EBV, Epstein-Barr virus; IM, infectious mononucleosis.

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those who have IM can cite a previous contact with another person who had IM. It is clear then that acute IM patients do not have to be isolated. There may be some predisposing factors such as for other viral infections. Among the 25% of West Point Military Academy cadets who became ill during seroconversion, a set of interrelated psychosocial risk factors was predictive for the development of the clinical illness. Psychosocial risk factors also predicted the length of hospitalization. Some have tried to infer an association between EBV and the chronic fatigue syndrome (CFS) (see Chapter 38). Since almost all adults are seropositive to EBV, antibody testing for EBV cannot be used as a diagnostic tool for CFS. There are a variety of precipitating events for CFS, and in a few rare cases, IM may be the apparent triggering event. However, for the vast majority of patients with CFS there is no evidence at all that EBV is the cause, so one should not use the term chronic Epstein-Barr virus infection synonymously with CFS. EBV infection is generally asymptomatic or mildly symptomatic. Fatalities are extremely rare. Persons living in college dormitories or military barracks may have an increased morbidity rate, accounting for 5% of all hospitalizations of college students. About 10% of susceptible students undergo EBV seroconversion yearly. EBV infection does have a significant impact on days lost from school or work in these settings, although the impact on the general population is unknown as it is not a reportable condition. 4 4.1

CLINICAL SYNDROMES Epstein-Barr Virus–Related Infectious Mononucleosis

The incubation period is approximately 30–50 days. Typically, EBV-related IM is an acute illness characterized by sore throat, fever, and lymphadenopathy. There are usually an associated mononucleosis and atypical lymphocytosis in the peripheral blood (Table 1). Although the onset is usually abrupt, there may be a nonspecific prodrome of anorexia and malaise. Loss of taste for cigarettes, retro-orbital headaches, myalgias, and feelings of abdominal fullness are common (Table 2). The sore throat may be the most severe the patient has ever experienced. There may be facial puffiness, especially around the eyes. Fevers may be as high as 40⬚C and may last 1–2 weeks. The findings on physical examination are fairly characteristic (Table 3). The hallmark of IM is the presence of a white/gray membrane on the tonsils in about one-third of cases.

Table 1 Manifestations of Epstein-Barr Virus–Induced Infectious Mononucleosis Clinical Fever Sore throat Lymphadenopathy Hematological >50% Mononuclear cells >10% Atypical lymphocytes Serological Transient appearance of heterophile antibodies Permanent emergence of antibodies to Epstein-Barr virus (EBV)

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Table 2 Symptoms of Infectious Mononucleosis Symptom Sore throat Malaise Headache Anorexia Myalgias Chills Nausea Abdominal discomfort Cough Vomiting Arthralgias

Percentage 80–90 50–75 40–55 10–30 10–20 10–20 2–15 2–15 5 5 2

The tonsillar enlargement can be quite striking as occasionally the tonsils may meet at the midline (‘‘kissing tonsils’’) and may even result in pharyngeal obstruction. Palatal petechiae may be seen in about half of the cases, and they usually occur at the junction of the hard and soft palate. Posterior cervical lymphadenopathy is almost universal; it is symmetrical and is usually not very tender to palpation. Lymphadenopathy may also occur in other areas, although occipital lymphadenopathy is uncommon. Hepatomegaly occurs in only 10%–15% of cases, but ‘‘punch tenderness’’ of the liver is somewhat more frequent. Splenomegaly is clinically detectable in about half of patients but can be seen by ultrasonography in 100% of patients, especially by the second week of the illness. A rash is very infrequent and nonspecific in appearance. Ampicillin can produce a pruritic maculopapular eruption in 90%–100% of IM patients, which begins 7–10 days after the start of the drug. This does not necessarily indicate that the patient is allergic to penicillin. Results of routine laboratory tests can be strongly suggestive of IM. At least one of the liver function test results is abnormal in almost all cases of IM. These elevations are usually mild with individual values in the range of two to three times the upper limit of normal. Bilirubin level is only mildly elevated and frank jaundice is rare. Abnormalities

Table 3 Signs of Infectious Mononucleosis Sign Lymphadenopathy Pharyngitis Fever Splenomegaly Hepatomegaly Palatal enanthem Jaundice Rash

Percentage 100 70–90 100 50–65 5–15 25–60 5–10 0–15

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found on urinalysis, seen in 16% of patients, include proteinuria, pyuria, and microscopic hematuria. Presence of mixed cryoglobulins is extremely common. The hematological manifestations are usually very suggestive of IM. The peak white blood cell count can be up to about 20,000/mm3. There is a relative lymphocytosis in about 70% of the cases as monocytes and lymphocytes account for 60%–70% of the total white blood cells. Atypical lymphocytes are the hematological hallmark of IM. In acute EBV infection there are >10% atypical lymphocytes, though there is a wide range of response, from 5% to 90% of the circulating lymphocytes. The atypical lymphocytes are larger than the mature lymphocytes encountered in peripheral blood, and the cytoplasm is often vacuolated and basophilic. The edges have a ‘‘rolled-up’’ appearance. The presence of atypical lymphocytes in conjunction with the history and the physical findings noted previously are virtually pathognomonic of IM caused by EBV. Mild neutropenia and thrombocytopenia are also quite common. Atypical lymphocytes, however, can occur in other circumstances, but the clinical scenarios are so different that this finding hardly provides a diagnostic dilemma (Table 4) (also see the discussion of the differential diagnosis of IM). All patients who have had IM or EBV infection have lifelong immunity. There is no clear evidence that classical IM is dangerous during pregnancy to either the mother or the fetus. Most patients recover without sequelae. Studies have shown, though, that up to 38% of patients are still symptomatic (as self-reported) at 2 months and 12% at 6 months. There were no objective measures that characterized patients who self-reported failure to recover fully. Occasionally patients may present with atypical symptoms, causing diagnostic confusion. Patients above 40 years of age experience less pharyngitis and lymphadenopathy and often have fever lasting more than 2 weeks. These older patients have increased rates of hepatitis with higher levels of transaminases and bilirubin and hepatomegaly. Older patients may also have a less significant lymphocytosis. In one study, 16% of patients above age 40 had <5% atypical lymphocytes. Older patients may also experience a more prolonged illness. 4.2

Laboratory Diagnosis

Although the clinical syndrome is quite suggestive of EBV-related IM, laboratory confirmation should generally be done. Confirmatory tests also help exclude other illnesses that present similar symptoms. Confirmation can ultimately be done by demonstrating the presence of antibodies that denote the presence of EBV. There are two diagnostically important types of antibodies that occur in IM: (1) heterophile antibodies and (2) specific antibodies directed against EBV. Heterophile antibodies are antibodies produced by humans that subsequently bind tissues from other species, in particular, sheep erythrocytes. They do not bind to EBV antigens. These heterophile antibodies occur in 90% of cases of IM. The classic heterophile antibody titer has been reported as the highest serum dilution at which sheep erythrocytes are agglutinated after absorption of the serum by guinea pig kidney. This absorption helps to increase the specificity of the antibody for diagnosing IM. This is known as the classic Paul-Bunnell test. Horse red blood cell agglutination is an even more sensitive test for diagnosing IM, but positive antihorse antibody findings may persist for a year after acute IM. Currently, these heterophile antibodies are no longer determined by serum dilution, as that test has been supplanted by mononucleosis diagnostic slide tests (monospot). These rapid tests detect immunoglobulin M (IgM) heterophile antibodies with

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Table 4 Syndromes in Which an Atypical Lymphocytosis May Be Found Epstein-Barr virus–induced infectious mononucleosis Cytomegalovirus infections Human herpesvirus 6 infection Toxoplasmosis Acute viral hepatitis Acute human immunodeficiency virus (HIV) infection Rubella Roseola Mumps Drug reactions

a latex agglutination assay. They have a sensitivity of 70%–85% and a specificity of 85%– 100%. During the first week of illness, 40% of patients have a positive test (Monospot) result. This proportion increases to 80%–90% during the second week. Therefore, it is important to recognize that not all patients who have EBV-related IM are heterophilepositive. Further testing for specific EBV antibodies may be indicated if the rapid test finding is negative. There may be occasional ‘‘false-positive’’ monospot results among patients who have lymphoma, hepatitis, or autoimmune disease. The test result can remain positive for up to 1 year after acute EBV infection. A positive test result should, therefore, not be construed as indicating ongoing active disease. Because of the long-lasting nature of a positive test result, patients may have other intercurrent illnesses during that year that may be misinterpreted as acute EBV infection. The monospot test result is usually negative in EBV infections in children less than 5 years of age. Despite these caveats, if your patient has a sore throat, lymphadenopathy, mononucleosis, and a positive monospot test, then he or she almost certainly has EBV-associated IM. Heterophile-negative (monospotnegative) mononucleosis can be due to EBV, but other conditions, especially presence of cytomegalovirus (CMV), become more important (Table 4). In the presence of heterophile-positive mononucleosis, one need not do any further serological testing to prove that the illness is due to EBV. However, for patients who have atypical presentations or who are heterophile-negative, further testing for antibodies directed against EBV may be indicated. Antibodies can form to EBV viral capsid antigen (VCA), early antigen (EA), and nuclear antigen (NA). The type of antibody response (IgM or IgG) and sequential pattern of antibody formation (early or late) and longevity of antibody response (acute or chronic) may help differentiate acute from more remote EBV infection (see Table 5). The first antibody response is to the VCA. Both IgM and IgG levels rise rapidly and generally yield a positive finding by the time the patient seeks medical attention. The IgM is usually diagnostic of acute EBV infection. The IgM level wanes and yields a negative finding over several months. The IgG to the VCA yields a positive finding in >90% of patients and persist for life. Antibodies to the EA can be of two types: EA-D pattern is a diffuse immunfluorescent staining of the nucleus and cytoplasm; the EA-R pattern shows staining restricted to the cytoplasm only. EA-D antibodies appear after 3–4 weeks of symptoms and are present

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Table 5 Serological Diagnosis of Epstein-Barr Virus Infection

Phase of illness, months Acute infection (1–3) Convalescent (3–6) Past infection (6–12)

Heterophile antibody (Monospot) ⫹ ⫾b ⫺b

Viral capsid antigen (VCA)

Early antigen (EA)

IgM

IgG

EA-D EA-R

⫹c ⫾d ⫺

⫹ ⫹ ⫹

⫹e ⫹f ⫺

⫺g ⫾h ⫾

Nuclear antigen (NA) ⫺ ⫹i ⫹

⫹, present; ⫾, present sometimes; ⫺, absent; EA, early antigen; EA-D, diffuse pattern; EA-R, restricted pattern. Finding may remain positive for 3–12 months. c Diagnostic of acute Epstein-Barr virus (EBV) infection. d Immunoglobulin M (IgM) finding remains positive for 4–8 weeks. e Present after 3–4 weeks. f Present in 70% of patients, especially those with severe disease. Lasts 3–6 months. g Generally absent; if present, appears 2 weeks to months after onset. Appears later then EA-D. h May be seen in severe infections. i Usually appear 6–12 months after initial symptoms. a

b

in about 70% of patients with acute IM, especially those with severe symptoms. Antibodies to EA-D in the presence of IgM to the VCA is suggestive of recent infection. EA-D antibodies are also seen in patients with nasopharyngeal carcinoma. EA-R are rarely present in acute EBV infection but may be seen in patients with African Burkitt’s lymphoma. Antibodies to nuclear antigen are detectable after 3–6 months. They persist for life. The absence of antibody to NA in a patient who is VCA IgG–positive but VGA IgM– negative suggests a recent infection. The finding of anti-EBV NA early in the course of an illness precludes a diagnosis of acute EBV infection. The simplest test to do for confirmation of recent EBV infection is the IgM VCA. It is very sensitive and specific and can be done on serum during acute illness, rather than waiting for a convalescent period. On rare occasions CMV infection of cells latently infected with EBV can cause the production of VCA IgM, causing a false-positive test result. EBV can be cultured from oropharyngeal washings or from circulating lymphocytes, but this culture is certainly not routinely available and is less useful in diagnosing acute IM as the virus may be detectable in healthy persons or those with unrelated illnesses. Viral DNA may also be detectable in oropharyngeal washings or lymphocytes, but this finding is also not diagnostic of acute infection. There are a variety of immune abnormalities that occur during the course of IM. Polyclonal increases in immunoglobulin are a result of the proliferation of infected B cells. These are often associated with abnormal antibodies of the IgM class. These abnormal antibodies include Venereal Disease Research Laboratories (VDRL) test for syphilis antibodies, antinuclear antibodies (ANA), rheumatoid factor (RF), and anti-i antibodies, which may be associated with hemolytic anemia. 4.3

Complications of Infectious Mononucleosis

Most IM patients recover quite uneventfully. The acute symptoms of sore throat and fever usually pass in 1 to 2 weeks. The swollen glands, fatigue, and lack of energy almost always disappear in 2 to 4 weeks. Follow-up studies of university students with IM have established that 20% return to school within 1 week and 50% within 2 weeks. When many

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patients are given a diagnosis of IM they fear that they will be very ill and fatigued for months. They should be reassured that this is not the case at all and that they have a selflimited illness and should be able to return to school or work quickly. Even though complications of IM are quite rare, they have been widely reported because this infection is so common in the community. These complications include autoimmune hemolytic anemia (0.5%–3%), profound thrombocytopenia, and neutropenia with secondary infections. Rupture of the spleen is a popularized complication that is actually very rare (0.1%–0.2% of all cases). Splenic rupture occurs most frequently during the second or third week of illness and should be suspected if there is abdominal pain and/or syncope. Splenectomy is usually required. There often is a history of preceding trauma or Valsalva maneuver in association with straining at stool. Because of this problem, it has been advocated that one should palpate the spleen gently, treat constipation, and avoid contact sports at least in the first few weeks after diagnosis. Neurological complications occur in <1% of patients admitted to a hospital. Complications have included reversible encephalitis, cerebellitis, Guillain-Barre´ syndrome, transverse myelitis, and cranial nerve palsies. The vast majority of patients who have neurological complications recover completely. Death from IM is very rare. Duncan’s syndrome, an X-linked immunodeficiency syndrome, has been associated with overwhelming EBV infection and higher mortality rates. There may be a more chronic EBV infection associated with agammaglobulinemia or lymphoma. In otherwise apparently healthy persons, deaths have resulted from the neurological complications, splenic rupture, or upper airway obstruction. 4.4

Treatment

In the vast majority of cases, no intervention is required and patients recover quickly and completely. Treatment of uncomplicated EBV infection is supportive. Nonsteroidal antiinflammatory agents and acetaminophen can be used for control of pain and fever. Aspirin should be avoided since it has been associated with cases of Reye’s syndrome. As noted previously, contact sports and heavy lifting should be avoided during the first 2 to 3 weeks of illness and constipation should be treated with a gentle laxative. Corticosteroids may be required for some of the complications, such as airway obstruction, severe thrombocytopenia, or hemolytic anemia. Prednisone could be given in a dosage of 1 mg/kg/day for 1 week or so and then tapered over the next 1 to 2 weeks. Steroids have also been suggested for severe malaise and fatigue; but their use for those symptoms is controversial. There is no role for antiviral therapy since it does not produce any clinical benefit in uncomplicated IM. The role for antivirals in the X-linked Duncan’s syndrome or in EBV-associated posttransplantation lymphoproliferative disease is less certain. Acyclovir, ganciclovir, interferon-␣, and interferon-␥ have been shown to inhibit EBV replication in vitro. Group A ␤ -hemolytic streptococci are commonly found in the throats of patients with IM but it is not clear that this finding should be treated. Ampicillin should not be used because of the marked prevalence of skin rash during IM. 5

OTHER ILLNESSES ASSOCIATED WITH EPSTEIN-BARR VIRUS

In patients who have human immunodeficiency virus (HIV) infection, EBV can cause oral hairy leukoplakia (white lesions, usually on the sides of the tongue, which cannot be scraped off) and primary central nervous system (CNS) lymphoma.

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In the non–HIV-infected, EBV can cause Burkitt’s lymphoma and nasopharyngeal carcinoma. Burkitt’s lymphoma is EBV-associated in 90% of African cases and only 15% of U.S. cases. Other EBV-related malignancies include anaplastic nasopharyngeal carcinoma, gastric carcinoma, T-cell lymphoma, thymoma, and Hodgkin’s disease. EBV-associated lymphoproliferative disease can be seen in patients who have congenital or acquired immunodeficiency, including those who have acquired immunodeficiency syndrome (AIDS) and renal and bone marrow transplantation, especially those treated with cyclosporin A. Posttransplantation lymphoproliferative disorder (PTLD) is defined as the presence of an abnormal proliferation of lymphoid cells. Many of these lesions are histologically malignant lymphomas. Other lesions, although clinically acting similarly to lymphomas, do not meet histological criteria for malignancy. Patients may have an IM-like illness, fever, and leukopenia or focal organ involvement of the gastrointestinal tract, central nervous system, or the allograft. 6

DIFFERENTIAL DIAGNOSIS

Generally EBV-related IM is not a difficult diagnosis to make. There are illnesses, though, with mononucleosis-like presentations that are heterophile-negative and must be differentiated from EBV infection (see Table 6). An estimated 10%–20% of IM patients do not have acute EBV infection. In a study of 50 patients who had an absolute lymphocytosis or atypical lymphocytes but who were heterophile-negative, infection was caused by EBV in 20%, CMV in 22%, human herpes virus type 6 (HHV-6) in 9%, and toxoplasma in 2%. 6.1

Cytomegalovirus

CMV infection is the most common cause of heterophile-negative mononucleosis. Like EBV, it is a member of the Herpesviridae, the herpes family of viruses, capable of forming a latent infection and reactivation. Primary infection with CMV can produce a febrile illness with lymphadenopathy and lymphocytosis. It is not, however, generally associated with severe sore throat, tonsillar membrane formation, or splenomegaly. Fever, the major

DIFFERENTIAL DIAGNOSIS OF EPSTEIN-BARR VIRUS AND INFECTIOUS MONONUCLEOSIS Syndromes with atypical lymphocytosis (see Table 4) Differential diagnosis of infectious mononucleosis (see Table 6) Cytomegalovirus Most common Less pharyngitis, splenomegaly Mildly abnormal liver function test (LFT) findings Diagnosis by positive immunoglobulin M (IgM) finding or fourfold rise in antibody titer Differential diagnosis of lymphadenopathy (see Table 7) Other Epstein-Barr virus– (EBV)-related illnesses Burkitt’s, T-cell, and Hodgkin’s lymphoma Nasopharyngeal and gastric carcinoma Lymphoproliferative syndrome Organ transplantation recipients

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Table 6 Differential Diagnosis of Infectious Mononucleosis EBV infection Cytomegalovirus Toxoplasma a Rubella a Herpes simplex a Viral hepatitis a Adenovirus infection a Streptococcal b pharyngitis/tonsillitis Diphtheria b Vincent’s angina b Leukemia Lymphoma Agranulocytosis or aplastic anemia Drug reactions a

May be accompanied by atypical lymphocytosis though generally <10%. EBV, Epstein-Barr virus. b No atypical lymphocytosis.

symptom, can last from 9 to more than 30 days. Maculopapular rashes can occur or be caused by the use of ampicillin as with EBV. Lymphocytosis can range from 55% to 86% with atypical lymphocytes ranging from 12% to 55%. Most patients have a small elevation of hepatic transaminase level. The mode of transmission is often not clear; however, kissing and blood transfusions have been identified as sources. As with EBV infection, transient elevations of mixed cryoglobulin, RF, ANA, and cold agglutinin levels can occur. Complications of CMV mononucleosis such as pneumonitis, severe hepatitis, GuillainBarre´ syndrome, meningoencephalitis, myocarditis, thrombocytopenia, and hemolytic anemia are uncommon. Diagnosis is generally made by demonstrating a significant rise in total anti-CMV antibody (by complement fixation or enzyme-linked immunosorbent assay [ELISA]) in paired sera or by the presence of IgM to CMV in a single serum sample. Therapy is not indicated because of the self-limited nature of the illness. 6.2

Human Herpesvirus Type 6

HHV-6 is another of the human herpesviruses. Although originally called human B-lymphotrophic virus when discovered in 1986, the virus has a tropism predominantly for T cells. It is the causative agent of exanthem subitum (roseola or sixth disease). Most people have been infected by age 1–2 years and demonstrate serological evidence of infection. HHV-6 can cause a mononucleosis-like illness, which is generally mild; patients have lower levels of atypical lymphocytes than in EBV infection. Most adults are seropositive. 6.3

Toxoplasmosis

Toxoplasma gondii is a coccidian parasite that can cause severe illness if acquired congenitally or reactivated in immune-compromised hosts such as those with AIDS. In the immunologically normal host toxoplasmosis can cause an IM-like illness. Transmission is by ingestion of poorly cooked contaminated meat or fecal-oral contamination with infected

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cat feces. Toxoplasma mononucleosis accounts for only about 1% of heterophile-negative IM. The patient who has acute infection may exhibit cervical lymphadenopathy (which may be tender), fever, maculopapular rash, hepatosplenomegaly, and an atypical lymphocytosis (though <10%). Lymphadenopathy can occur in other areas, and retroperitoneal lymph node enlargement can produce abdominal pain. Pharyngitis does not occur, and splenomegaly is very unusual when compared with that in EBV infections. The disease is usually benign and follows a self-limited course, though lymphadenopathy can persist for months. Disseminated infection with retinitis (see Chapter 21) myocarditis, pneumonitis, hepatitis, and encephalitis is very uncommon in those with normal immune systems. Diagnosis is by demonstration of a fourfold rise in IgG level and/or the presence of IgM antibodies. It must be recognized that a large number (up to 70% in some populations) are seropositive for T. gondii; a single positive IgG titer finding may be indicative only of past infection. Treatment is generally not indicated in the nonimmunocompromised adult. 6.4

Human Immunodeficiency Virus

Primary HIV infection may mimic IM because of the generalized lymphadenopathy, hepatosplenomegaly, and skin rash. Myalgias may be more frequent in HIV, whereas severe pharyngitis is more frequent in EBV infections. HIV serological tests and a mononucleosis diagnostic test are required to differentiate the two conditions (see Chapter 25). 6.5

Rubella

Rubella or German measles is an acute exanthematous viral infection of children. Nonimmune adults with acute rubella may have fever, malaise, and maculopapular rash. The lymphadenopathy is mostly posterior cervical, posterior auricular, and occipital. Leukopenia and atypical lymphocytes may be present. The diagnosis is confirmed serologically (see Chapter 7). 6.6

Viral Hepatitis

Since IM usually is associated with hepatitis, one would have to consider other forms of viral hepatitis in the differential diagnosis. They are usually not associated with higher levels of atypical lymphocytes, pronounced cervical lymphadenopathy, tonsillar enlargement/exudate, or splenomegaly. Jaundice is also unusual in EBV-associated IM (see Chapter 23). 6.7

Pharyngitis

Because of the exudative pharyngitis characteristic of EBV infection, other infections that can cause exudative pharyngitis need to be considered in the differential diagnosis. Infection with ␤ -hemolytic streptococcus, anaerobic bacteria (Vincent’s angina), Arcanobacterium haemolyticum, adenovirus, and diphtheria may be associated with similar pharyngeal pain and tonsillar membranes, but they do not have the same extrapharyngeal clinical manifestations of EBV infection (see Chapter 10). 6.8

Noninfectious Causes

Occasionally drug reactions, such as an allergic reaction to phenytoin, may mimic IM. Since lymphadenopathy may be a prominent finding of IM, other illnesses that cause lymphadenopathy must be considered in the differential diagnosis (see Table 7).

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Table 7 Common Causes of Lymphadenopathy a Disease

Comment

EBV IM

Prominent pharyngitis Atypical lymphocytes >10% Causes 20% of monospot-negative IM-like illness Compared to EBV, less LAD and splenomegaly and more systemic symptoms such as fever Causes <1% of IM-like illnesses Asymptomatic posterior cervical LAD that may wax and wane for months Caused by Bartonella henselae Regional LAD localized to area of cat scratch or bite May be fluctuant See Chapter 37 Seen with herpes simplex, chancroid, lymphogranuloma venereum Bilateral, tender, inguinal region LAD Genital ulceration or discharge See Chapters 16 and 17 Caused by Francisella tularensis Transmitted by ticks, fleas, or animal contact Suppurative LAD associated with ulceration at site of inoculation See Chapter 37 Scrofula Painless, unilateral, cervical Extranodal disease and systemic symptoms usually absent Posterior cervical, posterior auricular, occipital LAD Rash Caused by Yersinia pestis Transmitted by flea bite Very tender, firm regional LAD (buboes) Fulminant course with fever, headache Firm, rubbery, matted, nontender LAD Often cervical Bilateral mediastinal in Hodgkin’s disease Bilateral hilar and paratracheal Nontender, firm, rubbery Cervical, axillary, epitrochlear, and inguinal Unilateral, hard, fixed Supraclavicular always pathological Pancytopenia, bleeding, hepatosplenomegaly ALL more often than AML Lymph node enlargement reported with these illnesses but generally not major aspect of clinical illness

CMV IM

Toxoplasma IM

Cat-scratch disease

Sexually transmitted diseases

Tularemia

Tuberculosis

Rubella Bubonic plague

Lymphoma

Sarcoidosis

Metastatic malignancy Leukemia Drug reactions, SLE, RA, dermatomyositis, hyperthyroidism a

IM, infectious mononucleosis; CMV, cytomegalovirus; EBV, Epstein-Barr virus; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; LAD, lymphadenopathy.

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BIBLIOGRAPHY Auwaeter PG. Infectious mononucleosis in middle age. JAMA 281:454–459, 1999. Buchwald DS, Rea TD, Katon WJ, Russo JE, Ashley RL. Acute infectious mononucleosis: Characteristics of patients who report failure to recover. Amer J Med 109(7):531–537, 2000. Godshall SE, Kircher JT. Infectious mononucleosis: Complexities of a common syndrome. Postgrad Med 7:175–186, 2000. Tsaparas YT, Brigden ML, Mathias R, Thomas E, Raboud J, Doyle PW. Proportion positive for Epstein-Barr virus, cytomegalovirus, human herpes 6, toxoplasma and human immunodeficiency virus type-1 and 2 in heterophile-negative patients with an absolute lymphocytosis or an instrument-generate atypical lymphocyte flag. Arch Pathol Lab Med 124:1324–1330, 2000.

40 Evaluation of the International Traveler Beth D. Kirkpatrick University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

The ability to evaluate and treat travelers is important to the clinician. Increasing numbers of North Americans are visiting less developed nations (27 million in 1993). Approximately 50% of short-term travelers report a health problem during their trip and 1%–5% seek medical attention. The speed of air travel has increased the possibility that travelers will arrive home during the incubation period of a travel-related infection. Many infections not considered endemic to North America have to be promptly recognized and treated. Health care providers with special training in travel medicine and infectious diseases are an important resource for clinicians caring for travelers at special risk, including children, pregnant women, and patients with chronic diseases, such as diabetes or human immunodeficiency virus (HIV). This chapter reviews the pre-travel evaluation and evaluation of the ill returning traveler. 2

PRETRAVEL EVALUATION

The pretravel evaluation serves an important role in alerting the traveler to exposures and risks abroad. Four major topics are discussed in this section: risk counseling and prevention, immunizations, malaria prophylaxis, and traveler’s diarrhea. The cornerstone of the evaluation is a thorough understanding of the location and itinerary of travel including length of stay, living conditions, and planned activities. The traveler staying in a ‘‘fourstar’’ resort faces far fewer risks of infection than the adventurous traveler planning an extended stay in remote areas. 2.1

Counseling and Prevention

General advice should be given to educate the traveler on the availability of medical care, safety of transfusions, and evacuation in case of medical emergency. Travel advisories and consular phone numbers are available from the U.S. State Department on line at http:// travel.state.gov/travel㛭warnings.html. A basic health care kit can help manage most minor illnesses and injuries (see Table 1). Travel insurance should be considered for patients with serious medical problems or travelers to volatile areas. In case of illness abroad, the International Association for Medical Assistance to Travelers (IAMAT) publishes a listing 749

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PRE–INTERNATIONAL TRAVEL EVALUATION Consultation of up-to-date resources for recommendations concerning vaccines, malaria prophylaxis, travel risks: Websites: http://www.cdc.gov/travel/yellowbk/home.htm www.cdc.gov/travel/bluesheet.htm http://travel.state.gov International travel clinics Counseling and testing Travel health kit (see Table 1) Avoidance of uncooked food and nonbottled water Condom and spermicide use for sexual activity Diethyltoluamide- (DEET)-containing insect repellents at night Avoidance of freshwater contact and walking barefoot Immunizations (see Table 2) Review and update of routine vaccinations: measles, mumps, rubella (MMR), tetanus and diphtheria toxoid (Td), polio Yellow fever and meningococcal as required Recommended: hepatitis A virus (HAV), HBV, typhoid, and Japanese encephalitis virus ( JEV) and rabies as needed Malaria prophylaxis (see Table 3) Needed in most areas of Central and South America, Africa, Southeast Asia, India, Middle East, and southern China Increasing concern about chloroquine-resistant malaria, which requires mefloquine hydrochloride, atovaquone; proquanil hydrochloride, or doxycycline Increasing concern about mefloquine resistance in Southeast Asia Travelers diarrhea (see Table 4) Consideration of prophylaxis by those with serious underlying illnesses Self-treatment with ciprofloxacin for dysentery-like symptoms

of qualified English-speaking physicians willing to see travelers. The booklet can be obtained by calling (716)-754–4883. Those who have chronic or complex medical problems should also take a letter from their physician outlining their medical issues, medications and dosages, allergies, and a contact person at home. Supplies of vital medications should be split between carry-on and check-in luggage in case either is lost. During travel, especially prolonged air travel, patients should be advised to walk around or exercise their legs in order to prevent deep venous thrombosis (DVT). This is especially true for those at high risk for DVT, including patients who have had recent surgery, obese persons, those who have a history of previous DVT, and women who are pregnant or are taking hormonal therapy. 2.1.1

Food and Water Precautions

Travelers to ‘‘underdeveloped’’ countries should be advised to monitor their food and drink intake rigorously. Unpeeled fruits and vegetables, unpasteurized milk products, and inadequately cooked food are the main sources of enteric pathogens. Food is generally considered safe when served ‘‘piping hot.’’ Meats and seafood should never be eaten raw or undercooked, and eating food from street vendors should be discouraged. Vigilance about

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Table 1 Travel Health Kit Physician letter outlining medical issues, prescriptions and doses, allergies, and contact phone numbers All prescription medications with generic names and doses Eyeglass prescription (or extra set) Diethyltoluamide- (DEET)-based insect repellent Sunscreen Wound dressings (antiseptic and topical antibiotic) Analgesic (acetaminophen or ibuprofen) Medications for traveler’s diarrhea (e.g., Imodium and ciprofloxacin) Antimalaria prophylaxis Motion sickness medication Water purifier or iodine tablets Cold/cough/congestion medication Antacids Thermometer Bandages Gauze Tape Tweezers

water is important for all travelers. Tap water, even for teeth brushing, should be avoided. Drinking water should be bottled or boiled for 1 minute. Disinfection with iodine or chlorine is useful but cannot kill the resistant cysts of Cryptosporidium parvum. All ice, even in alcoholic beverages, should be avoided unless the traveler can be assured that it is made from purified water. The risk of hepatitis E infection to pregnant women (discussed later) should be emphasized. 2.1.2

Sexual Activity

A large number of travelers (>19%) have a new sexual contact during travel, particularly young or homosexual men, business travelers, and long-term travelers. Lack of consistent condom use with new sexual contacts abroad occurs in half of women and 59% of men. Advice on the prevalence of sexually transmitted diseases including HIV should be given, and travelers should recognize that access to care after exposure to HIV or sexually transmitted diseases (STDs) is limited in developing countries. Condom and spermicide use for any sexual activity should be encouraged and travelers should carry their own condoms. 2.1.3

Insect Exposure

Insect bites can be avoided with a combination of protective clothing, repellents, and bed nets embedded with permethrin. Hats, long pants, and shirts should be worn as much as possible (particularly at night in malarious areas) and a diethyl toluamide– (DEET)-containing insect repellent should be used. All concentrations of DEET >10% are useful in preventing bites; however, the duration of action increases with the concentration (99% DEET lasts 8–10 hours). Although serious toxic reactions to DEET are rarely reported, limiting its use to concentrations <35% is recommended, particularly for children. Bed nets embedded with permethrin, a long-lasting pesticide of low toxicity, are efficacious in

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preventing insect bites at night for up to 6 months per application. Permethrin can also be sprayed on clothing and reduces insect exposure effectively when used with a DEETbased repellent. 2.1.4

Animal Exposure

Rabies is uniformly fatal. It is endemic in many parts of the developing world, including the former Soviet Union. Petting or touching any wild or stray animal, particularly dogs, should be avoided. Bites or scratches require prompt and aggressive cleaning as well as rabies immune globulin (RIG) (see Chapter 37). Preexposure rabies vaccine is recommended for high-risk travelers such as animal handlers, cave explorers, and persons who expect to stay in rural areas for a prolonged time and in areas where postexposure care is suboptimal. 2.1.5

Soil and Sand Exposure, Swimming

Walking barefoot in the tropics exposes travelers to stronglyloidiasis, cutaneous larva migrans, and infestation with the sand flea (tungiasis). Shoes, rather than sandals, should be worn whenever possible. Swimming in freshwater lakes or ponds in developing countries should be discouraged because of the risk of schistosomiasis and leptospirosis. 2.2

Immunizations

The need for immunizations should be balanced against the traveler’s likelihood of exposure to the pathogen (see Table 2). The practice of giving the patient all available vaccines for any conceivable risk is expensive and impractical. Travel immunizations can be classified as (1) routine childhood and adult immunization, (2) required to cross international borders (such as yellow fever and meningococcus immunization) or (3) recommended on the basis of exposure risk. Travelers who require multiple vaccinations or are planning either emergent or extended travel may need referral to a travel clinic familiar with issues of simultaneous administration of vaccines, concurrent use of multiple live vaccines, and accelerated immunization schedules. The Centers for Disease Control and Prevention (CDC) book Health Information for International Travel (the ‘‘Yellow Book’’) is a valuable reference for all providers and is available on line (http://www.cdc.gov/travel/ yellowbk99.pdf). 2.2.1

Routine Immunizations

The traveler’s vaccine history should be reviewed and updated. Many North American adult patients remember only that all childhood vaccines were completed. The provider should be certain that the adult traveler has (1) received two doses of measles, mumps, rubella (MMR) vaccine if born after 1957 and (2) is updated on tetanus/diphtheria (Td) boosters. Td should be given every 10 years or every 5 years if at very high risk for injury or contamination of wounds. The traveler should also receive a single dose of inactivated polio vaccine (IPV) as an adult if he or she received the full childhood schedule of poliovirus vaccine. Polio boosters are not needed for travel in the Western Hemisphere except in Haiti and the Dominican Republic. Influenza and pnemococcal vaccines should be provided for elderly and chronically ill patients. Varicella vaccine should be considered for immunocompetent adults without a history of chickenpox or serological evidence of exposure.

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Table 2 Immunizations for the Adult Traveler Class Recommended Japanese encephalitis

Side effects

Local reactions, systemic reaction (10%) 50% Mild local reactions, 3%–10% mild systemic reaction 10%–20% Mild local reactions Rare systemic reaction

Hepatitis A

Inactivated

Three doses (q week ⫻ 3) (completed 10 days before travel) Two doses (0, 6–12 mo)

Hepatitis B

Recombinant

Three doses (0, 1, 6 mo)

Immune globulin

Fractionated immunoglobulins

Rabies

Inactivated

One dose (0.02 mL/kg if <3 mo travel) (0.06 mL/kg if >4 mo travel) Three doses (day 0, 7, 21–28)

Typhoid, oral

Live attenuated a

Four doses (day 0, 2, 4, 6)

Polysaccharide

One dose

Polysaccharide Live attenuated a

One dose One dose (10 days before travel)

Fever, local reactions Rare immediate hypersensitivity Systemic reactions (5–10 days) uncommon

Live attenuated a

Two doses for primary immunization

Polio, injectable

Inactivated

Influenza

Inactivated

One booster as adult (adult primary 0, 2, 6–12 mo) Annually

Local reactions, fever, rare allergic reactions Avoided when allergy to egg or neomycin Mild local reactions

Pneumococcal Tetanus-diphtheria

Polysaccharide Adsorbed toxoids

One dose Primary two doses (0, 4–8 wk), booster every 10 yr

Varicella

Live attenuated a

Primary two doses (0, 4–8 wk)

Typhoid, injectable Required Meningococcal Yellow fever

Routine Measles, mumps, rubella (MMR)

a

Primary schedule

Inactivated

20% Mild systemic reactions, 6% immune complex reactions Gastrointestinal symptoms, uncommon Local reactions common

Occasional systemic or allergic reactions, avoided when allergy to egg 71% Local reactions Local reactions, arthus reactions with multiple boosters Fever, rash, local reactions

Live vaccines are contraindicated for immunocompromised hosts and pregnant women.

2.2.2

Required Vaccines

Only two vaccines are legally required for entry into countries where disease is present: yellow fever and meningococcus. Cholera vaccination is not required by any country. Yellow fever vaccine is required for entry into any country with the disease and for travel from many countries with reported yellow fever. Yellow fever is endemic in equatorial Africa and South America, though other areas of Asia, India, the Middle East, and North Africa may also pose a risk. Countries requiring yellow fever vaccination are listed on the CDC travel web page (discussed later). Yellow fever vaccine is only administered in approved vaccine centers. Documentation of yellow fever vaccination should be carried with the traveler on the yellow International Certificate of Vaccination card given by the

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clinic. Yellow fever is a live vaccine. Its advantages should be carefully weighed against the exposure risk in immunosuppressed travelers, including pregnant women and patients with cellular immune defects such as HIV. The meningococcal vaccine is protective against Neisseria meningitis serogroups A, C, Y, and W135. Vaccination is recommended for long-stay travel to countries with epidemic meningococcal disease including the ‘‘meningitis belt’’ of Subsaharan Africa from Mali to Ethiopia. Vaccination is also recommended in other areas of known outbreaks such as Nepal, New Delhi, Chad, Kenya, Tanzania, and Burundi. Meningococcal vaccine is only required for entry into Saudi Arabia for pilgrims to Mecca during the hadj. Updated information about the prevalence of yellow fever, cholera, and meningococcal meningitis can be found through the CDC at the ‘‘Summary of Health Information for International Travel’’ site: http://www.cdc.gov/travel/blusheet.htm. 2.2.3

Recommended Vaccines

Hepatitis A virus (HAV) infection is endemic in areas of poor sanitation and is the most common vaccine-preventable infection among travelers (see section 3.2.2). HAV vaccine is recommended for all international travelers, particularly long-term and adventurous travelers. A single dose of vaccine is protective against infection (>90%), and two doses (given 6–12 months apart) are thought to confer lifelong resistance. Passive immunization with HAV immunoglobulin (0.02 mL/kg) may be given to travelers leaving immediately for high-risk destinations but is less effective (60%–70%). Hepatitis B virus (HBV) vaccine is becoming a universal vaccine, and many children and teens may already be vaccinated. It is recommended for travel to countries with a high prevalence of HBV infection, for long-term travelers, for health care and lab workers, and for any others whose activities place them at risk for needing parenteral medications or transfusions. Salmonella typhi and S. paratyphi, the agents of typhoid fever, are spread through contaminated food and water. Typhoid fever is a concern throughout the developing world, particularly in India, Senegal, and North Africa. The oral Ty 21a and the parenteral Vi capsular polysaccharide typhoid vaccines are similarly protective (50%–80%, depending on infective dose). Typhoid vaccines are recommended for long-term travelers (>3 weeks), especially to areas of poor sanitation or off common tourist routes and those visiting relatives and friends. Japanese encephalitis virus (JEV) is a mosquito-borne virus that may cause viral encephalitis with a high fatality rate (30%) and neurological sequelae in 50% of survivors. Vaccination is recommended for travelers to the rural Indian subcontinent and parts of Southeast Asia with stays of >30 days, especially with rural exposures and during summer months. The CDC ‘‘Yellow Book’’ outlines the seasonal risks of all countries. The JEV vaccine has a rare but serious hypersensitivity reaction in 0.6% of vacinees, which includes urticaria, angioedema, and respiratory distress. The reaction may occur immediately or up to 1 week after vaccinations. It is responsive to epinephrine, antihistamines, and/or steroids. To monitor for side effects, the full course (three doses) of vaccination with JEV vaccine should be completed more than 10 days before travel. Rabies vaccine is usually reserved for animal handlers, cave explorers, and travelers expected to spend prolonged time in areas of significant threat. Vaccines against plague, tick-borne encephalitis, and cholera are rarely recommended for travelers and should be given in consultation with a travel medicine expert. Parenteral cholera vaccine is poorly immunogenic. A newer live oral formulation, CVD 103-HgR, is more immunogenic, but neither vaccine is available in the United States.

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755

Malaria Prophylaxis

Malaria is a parasitic infection caused by Plasmodium spp. characterized by fever, headache, and hemolytic anemia. It is transmitted by the Anopheles mosquito. It is endemic in Central and most of South America, most of Africa, the Middle East, India, and Southeast Asia, including southern China. There are four species: P. malariae, P. vivax, P. ovale, and P. falciparum. The most lethal form of malaria is caused by P. falciparum (see Chapter 2). Most P. falciparum are resistant to the tradition prophylaxis agent, chloroquine. Generally P. malariae, P. vivax, and P. ovale are sensitive to chloroquine. There are, though, increasing reports of chloroquine-resistant P. vivax in Southeast Asia. Approximately 1000 cases of imported malaria in returning travelers are diagnosed annually in the United States. The best prevention against malaria is avoidance of mosquito bites (see section 2.1.3). Travelers to malarious regions should be advised that the Anopheles sp. mosquito bites from dusk to dawn, and nighttime outdoor activity should be limited. Medical prophylaxis against malaria depends on the region of the world, length of stay in the endemic area, and activities of the traveler. Prophylactic agents are taken before travel to ensure adequate blood levels during travel and post travel to eradicate protozoa potentially in the bloodstream. Since prophylaxis is not completely effective and only approximately 50% of travelers fully adhere to their prophylactic regimens, travelers should be educated about the symptoms of malaria (unexplained fever with or without headache, chills, weakness, vomiting, and diarrhea). All travelers to endemic areas need to recognize that malaria can be fatal unless treated early and prompt medical evaluation is necessary for symptoms suggestive of malaria. Areas of drug-resistant P. falciparum malaria are rapidly changing. Throughout most of the world, the traditional prophylactic agent, chloroquine sulfate, can no longer be used to prevent malaria. The CDC web sites (listed later) should be contacted for up-to-date drug resistance information. Agents used for malaria prophylaxis and dosages are listed in Table 3. Areas of chloroquine-sensitive P. falciparum malaria are increasingly few. Chloroquine prophylaxis can be safely used only in Haiti, the Dominican Republic, Central America west of the Panama Canal, Egypt, and parts of the Middle East.

Table 3 Drugs for Malaria Prophylaxis

Drug

Adult dose

Started before travel

Stopped after travel

2 Weeks

4 Weeks

2 Weeks

4 Weeks

Contraindicated

Important side effects Dizziness, depression, anxiety, insomnia Sun sensitivity, esophageal ulceration, vaginitis Abdominal pain, nausea, vomiting, headache Itching, nausea, headache, occasional alopecia, skin eruptions, corneal precipitates

Mefloquine hydrochloride (Lariam) Doxycycline

250 mg Once weekly 100 mg Once daily

Atovaquone; proguanil hydrochloride (Malarone) Chloroquine phosphate (Aralen Phosphate)

One tablet (250/ 100) once daily

3 Days

7 Days

History of seizures, psychosis Pregnant women, children <8 years Unknown

500 mg Salt (300 mg base) once weekly

2 Weeks

4 Weeks

History of seizures

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Mefloquine hydrochloride (Lariam) is currently the drug of choice for travel to areas with chloroquine-resistant malaria. It has a long half-life and is taken weekly. Anecdotal reports suggest that mild to moderate neuropsychiatric side effects such as dizziness, depression, and anxiety occur in 1 of 140 travelers. Mefloquine hydrochloride should not be used by travelers with a history of psychiatric illness or seizures or cardiac conduction abnormalities. Doxycycline and atovaquone; proguanil hydrochloride (Malarone) are alternates to mefloquine but require daily dosage. They are effective in areas of multidrug-resistant P. falciparum, including areas with resistance to mefloquine such as the borders of Thailand, Burma, and Cambodia. Side effects of doxycycline include vaginitis, sun sensitivity, and esophageal ulcerations. It should not be used by pregnant women or children below 8 years. Atovaquone; proguanil hydrochloride is generally well tolerated but should be taken with a milky drink and is considerably more expensive ($5/day) than the other agents. 2.4

Prevention and Selftreatment of Traveler’s Diarrhea

Despite vigilant attention to food and drink, traveler’s diarrhea (TD) occurs in up to half of all travelers to developing countries. TD, defined as more than three unformed stools in a 24-hour period, usually occurs around the end of the first week of travel and may be associated with abdominal cramps, nausea, or fever. Enterotoxigenic Escherichia coli (ETEC) causes approximately 50% of cases. It produces a profuse watery, noninflammatory (no white blood cells seen on stool exam) diarrhea that generally lasts 1–5 days though illness lasting up to 10 days can occur. Other less common causes of TD include Salmonella, Shigella, and Campylobacter spp. and parasites. As a result of concerns about widespread antibiotic overuse and resistance, antibiotics are generally not recommended to prevent TD. Prophylaxis with antibiotics (ciprofloxacin 500 mg PO/day or norfloxacin 400 mg PO/day) or with bismuth subsalicylate (taken as two tablets four times a day, totaling 2.1 g/day) is recommended only for travelers with serious underlying medical conditions. Patients for whom TD prophylaxis should be considered include those who have chronic renal failure, immune suppression (including advanced HIV infection, organ transplantation, or high-dose steroid use), poorly controlled diabetes mellitus, inflammatory bowel disease, and hypochlorhydria. Since TD is easy to treat, unpleasant, and inconvenient, many travelers choose selftherapy. Treatment includes rehydration, antimotility agents, and antibiotics (see Table 4). Hydration is the most important part of treatment. Rehydration with most noncaffeinated liquids is adequate for mild to moderate diarrhea. For moderate to severe diarrhea, the World Health Organization– (WHO)-formulated oral rehydration solutions (ORSs) are a simple and effective method of replacing fluids and electrolytes and have been successful worldwide. Antimotility agents such as loperamide hydrochloride (Imodium) can be taken with the first diarrheal stool (up to 16 mg/24 hr) to reduce diarrhea and abdominal discomfort. They should not be used with dysentery (fever and abdominal cramps with blood and mucus in stool) and should only be used with antibiotics in cases of severe diarrhea with fever. Antibiotics are best reserved until the patient has more than three stools in a 24-hour period. Trimethoprim & sulfamethoxazole (TMP-SMZ) and doxycycline are no longer recommended. The quinolones (ciprofloxacin and norfloxacin) are drugs of choice but should not be used by children and pregnant women. 3

EVALUATION OF THE ILL RETURNING TRAVELER

Most travel illnesses are neither tropical diseases nor infections. When evaluating an ill returning traveler, the clinician should begin with a complete travel history (see Table 5).

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Table 4 Treatment of Traveler’s Diarrhea a Drug/product Rehydration products WHO-formulated oral rehydration solutions (e.g., Ceralyte) Antimotility agents Loperamide hydrochloride (Imodium, 2-mg tablets)

Antibiotics Ciprofloxacin

a

Dose

Notes

One packet mixed with 1 L clean water

Replacement of fluid and electrolyte losses

Two-tablet loading dose One tablet after each loose stool Maximum 8 tablets/24 hr

Not to be used in dysentery Used only with antibiotics for fever, severe diarrhea

500 mg bid ⫻ 3 Days

Not for pregnant women or children Not for pregnant women or children Bacterial resistance increasing, use in pregnancy If quinolone-resistant Camplyobacter sp. suspected

Norfloxacin

400 mg bid ⫻ 3–5 Days

Co-trimoxazole

1 DS bid ⫻ 3–5 Days

Azithromycin

500 mg/day ⫻ 3 Days

WHO, World Health Organization; DS, double-strength.

The travel itinerary is crucial to determining exposure to infectious pathogens. For example, the diseases that cause fever in the Andes of Peru are dramatically different from those in the Peruvian jungle in terms of season, temperature, vectors, and altitude. Fever, persistent diarrhea, eosinophilia, and rash are the most common problems of the returning traveler and are discussed later. 3.1

Fever in the Returning Traveler

Fever in the returning traveler has an extensive differential diagnosis, which includes infections unrelated to travel (such as urinary tract or respiratory infections) and clinical syndromes and illnesses that cause an undifferentiated fever syndrome (see Table 6). The most common causes of travel-related fever are malaria, hepatitis A virus infection, typhoid fever, and dengue. Malaria due to P. falciparum can be rapidly fatal and should be ruled out in all febrile travelers returning from malarious regions (see Chapter 2). Specific questions about the fever itself include its duration, onset and timing (how soon it began after travel), pattern, and any associated symptoms such as sweats, headache, muscle or joint pains, diarrhea, rash, or bleeding. 3.1.1

Incubation Period

The dates of travel help determine the likely incubation period of infection and narrow the differential diagnosis of fever. With the increase in air travel, many tourists, immigrants, and expatriates arrive home during the incubation period of a recently acquired infection and may not become symptomatic until weeks or months later. Arboviral infections, for example, have short incubation periods, ranging from 3 to 7 days, whereas other infections (such as viral hepatitis) may have incubation periods of more than a month. Table 7 lists common causes of fever and their incubation periods.

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ILL RETURNING TRAVELER WITH FEVER Complete history (see Table 5) Approach to the febrile patient (see Table 10) Review of immunizations and malaria prophylaxis Common and uncommon infectious causes of fever (see Table 6) Illnesses with short vs. long incubation periods (see Table 7) Exposures and infection risks (see Table 8) Common causes Malaria ‘‘Fever in the returning international traveler is malaria until proved otherwise’’ Tick and thin smear; can be repeated twice Treatment (see Table 11) Hepatitis A and E Fecal-oral route Incubation period of 2–7 weeks Fever, malaise, jaundice Enteric fever S. typhi or S. paratyphi Fever, headache, constipation or diarrhea, hepatosplenomegaly and rash Diagnosis with blood and stool culture Therapy with ciprofloxacin Dengue Viral infection Spectrum of illness from mild and self-limited to severe dengue hemorrhagic syndrome and shock Supportive therapy

Table 5 Travel History Travel Specific location of travel Duration of travel to each area Any symptoms before travel Immunizations and medications Travel vaccines Medications used presently Medications used during travel Prophylactic antibiotics Exposures Foods Water and ice Sexual contacts Arthropod bites/stings Swimming and sand exposure Animal contacts Blood products Altitude/diving

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Table 6 Selected Causes of Fever in the Returning Traveler More commona Malaria Infectious hepatitis Dengue fever Typhoid fever Tuberculosis Acute HIV Upper respiratory tract infections Urinary tract infections Mononucleosis (EBV) Amebic liver abscess Meningitis Rickettsial infection Less common Brucellosis Toxoplasmosis Filaria Yellow fever Leptospirosis Tick typhus Acute schistosomiasis Plague Hemorrhagic fevers Relapsing fever Poliomyelitis Flea-borne typhus a

HIV, human immunodeficiency virus; EBV, Epstein-Barr virus.

3.1.2

Exposures

The precise geography (microepidemiological features) of travel determines whether the disease exists in the area traveled. Duration of exposure is important as well; many infections are contracted only after an extended exposure (filarial infections, leprosy) and do not usually affect the short-term traveler. In contrast, infectious agents such as Malaria spp. and Schistosoma spp. may cause infection after brief exposure. The exposure history includes contact with insects, food and water, sand, and soil and sexual contacts (see Table 8). Classic examples demonstrating the utility of the exposure history include travelers’ swimming in freshwater lakes in Africa (Schistosoma mansoni, which causes schistosomiasis) and tick exposure after an African safari (Rickettsia conorii, which causes African tick typhus). 3.1.3

Immunizations

A full immunization history, including travel vaccines, helps to determine susceptibility to infection. Yellow fever and hepatitis A virus vaccination, for example, are protective in most (>90%) travelers. However, other vaccines such as oral typhoid vaccine may be only 60%–70% effective, and illness can occur with a high bacterial inoculum.

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Table 7 Selected Causes of Traveler’s Fever by Incubation Period Short incubation period (<10 days) Yellow fever Dengue fever and other arboviral illnesses Typhus and spotted fevers Typhoid and paratyphoid fever Medium incubation period (10–21 days) Malaria (all species) Typhoid and paratyphoid fever Typhus and spotted fevers Leptospirosis Hemorrhagic fevers Long incubation period (>21 days) Malaria (P. vivax, ovale, malariae) Viral hepatitis (A, B, C, D, E) Tuberculosis Acute human immunodeficiency virus (HIV) Amebic liver abscess Rabies Visceral leishmaniasis Acute schistosomiasis

3.1.4

Medication and Chemoprophylaxis Use During Travel

Infections that have been partially treated, with either antibiotics or prophylactic medications, may have atypical presentations. All medications and chemoprophylaxis during the period of travel should be closely reviewed. The physician interviewing the febrile traveler who has been prescribed malaria prophylaxis should remember that most patients are incompletely compliant with malaria prophylaxis, particularly in the 4 weeks post travel; that no prophylaxis is 100% effective; and that drug resistance patterns are changing rapidly worldwide. Malaria with a low parasite count occurs in individuals with fever who have used malaria prophylaxis. Repeated examinations of thick and thin Geimsa stained malaria smears are indicated in this situation. Adverse drug reactions to any medication should also be considered. 3.1.5

Physical Examination

The thorough physical examination often reveals diagnostic clues to the cause of fever. Examples of physical examination findings and associated causes of fever are shown in Table 9. 3.1.6

Work-up of Undifferentiated Travelers’ Fever

Despite a complete history and examination, many travelers’ fevers remain undifferentiated. An initial approach is shown in Table 10. Acutely ill patients with suspected viral hemorrhagic fever or P. falciparum malaria should be hospitalized. Most individuals without signs of systemic toxicity can be evaluated as outpatients.

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Table 8 Exposures and Selected Causes of Fevera Insects/arthropods Mosquitos: malaria, dengue, yellow fever, JEV, other arboviral infections, lymphatic filaria Ticks: spotted fevers, endemic relapsing fever, Q fever, viral encephalititis, Lyme disease, ehrlichiosis, tularemia, babesia Fleas: plague, murine typhus Sandflies: leishmania, bartonellosis, sandfly fever Flies: onchocerciasis, loa loa, African trypanosomiasis Animal exposures Tularemia, rabies, plague, anthrax, viral hemorrhagic fevers, brucellosis, rat-bite fever Raw meats/seafood Hepatitis A and E, trichinosis, bacterial and viral gastroenteritis, toxoplasmosis, anisakasis, Angiostrongylus spp., Vibrio cholerae, V. vulnificans, pork and beef tapeworms (Taenia solium and T. saginata), Campylobacter jejuni Unpasteurized milk Brucellosis, listeriosis, Q fever, Salmonella spp. Contaminated water/vegetables Amebiasis, hepatitis A and E, leptospirosis, typhoid fever, nontyphoid salmonellosis, shigellosis, viral gastroenteritis Swimming, fresh water Schistosomiasis, leptospirosis Ill contact exposure Shigellosis (bacillary dysentery), typhoid fever, mengingococcal meningitis, flavoviral infections (Ebola, Marburg virus) Sexual contacts Gonorrhea, hepatitis B and C, HIV, HTLV-1, syphilis, chlamydia a

JEV, Japanese encephalitis virus; HIV, human immunodeficiency virus; HTLV-1, human T lymphotropic virus type 1.

3.2

Common Causes of Fever in Returning Travelers

The most common causes of fever in the returning international traveler are malaria, typhoid fever, hepatitis A and E virus infection, and dengue. 3.2.1

Malaria

Malaria is by far the most common cause of tropical fever of travelers. Approximately 1000 cases a year are imported to North America, the majority in Canada. Health care providers treating travelers should remember the axiom ‘‘Fever in the returning traveler is falciparum malaria until proved otherwise.’’ It is a priority to consider, diagnose, and treat malaria expeditiously as P. falciparum or ‘‘malignant’’ malaria can rapidly lead to severe disease with marked hemolytic anemia, renal failure, coma, and death. Even when managed in intensive care units, severe P. falciparum malaria has a mortality rate >20%. Of travelers who have malaria 90% do not have signs or symptoms until they have returned home. Malaria can be a primary infection, recur, or be asymptomatic (only in those with prior immunity). P. falciparum malaria is manifested within the first 2 months of return (90%), whereas P. vivax and P. ovale malaria can appear up to several years post travel and may also recur. Any symptom can be associated with malaria, including fever, chills, malaise, myalgias, headache, gastroenteritis, and cough. The fever pattern is not helpful in early disease

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Table 9 Physical Examination Findings and Selected Causes of Traveler’s Fever Temperature-pulse dissociation High fever, low pulse: typhoid fever, leptospirosis, yellow fever Low fever, high pulse: acute rheumatic fever (carditis), Chagas disease, tetanus (no fever) Hepatomegaly Amebic or bacterial liver abscess, malaria, typhoid, leptospirosis Splenomegly Chronic malaria, schistosomiaisis, visceral leishmaniasis, typhus Lymphadenopathy Acute human immunodeficiency virus (HIV), dengue fever and other arboviruses, visceral leishmaniasis, brucellosis Eschar Anthrax, Lyme disease, typhus Facial edema Trichinellosis Hemorrhage Crimean-Congo hemorrhagic fever, Lassa fever, Ebola virus, Marburg virus, dengue fever, yellow fever, meningococcus, Rocky Mountain spotted fever, Rift Valley fever Jaundice Yellow fever, viral hepatitis, dengue, leptospirosis Joint swelling Loa loa (calabar swelling)

and is not synchronized with the classic tertian or quartan patterns until the parasites have gone through multiple replication cycles. In severe falciparum malaria, parasites sequester in peripheral tissues. Despite a high parasite load, a patient with severe malaria may look well but within a short period can be acutely ill with shock and mental status changes. Patients with severe malaria (or the possibility of it) need immediate intensive care support and urgent consultation by a physician trained in the care of malaria.

Table 10 Initial Workup of Fever in the Returning Traveler Detailed travel and exposure history (see Table 8) ↓ Determination of likely incubation period (see Table 7) ↓ Physical exam findings (see Table 9) ↓ Consideration of the more common infections first (see Table 6) ↓ Thick and thin blood smears (repeat q8–12h) Complete blood count (CBC) with manual differential Blood cultures (twice) Hepatic transaminase levels Stool culture and ova and parasite exam (if diarrhea) Urinalysis and culture Consideration of acute serum for storage

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The diagnosis of malaria is missed in over half of the cases. Many patients see more than three physicians before an accurate diagnosis is made. Malaria is diagnosed by thick and thin blood smears, which take considerable expertise to read correctly. The thin smear is specific for the P. plasmodium species and the thick smear, which is made with more blood, is more sensitive for the presence of malaria parasites. A competent microscopist can detect 5 to 10 parasites/␮L of blood on the thick film. Thick and thin smears that yield negative results should be repeated every 8–12 hours three times in order to rule out malaria. Other diagnostic tests such as the quantitative buffy coat, enzyme-linked immunosorbent assay (ELISA), and histidine-rich parasite antigen (ParasiteF) tests have greater sensitivity than blood smears but are expensive and not readily available in all settings. The treatment of uncomplicated malaria is summarized in Table 11. Medical therapy for malaria depends on the severity of infection, species present, and antibiotic resistance patterns. The most updated data on resistance patterns must be obtained before treatment (CDC Malaria Hotline 404-332-4555). Resistance to antimalarial agents worldwide is rapidly evolving. Globally, most areas have chloroquine-resistant P. falciparum, and some areas such as Southeast Asia have falciparum malaria resistant to all known forms of therapy. Drug-resistant P. vivax has also been reported in Oceania. Mild cases of malaria including most cases of nonfalciparum malaria can be treated orally on an outpatient basis with close follow-up. Severe cases of malaria including most infections with P. falciparum should receive inpatient monitoring and intravenous antibiotics. Many need intensive care unit (ICU) attention. Supportive care of these patients, including transfusions, fluid management, dialysis, and plasmapheresis, may be necessary and must be done in consultation with a malaria expert. Patients diagnosed with either P. vivax or P. ovale are at risk for recurrence of malaria because of the presence of the hypnozoite form of the parasite that resides in the liver, which is not eradicated by routine malarial agents. Primaquin (see Table 11) must also be

Table 11 Therapy of Uncomplicated Malaria a Chloroquine-sensitive Chloroquine b 1 g (Salt) at 0 hr, then 500 mg PO at 6, 24 and 48 hr or 1 g At 0 hr then 500 mg PO at 12, 24, and 36 hr or 1 g At 0 and 24 hr then 500 mg PO at 48 hr Chloroquine-resistant Quinine sulfate 650 mg (base) PO q8h for 3–7 days plus Doxycycline 100 mg PO bid for 7 days or Mefloquine 15 mg/kg PO at 0 hr then 10 mg/kg at 8–24 hr Mefloquine-resistant Quinine and doxycycline (as above) Terminal (hepatic phase) therapy for P. vivax, P. ovale Primaquine 15–30 mg PO/day for 14 daysc a

Severe malaria: consult expert trained in care of severe malaria. 1 g Salt = 600-mg base of chloroquine. c Check G6PD level before use. b

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given when treating P. ovale and P. vivax to prevent relapses. A G6PD level should be checked on all patients before use of primaquin since the drug can cause hemolysis in those with G6PD deficiency. 3.2.2

Hepatitis A and E

Viral hepatitis in the traveler is largely due to HAV infection contracted after ingestion of contaminated food and water. The infection is spread via outbreaks in developed nations but is globally endemic in areas with poor sanitation. After a long incubation period of 2–7 weeks, the infection produces fever, malaise, and nausea in the preictal period. Fever usually disappears after several days with the onset of jaundice. Patients remain infectious from the latter half of the incubation period to approximately after the first week of jaundice. Children are often asymptomatic and mild infections in healthy adults last 1–2 weeks. Severity increases with age, however, and infection may cause months of disability. In healthy hosts, full recovery without sequelae is the norm. Cases of HAV infection in the traveler are expected to decline with the use of the HAV vaccine, which has >90% effectiveness compared to the 60%–70% effectiveness of intravenous (IV) immunoglobulin. The diagnosis of HAV infection is made by demonstrating immunoglobulin M (IgM) anti–hepatitis A antibodies in association with elevated transaminase levels or by demonstrating a fourfold rise in antibody titer. Treatment is symptomatic. Hepatitis E virus (HEV) is found predominantly in the tropics and subtropics. It is spread via the oral-fecal route and cannot be distinguished clinically from HAV infection. Epidemics have been reported in Asia, Africa, the Middle East, and Central America. Pregnant women in the third trimester are at very high risk of fulminant hepatitis and death (30%) of HEV infection. Commercial serological tests for HEV infection are not available. Pregnant women should consider deferring travel to high-risk areas. Vigilant hand washing and attention to food and water precautions are advised for all travelers. 3.2.3

Enteric Fever

Enteric fever due to the gram-negative bacillus Salmonella typhi (typhoid fever) or Salmonella paratyphi (paratyphoid fever) can be contracted worldwide through ingestion of contaminated food and water. Most cases of typhoid fever diagnosed in the United States are contracted in India, Mexico, and Peru. High incidence rates are also found in Pakistan, Chile, and Haiti. The incubation period of typhoid fever varies with the infecting dosage (3–60 days). Clinical features include an initially remittent fever that becomes sustained. Malaise, headache, abdominal pain, and sleep disorders are common. Constipation in adults is common, rather than diarrhea. Hepatosplenomegly, transient ‘‘rose spots’’ on the trunk, and a temperature-pulse dissociation may be found on exam. The leukocyte count is normal. Complications of typhoid fever include gastrointestinal hemorrhage, bowel perforation, mental status changes (‘‘typhoid state’’), and hepatitis. Without appropriate treatment, the mortality rate can be >10%, with a higher rate of complications. Approximately 5%–10% of untreated patients relapse. Patients who excrete S. typhi for over 12 months are considered ‘‘chronic carriers’’ and are the unique reservoir for S. typhi. Diagnosis is made by isolation of the organism. Of blood cultures 80% yield a positive result in the first week while stool culture results are positive in <50% of patients. Bone marrow culture is the most sensitive test, particularly if the patient has been treated with antibiotics, and can yield positive findings in up to 94% of cases. Treatment goals are to cure acute disease and to prevent relapses, the chronic carrier state, and spread of the disease. The regimen of choice is ciprofloxacin 500 mg PO bid

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for 10 days. Because of drug resistance, amoxicillin, co-triamoxazole, and chloramphenicol have a lower cure rate and may not reduce the risk of relapse or chronic carriage. Chronic carriers are treated with the quinolones (i.e., norfloxacin) for 4 weeks. Patients with central nervous system manifestations of typhoid fever may require treatment with IV dexamethasone and should be urgently evaluated by a specialist. 3.2.4

Dengue Fever

Throughout the tropics, dengue is the most widespread arboviral infection. Once close to eradication, it is again endemic in Central and South America, parts of the Caribbean, and Mexico. Dengue is spread by the peridomestic Aedes egypti mosquito. Infection ranges from a mild undifferentiated fever to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which manifests thrombocytopenia, hemoconcentration, and hemorrhage that can progress to coma and circulatory collapse. DHF and DSS are unlikely to occur during the traveler’s first infection with dengue. Dengue has four serotypes, which do not confer cross-resistance. The incubation period of dengue is 5–8 days. Symptoms and signs of ‘‘classic dengue’’ include sudden onset of severe myalgias, fever (‘‘break bone fever’’), and retro-orbital headache. A scarletinaform or maculopapular rash appears 3–5 days into the illness. The fever often has a classic ‘‘saddle back’’ pattern, with a characteristic dip at day 3–5. Classic dengue fever is usually self-limited and lasts approximately 1 week. The diagnosis is made clinically and confirmed by a fourfold rise in acute and convalescent titers. Leukopenia, thrombocytopenia, and transaminase level elevations are common. Therapy is supportive with careful fluid management in DHF/DSS. No vaccine or specific therapies are available. 3.3

Diarrhea in the Returning Traveler

Diarrhea is a common part of travel to developing nations because of differences in sanitary conditions and changes in dietary habits. Unlike in traveler’s diarrhea, which is

ILL RETURNING TRAVELER WITH DIARRHEA, EOSINOPHILIA, OR SKIN LESIONS Diarrhea (see Table 12) Acute form usually due to bacteria or viruses Persistent (>2 weeks) form often due to parasites (protozoa) May be part of a systemic illness such as malaria, typhoid fever Eosinophilia (see Chapter 32, Tables 2 and 3) Invasive helminth infection, drug reactions Review of duration of travel, exposure to fresh water, ingestion of raw seafood or meat Skin lesions Systemic illnesses associated with rash (see Table 13) Assessment by character of rash (see Table 14) Diffuse Papules/linear lesions Nodules Ulcers and eschars Migratory lesions

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usually acute, self-limited, and of bacterial origin, infectious agents of persistent (>14 days) diarrhea syndromes or those that begin after return home are more likely due to a viral or parasitic pathogen. Posttravel diarrhea may be part of a systemic infection such as malaria or typhoid fever. Noninfectious causes of diarrhea include postinfectious mucosal damage, with malabsorption of fats or carbohydrates (such as lactose), antibiotic-associated colitis (Clostridium difficile), tropical sprue, and unrelated gastrointestinal (GI) diseases. Table 12 shows a selected list of infectious causes of persistent posttravel diarrhea (see Chapter 22). 3.4

Eosinophilia

An elevated eosinophil count in the traveler is classically thought to be due to invasive helminth infections (especially the larvae and adult nematodes, flukes, and tapeworms). However, eosinophilia has many nonparasitic and noninfectious causes, including preexisting rheumatological and allergic conditions (see Chapter 32, Tables 2 and 3). The travel history, duration, and timing of travel are important to determine the incubation periods of possible parasitic infection. Eosinophilia may be due to immature/ larval parasite forms, which cannot be detected in the stool until they have matured to the adult form (i.e., larval nematodes such as hookworm). Duration of travel is important since many of the infections that cause eosinophilia require extensive exposure and are unlikely to affect short-term travelers (e.g., filarial infections). Travelers should be asked about exposures to water (drinking and bathing) and ingestion of raw seafood or meat. A definitive diagnosis of an infection that is causing eosinophilia is difficult, possible in only 38% of one reported series. Regardless, most patients have a normal eosinophil count within 2–4 months. In contrast, some parasitic infections (such as Stronglyoides spp. infection) cause eosinophilia that persists for years. 3.5

Rash

Skin problems of travelers are a common reason for seeking medical advice. Often, travelrelated skin disorders are not due to infection and may represent aggravation of underlying

Table 12 Selected Infectious Agents of Diarrhea in Travelers Acute diarrhea Enterotoxigenic Escherichia coli (ETEC) Salmonella spp. Shigella spp. Campylobacter jejuni Vibrio parahaemolyticus Yersinia enterocolitica Aeromonas hydrophilia Rotavirus Norwalk virus Persistent diarrhea (>14 days) Giardia lamblia Cryptosporidium parvum Entamoeba histolytica Strongyloides stercoralis Cyclospora cayatensis

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skin conditions such as eczema or psoriasis, insect bite reactions, severe sunburns, and nonspecific dermatitis. The common diagnoses among travelers with rash include cutaneous larva migrans, pyodermas, arthropod-reactive dermatitis, myiasis, urticaria, and cutaneous leishmaniasis. Common bacterial infections of the skin such as streptococcal and staphyloccal infections are also more common in tropical climates. Rash may represent a local phenomenon or be part of a systemic illness. Evaluation of a traveler’s rash begins with a detailed travel history (Table 5) with specific emphasis on exposures and life-style issues. Duration of travel is important, since long-term residents may have different responses (e.g., rashes and level of eosinophilia), particularly to helminth infections, from those of transient visitors. Rashes are organized here by appearance: diffuse lesions, papules/linear lesions, ulcers and eschars, nodules/subcutaneous swelling, and migratory lesions (also see Chapter 32, Table 4). 3.5.1

Diffuse Rash

Many types of pathogens that cause systemic illness can be associated with diffuse rashes (see Table 13; also see Chapter 7). Since these infections represent bloodstream invasion, many require immediate attention (e.g., meningococcemia). The rickettsial infections are an important group of infections in this category, although rickettsial rashes vary by species (e.g., tache noir eschar with R. conorii infection vs. a diffuse rash with scrub typhus, R. tsutsugamushi). Dengue fever and vaccine-preventable infections such as measles and rubella can cause other diffuse erythroderma-like rashes. Skin penetration by pathogens also causes systemic rashes; these rashes in general are extremely pruritic. Cercarial dermatitis (‘‘swimmer’s itch’’), for example, is due to penetration of skin by avian or human schistosomal cercariae. Similarly, jellyfish larvae cause ‘‘sea bather’s eruption’’ in a bathing suit distribution after skin penetration.

Table 13 Selected Systemic Infections Associated with Rash Dengue fever Enteroviral infections Erlichiosis Gonococcemia Acute human immunodeficiency virus (HIV) Visceral leishmaniasis Leptospirosis Lyme disease Measles Meningococcemia Rickettsial infections Rubella Strongyloidiasis Syphilis Toxic shock syndromes Typhoid fever Varicella Viral hemorrhagic fevers

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Papules/Linear Lesions

The most common causes of papules are arthropod bites that cause allergic or local hypersensitivity reactions (see Table 14). Pruritic insect bites may persist for weeks to months after return from the tropics, particularly those from fleas or bedbugs. Many bites are exquisitely painful, including tsetse and blackfly bites. Stinging arthropods include scorpions and brown recluse spiders, both of which may cause considerable local necrosis.

Table 14 Evaluation of Rash by Lesion Type Papules/linear lesions Insect bites Scabies Body or head lice Milaria rubra (prickly heat) Filariasis (onchocerciasis) Drug reaction Candiasis Cercarial dermatitis Sea bather’s eruption Cutaneous larva migrans Nodules and subcutaneous swellings Gnathostomiasis Myiasis Tungiasis Filariasis (loa loa, onchocerciasis, W. bancrofti) Mycobacterium marinum, M. ulcerans, M. leprae Echinococcosis Dracunculiasis Ulcers and eschars Anthrax Diphtheria Leishmania Mycobacterium marinum, M. ulcerans, M. leprae Pyoderma gangrenosum Syphilis Tick eschar Yaws Chancroid Amebiasis Cysticercosis (Taenia solium) Most invasive fungal infections Paracoccidioidomycosis Migratory lesions Cutaneous larva migrans Dracunculiasis Gnathostomiasis Loa loa Strongyloides Myiasis

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Scabies, from the mite Sarcoptes scabiei, is common worldwide and is often found in linear burrows in the finger webs, wrists, and genitalia. Other linear and serpiginous lesions include cutaneous larva migrans (hookworm larvae) and larva currens (Strongyloides spp.). 3.5.3

Ulcers and Eschars

Most tropical ulcers are rare, except the shallow and painful ulcers of ecthyma. These ulcers are due to streptococcal or staphylococcal infections that occur as bacterial suprainfections of underlying insect bites or areas of traumatized skin. In contrast, the classic ‘‘tropical ulcer’’ is caused by infection with the protozoan Leishmania spp. The lesion begins as a nodule and slowly develops into the classic ‘‘heaped-up’’ painless ulcer. Since cutaneous leishmaniasis ulcers are asymptomatic and indolent, they are often ignored for a long period after travel. Diagnosis is made by biopsy and specialized culture. Rectal and genital ulcers may be due to amebiasis or sexually transmitted diseases, including chancroid, granuloma inguinale, and syphilis (see Chapters 16 and 17 regarding sexually transmitted diseases). 3.5.4

Nodules and Subcutaneous Swelling

Nodules occur after lymphatic spread of pathogens or at the site of inoculation. The differential diagnosis of these lesions is broad, and nodules/cystic lesions can occur with all invasive fungal infections and many mycobacterial and parasitic infections. Biopsy of the site is often the most efficient method of diagnosis. Subcutaneous swellings due to furuncular myiasis are common skin lesions in returning travelers and represent an embedded larva of the human botfly Dermatobia hominis. Similarly, the sand flea Tunga penetrans penetrates the skin (usually between toes) and enlarges to approximately 1 cm about 1–2 weeks after penetration (tungiasis). The nodules can be painful and characteristically have a central pore through which the larvae breathes. Both myiasis and tungiasis may be single or multiple infections and are treated by extraction of the larvae or flea. Filarial infections also cause subcutaneous swelling (loa loa) and nodules (Onchocerca spp.) but are usually found among long-term travelers or indigenous populations of endemic areas. 3.5.5

Migratory Lesions

Migratory lesions are unique to parasitic infections and are immensely disconcerting to the patient. Many represent the migration of infecting larvae in an accidental host (human). ‘‘Creeping eruption’’ or cutaneous larva migrans from canine and feline hookworm species is common among returning travelers from beach vacations in the Caribbean. This serpiginous rash is usually found on the feet or exposed skin and is extremely pruritic. Strongyloides spp. also cause a similar but broader rash that is rapidly moving (5–10 cm/hr) and is often found in the rectal area. Most patients with migratory infections have eosinophilia that indicates the immune reaction to tissue invasion.

BIBLIOGRAPHY The Centers for Disease Control. The Yellow Book, CDC Health Information for International Travel. Available at http://www.cdc.gov/travel/yellowbk/home.htm. Blue sheet updates. Available at www.cdc.gov/travel/bluesheet.htm. Malaria Hotline (404) 332-4555.

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Guerrant RL, Walker DH, Weller PF, eds. Tropical Infectious Diseases, Prinicples, Pathogens and Practice. Churchill Livingstone, 1999. Manson’s Tropical Diseases, 12th ed. W.B. Saunders, 1996. U.S. State Department. Counsular information, travel advisories. Available at http://travel.state.gov/ travel㛭warnings.html Virka A. Advice for international travelers. Mayo Clin Proc 76:831–840, 2001. Wilson ME. A World Guide to Infections. Oxford University Press, 1991.

41 The Patient Living in a Nursing Home Henry S. Sacks Mount Sinai School of Medicine, New York, New York, U.S.A.

1

INTRODUCTION

The proportion of the United States population above age 65 (currently 13% or 35 million people) is increasing rapidly and the proportion above age 85 (currently 1.6%) is increasing even more rapidly. Most elderly live in households, but the likelihood of living in a nursing home increases with age. In 1990, nearly 1.6 million of the 31 million persons aged 65 years and above (5%) lived in nursing homes. Three of four residents of nursing homes in 1990 were aged 75 or older and 7 of 10 were women. In 2000 more than an estimated 2 million people resided in nursing homes. It is expected that this number will double or triple in the next few decades. Over one-third of those above 65 years of age will spend at least some time in a nursing home. Nursing home residents tend to be frailer, to have more medical problems, and to use more medications than community-living elderly. The majority of nursing home patients are cognitively impaired and therefore less able both to manage their personal hygiene and to give a clear history when they become sick. Age-related changes that predispose to infection are summarized in Table 1. Because of these health impairments and cognitive limitations, the elderly living in the nursing home may manifest infections in unusual forms (see Table 2). Nursing homes differ from acute care facilities in both the range of diagnostic and therapeutic services they can provide and the flexibility and rapidity with which they can perform these services. Because many nursing home residents may recently have been in a hospital, they are at increased risk of becoming infected with antibiotic-resistant organisms. Because they live in close proximity with other residents, they are at increased risk of transmitting infection to other residents and may also be exposed to infections transmitted either directly or indirectly from resident to resident by nursing home staff. Therefore, outbreaks of respiratory infections, diarrheal illness, conjunctivitis, scabies, and other highly communicable problems are major concerns. It has been estimated that the average nursing home resident experiences one to three infections per year, although there is great individual variability. The elderly also have higher infection-related mortality rates than younger patients (see Table 3). Higher mortality rates are especially significant for older persons residing in long-term care facilities. They account for the most frequent reasons for transfers to acute care facilities. 771

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Table 1 Age-Related Changes That Predispose to Infection Thinner and more fragile skin Slower wound healing Impaired cough Impaired swallowing Impaired bladder emptying Impaired humoral immunity: decreased antibody levels and function Impaired cell-mediated immunity Decreased ability to mount a febrile response

Table 2 Atypical Presentations of Infection in Older Persons Any change of temperature in either direction from baseline Any unexplained change in functional status or behavior Worsening cognition Lethargy or agitation Anorexia or change in appetite Falls Incontinence Focal neurological finding Tachypnea

Table 3 Mortality Rate of Infections in Elderly Compared to Young

Infection Pneumonia Upper urinary tract infection Sepsis Appendicitis Cholecystitis Tuberculosis Infective endocarditis Bacterial meningitis Source: Yoshikawa and Norman 1987.

Mortality rate in elderly compared to that in young 3 Times 5–10 Times 3 Times 15–20 Times 2–8 Times 10 Times 2–3 Times 3 Times

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URINARY TRACT INFECTIONS Increased incidence of asymptomatic bacteriuria occurs in male and female elderly adults. Do not treat asymptomatic bacteriuria. Asymptomatic pyuria is not an indication for treatment. All patients with indwelling urinary catheters become colonized. Asymptomatic infection should not be treated. Remove catheter if at all possible. Treat symptomatic cystitis with trimethoprim & sulfamethoxazole (TMP-SMZ), nitrofurantoin, or ciprofloxacin. Vaginal estriol cream and cranberry juice may help prevent colonization and infection in elderly women.

The most common infections, which constitute over 80% of all nursing home infections, are in three categories: Pneumonia, Urinary tract infections, and Soft tissue infections (acronym, PUS). This chapter reviews these entities in addition to herpes zoster infection, tuberculosis, and scabies among nursing home residents. 2

URINARY TRACT INFECTION

Urinary tract infection (UTI) is the most common bacterial infection in nursing home residents. However, it is frequently overdiagnosed and overtreated. 2.1

Asymptomatic Bacteriuria

Significant bacteriuria (>105 colonies/mL) without associated symptoms (fever, dysuria, frequency, or urgency) is common in elderly patients, both male (15%–30%) and female (25%–50%). Whether treatment of asymptomatic bacteriuria is of any benefit has been debated in the literature for years; there is no strong evidence that treatment is of benefit. Randomized controlled trials have shown that rates of recurrence after treatment remain high and rates of development of symptomatic infection do not differ in treated and untreated patients. The only significant differences between treated and untreated patients were higher rates of adverse drug reactions and increased antimicrobial resistance in treated patients. In patients without symptoms, a urinalysis finding negative for white blood cells or a dipstick test result negative for leukocyte esterase can help to identify those patients who do not need to be treated. Foul-smelling urine is not an indication for treatment. Patients who have significant bacteriuria and symptoms of a UTI should be treated. Bacteriuria in elderly women may be prevented with intravaginal estriol cream. One placebo-controlled trial suggested that drinking cranberry juice reduced bacteriuria among elderly women. 2.2

Diagnosis and Treatment

The diagnosis of UTI is easier to establish when patients are able to describe a history of dysuria, frequency, and urgency with or without fever and flank pain. The diagnosis is difficult to make when patients cannot give a clear history since they are likely to have a positive urine culture result. Therefore, culture is recommended only for those who have either clear symptoms or fever. Similarly, pyuria is not helpful since it can occur with

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asymptomatic bacteriuria even in the absence of bacteriuria. The absence of pyuria, however, may be helpful in excluding UTI. Ideally, treatment should be based on knowledge of the sensitivities of the infecting organism. This requires a clean-catch specimen, which may be difficult to obtain. Cultures obtained from bedpan specimens or pedibags are not reliable. Symptomatic infection may be treated (with modification depending on culture results) empirically with trimethoprim-sulfamethoxazole (TMP-SMZ) or nitrofurantoin. The newer quinolones such as ciprofloxacin are widely used but are more expensive and are more likely to lead to the emergence of resistant organisms. Duration of therapy probably should be longer than in younger patients. Seven days is recommended for cystitis, though some authorities believe a 3-day course should suffice; 10 to 14 days of therapy should be used for those with fever or flank pain. Recurrence of bacteriuria is common, so followup cultures are not recommended unless symptoms recur. 2.3

Bacteriuria in Patients with Chronic Drainage Catheters

To date, no method has been found that can reliably prevent the development of bacteriuria in patients with indwelling drainage catheters. Therefore, the first question should always be, Can the patient be managed without the catheter? Alternatives include more frequent offers of toilet or bedpan or for men external (condom) catheters. Use of silver alloy– impregnated catheters may be of some benefit at least for the short term. Well-designed studies have shown little or no benefit from instillation of antimicrobial agents into either the collection bag or the catheter. On the other hand, there is evidence that good aseptic technique and maintenance of a closed drainage system are of benefit, at least in the short term. Despite the best technique, in the majority of patients who have long-term catheterization bacteriuria, which is usually polymicrobial, eventually develops. The presence of bacteriuria, with or without pyuria, is not an indication for treatment unless the patient also has fever or hemodynamic changes. The optimal management of symptomatic infection in patients with chronic catheters is not well studied, but the following recommendations seem reasonable. In patients who develop fever, evidence of infection at other sites should be looked for. Evidence of catheter obstruction or periurethral infection should be sought. If the source of the fever is not clear and the patient’s condition is clinically stable, consider observing off antibiotics for 24–48 hours; many fevers resolve spontaneously during this time. If the patient appears ill, obtain blood and urine cultures and treat for a short period (3–7 days) with TMPSMZ, nitrofurantoin, or ciprofloxacin. The value of changing the catheter is also not clear.

3 3.1

SKIN AND SOFT TISSUE INFECTIONS Pressure Ulcers

Pressure ulcers are unfortunately common among the infirm elderly. It is estimated that 10% of elderly nursing home patients will develop a pressure sore or decubitus ulcers during a 1-year period. Lying in one position for prolonged periods leads to skin necrosis and tissue breakdown. These lesions may remain quite superficial or progress to full-skinthickness necrosis and osteomyelitis of contiguous bone. Associated infections can include cellulitis, abscess formation, fasciitis, myositis, and bacteremia. Prevention works better than treatment. Frequent repositioning of the patient and excellent nursing care cannot be overemphasized (see Table 4). The treatment of pressure sores involves many of the same

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PRESSURE ULCERS, ZOSTER, AND SCABIES Pressure ulcers Prevention (see Table 4) is more effective than treatment (see Table 5) Superficial breakdown can progress to cellulitis, abscess formation, and osteomyelitis. Aerobic and anaerobic polymicrobic bacteria are common. Culture results are difficult to interpret. Topical antibiotics are of limited efficacy. Topical antiseptics (povidine, Dakin’s solution, hydrogen peroxide) can be detrimental. Systemic antibiotics are prescribed for associated fever, abscess formation, osteomyelitis. Zoster Reactivation of dormant varicella zoster virus occurs. Painful vesicles, pustules, and erythema have a dermatomal distribution. Therapy may shorten course (see Chapter 20, Table 9) Postherpetic neuralgia Routine analgesics generally are not helpful. Topical lidocaine or capsaicin cream may help. Low-dose tricyclic antidepressants or gabapentin may be most effective. Scabies Pruritic papules and burrows occur. Fingers, flexor surfaces of wrist, axillae, and genital area are affected. Permethrin 5% cream (Elimite) is applied to the entire body (except head) overnight. Clean all linens and clothes. Itching may persist for weeks despite successful therapy.

Table 4 Prevention of Pressure Ulcers 1. Use a risk assessment tool to identify patients at risk for pressure ulcers. Modify risk factors (immobility, moisture or incontinence, and nutritional deficiencies) as possible. Reassess patients regularly. 2. Use a repositioning schedule to reposition immobile patients—at least every 2 hours for bedbound patients and every hour for chair-bound patients. Prevent positioning directly on the trochanter. Use pillows and other devices to lift heels completely off bed and prevent direct contact with bony prominences. Minimize elevation of head of bed. 3. Use a pressure-reducing seating surface (not the donut-type) for chair-bound patients and a pressure-reducing mattress or mattress overlay for at-risk patients in bed. 4. Provide skin care; inspect skin daily, cleanse regularly with a mild cleanser, use moisturizers for dry skin, and prevent massage over bony prominences. 5. For incontinent patients, cleanse skin at time of soiling and use topical moisture barrier ointment. Use underpads or briefs with a quick-drying surface against the skin. 6. Maintain adequate dietary intake of protein, calories, and fluids. Give daily multivitamin and multimineral supplement to at-risk patients. 7. Optimize activity level, mobility, and range of motion. Institute a rehabilitation program. 8. Educate patients, family, care givers, and health care providers about causes, risk factors, risk assessment, selection and use of support surfaces, skin care, positioning, and documentation. Source: Pressure Ulcers in Adults 1992.

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elements involved in prevention: repositioning, skin care, and nutrition. In addition, cleansing, bandaging, and pain relief must be provided (see Table 5). Topical antibiotics do not penetrate into wounds or surrounding tissues. They may cause local reactions and may lead to overgrowth with resistant organisms. They should be used only for short periods (up to 2 weeks). Topical antibiotics that have been shown in randomized controlled trials to be useful include gentamicin and silver sulfadiazine. However, topical antiseptics such as 1% povidone-iodine, 0.25% acetic acid, 0.5% sodium hypochlorite (Dakin’s solution), and 3% hydrogen peroxide may impair wound healing and should not be used. Pressure sore infections are polymicrobic, a mix of aerobic gram-negative rods (GNRs), anaerobes, streptococci, and staphylococci. Differentiating wound colonizers from pathogens is almost impossible. Wound swabs, even of pus, are of little value. Needle aspiration of a closed space collection or punch biopsy of infected tissue is the preferred method for determining the true bacteriology of a pressure ulcer. Alternatively, a two-step process of (1) thoroughly cleansing the wound with nonantimicrobial solution then (2) swabbing a 1-cm area of the wound base for 5 seconds with pressure sufficient to express fluid from the wound tissue may be tried. Systemic antibiotics are indicated for patients with signs of local (pus, erythema) or systemic (fever, leukocytosis) infection. Before beginning systemic antibiotic therapy obtain blood and wound cultures (as described) if possible. Antibiotics that have polymicrobic activity that may be useful for the treatment of infected ulcers include cefoxitin or cefotetan, ampicillin-sulbactam, ticarcillin-clavulanic acid, and piperacillin-tazobactam. Oral agents with combined aerobic and anaerobic activity include amoxicillin-clavulanate and the newer quinolones such as gatifloxacin, moxifloxacin, temefloxacin, grepafloxacin, and sparfloxacin. Oral antibiotics that have anaerobic activity (clindamycin or metronidazole) and aerobic GNR activity (cefixime, co-trimoxazole, ciprofloxacin) can also be used in combination. If there is no bone involvement a 10- to 14-day course should be adequate.

Table 5 Treatment of Pressure Ulcers 1. Assess ulcer(s) initially and then reassess weekly size (length, width, and depth), description of tunneling, undermining, necrotic tissue, odor, exudate, and cellulitis if present and condition of surrounding skin. 2. Relieve pressure: use a repositioning schedule and pressure-reducing support surface. 3. Assess and manage nutritional status: intake goal of 30–35 cal/kg/day, 1.25–1.50 g protein/kg/ day, and daily high-potency multivitamin, multimineral supplement. 4. Use autolytic, enzymatic, mechanical, or sharp de´bridement to remove necrotic tissue. Dry eschar on heels should be left in place unless evidence of infection is present. 5. Cleanse ulcer at each dressing change with saline solution or other nontoxic cleanser with technique that minimizes mechanical trauma to wound. 6. Select ulcer dressings that keep ulcer bed continuously moist and surrounding skin dry. 7. Bacteremia, sepsis, and cellulitis require systemic antibiotic therapy. Local infection (colonization) does not require systemic antibiotics and is more appropriately treated with topical antibiotics (not topical antiseptics). 8. For nonhealing ulcers, consider adjunctive therapy such as electrical stimulation. 9. Provide adequate pain relief. Source: Bergstrom N et al. 1994.

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Herpes zoster (Shingles)

The incidence of herpes zoster increases steadily with advancing age and its associated waning of immunity. In young adults, there may be only 1 or 2 cases per 1000 personyears, whereas in those above age 65, the rates may be 10 times higher. The rash typically occurs unilaterally in one or two adjacent dermatomes on the trunk, upper extremity, or face. The rash, which may or may not be preceded by pain in the same area, begins with erythema and vesicles that coalesce, form pustules, and crust over in 7 to 10 days. Pain is common and may persist for weeks or months after the skin lesions have healed. Acyclovir and its more recent family members, famciclovir and valacyclovir, have all been shown to reduce time of crusting and healing of lesions and postherpetic pain if started within 72 hours of the onset of symptoms (see Chapter 20, Table 9, for dosage and costs). The definition of postherpetic neuralgia (PHN) varies in different studies, leading to widely varying estimates from 2% to 30% of patients. PHN is more common in older patients, in those with more severe rash, and in those who had severe pain during the rash or pain before the rash appeared. Clinically, PHN may be defined as pain that lasts for more than 1 month after onset of the zoster rash. Treatment remains a frustrating problem for both patients and physicians. It is reasonable to start with aspirin and other analgesics, although both aspirin and narcotic analgesics have limited benefit. Topical lidocaine or lidocaine/prilocaine creams may be helpful. Capsaicin cream (0.025%–0.075%) has been shown to be beneficial to some patients but many cannot tolerate it. There is some suggestion that the newer drugs are more effective in reducing the incidence of postherpetic neuralgia, but there is not enough evidence for a clear recommendation of any one drug. Whether or not the addition of corticosteroids is beneficial remains unclear The tricyclic antidepressants amitriptyline and desipramine are generally considered the treatment of choice for refractory PHN. Either drug may be tried, starting with a low dose (12.5–25 mg) at bedtime and increasing the dosage at 1-week intervals until either relief is obtained or unacceptable side effects occur. Anticonvulsant drugs including phenytoin, valproate sodium, and carbamazepine have shown some benefit when added to the antidepressants. Unfortunately, the serotonin reuptake inhibitor antidepressant drugs (such as fluoxetine and paroxetin), which are better tolerated by the elderly than the tricyclics, have so far not been shown to be as useful for PHN. A recent study of gabapentin as monotherapy titrated from 900 mg/day to 3600 mg/ day showed dramatic benefit when compared to placebo and appears to be better tolerated than the tricyclics. There have been no direct comparisons with other symptomatic agents reported. Patients who do not respond to any of these measures may benefit from referral to pain specialists for nonpharmacolgical approaches such as transcutaneous electrical nerve stimulation (TENS). Acute herpes zoster is considered to be infectious until the lesions have crusted over. Those at risk are children or adults who have not had chickenpox (varicella), although over 90% of adults have antibodies to the herpes zoster/varicella virus whether or not they remember having had chickenpox. As the number of children receiving the herpes zoster/ varicella vaccine increases, it is hoped that the number of persons at risk will decrease. 3.3

Scabies

Scabies is a skin infestation with Sarcoptes scabiei that can cause outbreaks in nursing homes or other communal living facilities. The typical eruption consists of pruritic papules or vesicles and burrows where the causative mite has dug into the skin. Areas most likely

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to be affected are the webs between fingers, flexor surface of the wrist, axillae, and genital areas. In the elderly or immunosuppressed, an atypical presentation, including exfoliatve dermatitis, can occur. Therapy involves the application of a topical scabicide such as permethrin 5% cream (Elimite) or lindane on all skin from the neck down with special attention to axillae, groin, perineum, and finger and toe webs (see Chapter 20, Table 1 for dosage and costs). The cream is left on overnight. All clothing and bed clothing should be washed in very hot water. All persons sharing the patient’s room or having close contact should also be treated. Itching may persist for some time after treatment because of residual allergic reaction to the infestation. The decision whether or not to re-treat may be difficult. 4

RESPIRATORY INFECTIONS

In the elderly, as in the younger population, respiratory infections are the most common conditions for which medical attention is sought. 4.1

Influenza

Influenza occurs in annual cycles, usually in the fall and winter months, and varies greatly in its extent and severity (see Chapter 14). The illness begins abruptly with fever, myalgias, headache, runny nose, sore throat, cough, and malaise. In the elderly, chills, myalgia, sore throat, and runny nose are less common, whereas sputum production, cough, and dyspnea are more common. In more severe cases viral pneumonia or secondary bacterial pneumonia can develop. The disease is typically self-limited and usually lasts 3 to 5 days but may

PULMONARY INFECTIONS Influenza Fever, myalgia, pharyngitis, cough Can progress to viral pneumonia Can be complicated by secondary bacterial pneumonia with S. pneumoniae or S. aureus Diagnosis by rapid test of nasal swab or oropharyngeal wash treatment (see Chapter 14, Table 4) Importance of yearly influenza vaccination Pneumonia Atypical presentations without fever or cough (see Table 1) Increased risk related to feeding tubes, incontinence, recent viral infection, immobility, and stroke (see Table 2) S. pneumoniae, H. influenzae, M. catarrhalis, S. aureus, and gram-negative rods (GNRs) Can generally be treated in the nursing home; rapid initiation of therapy potentially more important than hospitalization Therapy (see Table 7) Importance of pneumococcal vaccine Tuberculosis Reactivation of dormant infection more common than acquisition of new infection Surveillance of nursing home patients (see Table 8) Purified protein derivative (PPD) testing of all new residents (see Chapter 13, Figure 2) Treatment of latent and active infection (see Table 9)

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persist for up to 2 weeks. The elderly, smokers, and those with cardiac or pulmonary disease, diabetes, or other chronic diseases are at higher risk for complications, including death. During influenza epidemics, up to 90% of the deaths attributed to pneumonia and influenza occur in those above age 65. Much of the morbidity and mortality can be prevented with influenza vaccination. As the virus is continually evolving, the vaccine must be updated and provided annually. Viral and secondary bacterial pneumonia are major concerns in the elderly. Viral pneumonia may develop early in the disease course with bloody sputum and tachypnea and may progress to respiratory failure. Secondary bacterial pneumonia may occur later in the course, often after initial improvement and defervescence. Streptococcus pneumoniae and Staphyloccus aureus are the bacterial pathogens most commonly reported. In patients with preexisting cardiac disease, influenza may cause worsening of heart failure and an increased likelihood of myocardial infarction. The diagnosis is usually made clinically on the basis of the time of year, knowledge of influenza reported in the area, and a compatible clinical picture. However, in nursing homes, where there is concern about outbreaks and the need to provide prophylaxis, laboratory information may be helpful to decision making. Three rapid (10–20 minutes) diagnostic tests for influenza A and B have recently been approved by the United States Food and Drug Administration: FLU O1A (Biostar), Quikone Influenza test (Quidel), and Zstatflu (ZymeTx). All have good specificity (93%–99%). The sensitivity of Zstatflu (57%–65%) is less than that of the other two (73%–81%). These join the already released Directigen Flu A, which detects only influenza A. All cost $15–$20. There have been no direct comparisons of the tests. A positive test result in the appropriate clinical setting can be highly predictive of influenza. A negative test finding does not rule out the diagnosis. Four drugs are currently available in the United States for the treatment and prevention of influenza. Amantadine and rimantadine block viral replication but are active only against influenza A (the most common variety). Both are highly effective in preventing illness in exposed subjects and in shortening the duration of illness if given within 48 hours of onset of symptoms. Both can cause nausea, vomiting, nervousness, anxiety, lightheadedness, and, rarely, seizures. Rimantadine may have fewer side effects. The dosage of both drugs should be reduced to 100 mg daily in the elderly. Two new drugs that act by inhibiting viral have recently been approved in the United States: Zanamivir (Relenza) and Oseltamvir (Tamiflu). They are active against both influenza A and influenza B and appear to be better tolerated than amantadine but are more expensive. Comparative trials have not yet been completed. Zanamivir is taken by inhaler twice daily; Oseltamivir 75 mg is taken orally twice daily. The treatment course is 5 days for both (see Chapter 14, Table 4, for dosage and costs). 4.2

Pneumonia

Pneumonia is much more frequent in nursing homes than in the community (see Chapter 12). It is the leading cause of death in patients living in long-term care facilities. Most of what is known about pneumonia in elderly adults is derived from studies of communityacquired pneumonia (CAP) of patients living at home rather than in nursing homes. Where important differences in nursing home–acquired pneumonia (NHAP) are clear, they will be noted. The case fatality rates of pneumonia remain around 20% in patients above age 65 and 40% in those above 85. Outbreaks of pneumococcal pneumonia have been reported in nursing homes, often in association with low rates of pneumococcal vaccination.

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It has been suggested since the days of Sir William Osler that older patients who have pneumonia may experience nonrespiratory symptoms. A large multicenter study has recently confirmed this impression. Patients older than 75 reported significantly fewer of the typical symptoms of pneumonia such as cough, dyspnea, sputum production, and hemoptysis. Pleuritic chest pain was only half as likely to be reported compared to reports by younger patients. Similarly, nonrespiratory symptoms (fatigue, fever, sweats, myalgia, inability to eat) were also less likely to be reported by elderly patients with pneumonia. Women reported fewer symptoms than men and nonsmokers reported fewer symptoms than smokers. These findings emphasize the need for a heightened level of suspicion. Predisposing factors include declining immunity; oropharyngeal colonization with potentially pathogenic bacteria, including S. aureus and GNRs; decreased clearance of respiratory secretions; chronic obstructive pulmonary disease; and recent viral respiratory infection, especially influenza. Additional risk factors for NHAP include declining immunity, urinary incontinence, tracheotomy or nasogastric feeding tube, bedbound status, and difficulty with swallowing and secretions. Unfortunately neither gastrostomy nor jejunostomy seems to reduce the risk of pneumonia. Establishing with certainty the cause of NHAP is often challenging because of difficulties in obtaining and interpreting sputum cultures. S. pneumoniae is the most frequently isolated pathogen in many studies, followed by Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and GNRs such as Klebsiella pneumoniae. Pathogens occasionally isolated included Legionella species and Chlamydia species. In many studies, over half of the cases have no specific etiological agent identified. Viruses that have been shown to cause pneumonia in nursing homes include influenza and parainfluenza viruses, respiratory syncytial virus (RSV), and adenovirus (see Table 6). Up to 50% of nursing home patients who have pneumonia are transferred to acute care hospitals. There are many factors considered in this decision including the wishes of the patient and family; the availability (or lack) of intravenous therapy, supplemental oxygen, and other treatment modalities at the nursing home; and the severity of the illness. It is worth noting that there is no evidence that transfer per se improves outcome. On the basis of the CAP studies it seems more likely that prompt initiation of therapy has a greater impact on outcome. If transfer delays the start of therapy, it can actually be counterproductive. Guidelines for treatment of CAP and hospital-acquired pneumonia have been published by several groups. There are currently no specific guidelines for NHAP. Antibiotic

Table 6 Causes of Nursing Home–Acquired Pneumonia Organism Streptococcus pneumoniae Staphylococcus aureus Gram-negative rods Legionella spp. Mycoplasma spp. Chlamydia spp. Other Viruses

Cases, % 5–39 2–33 3–50 0–6 0–1 0–6 6–20 0–10

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selection is empirical. Patients who are mildly to moderately ill may be treated with oral agents including cefaclor, amoxicillin/clavulanate, gatifloxacin, or levofloxacin. Intramuscular cefamandole or ceftriaxone can also be used. For patients who appear more ill or who have unstable vital signs (respiratory rate greater than 30/min, systolic blood pressure less than 90 mm Hg, or pulse greater than 120/min), intravenous antibiotics are recommended. Suitable choices include the newer quinolones (gatifloxacin or levofloxacin), second- or third-generation cephaloporins (cefotetan, cefuroxime, or ceftriaxone), and ␤-lactam/␤-lactamase inhibitor combinations (ampicillin/sulbactam, piperacillin/tazo-bactam). Ciprofloxacin has excellent activity against GNRs, but poor streptococcal activity and should not be used empirically because of the concern for S. pneumoniae. Aminoglycosides have limited activity in respiratory secretions and may cause greater nephrotoxicity in the elderly and should not be used to treat NHAP. TMP-SMZ has good activity against most bacteria that cause NHAP but may not have activity against penicillin-resistant pneumococci. The addition of a macrolide such as erythromycin or azithromycin to a ␤-lactam agent has been suggested for moderate to severe CAP to treat for Legionella and Chlamydia spp. Their use may be reasonable in NHAP also, although there is no clear evidence for or against their use. The newer quinolones have activity against atypical pathogens and may be used as single agents to cover both typical and atypical bacteria. Treatment options for mild to moderate infection are summarized in Table 7. Ancillary measures include supplemental oxygen, adequate hydration, pain control, and nutrition. 4.3

Tuberculosis

Tuberculosis (TB) is an uncommon cause of infection in nursing homes (see Chapter 13). However, most people who are elderly today grew up at a time and in places where tuberculosis was much more common than it is today and before antituberculosis drugs were available. Thus they may harbor asymptomatic infection that can reactivate as immunity declines. New infection can also be acquired from unrecognized cases, and outbreaks of tuberculosis in nursing homes have been reported. Rates of tuberculosis in elderly community residents are two to three times higher than in younger people. Rates in residents of long-term care facilities are higher still. Approximately 5% of the population above age 65 lives in extended care facilities, where 20% of the cases of TB occur. Recommendations for TB surveillance of nursing home patients are summarized in Table 8. All patients entering nursing homes should have baseline tuberculin skin testing; those who have negative test findings should have repeat testing in 10–14 days to detect false-negative results. The ‘‘booster phenomenon’’ is more common in elderly (see Chapter 13, Figure 2). Anergy testing is not recommended. Tuberculosis is often overlooked in the differential diagnosis of pneumonia in the nursing home patient. The presentation may be nonspecific, with less frequent occurrence of night sweats and hemoptysis and more common weight loss, cough, and weakness. Asymptomatic patients with recent skin test conversion are candidates for treatment of latent infection with a 9-month course of isoniazid (INH). Therapy for active tuberculosis in the elderly is essentially the same as for younger patients. Because of high rates of drug resistance, a four-drug regimen is recommended by the Centers for Disease Control and Prevention. The main drugs used are INH, rifampin, pyrazinamide, and ethambutol. The usual duration is 9 months (see Table 9). Many practitioners believe that since most cases in elderly adults are recurrences of infection acquired many years before, patients

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Table 7 Treatment of Mild to Moderate Nursing Home–Acquired Pneumonia Medication Oral antibiotics Azithromycin Cefuroxime axetil Amoxicillinclavulanate Levofloxacin Moxifloxacin Gatifloxacin Doxycycline Erythromycin Intramuscular antibiotics Ceftriaxone Cefotetan Intravenous antibiotics Cefuroxime Ampicillin-sulbactam Levofloxacin Gatifloxacin Piperacillin-tazobactam Ticarcillin-clavulanate

Dosage a

Costb

500 mg On day 1 then 250 mg once daily on days 2–5 c 250–500 mg bid 500 mg tid 500 mg/day 400 mg/day 400 mg/day 100 mg/day 250–500 mg qid d

$39

500 mg–1 g/day 1 g q12h

$250–$450 $290

750 mg q8h 1.5 g q8h 500 mg/day 400 mg/day 3.375 g q6h 3.1 g q6h

$282 $204 $390 $380 $660 $616

$81–$148 $106 $85 $87 $70 $24 $10–$20

a

Assuming normal renal function. Average wholesale price for a 10-day course of antibiotics. c Equivalent to a 10-day course. d Other preparations of erythromycin can be found in Chapter 3, Table 8. b

are unlikely to harbor resistant mycobacteria and therefore can be treated with a two- or three-drug regimen. Patients being treated for active TB should have monthly sputum samples collected for acid-fast bacillus (AFB) smear and culture. It is important to try to establish whether the patient was ever treated in the past for tuberculosis and with which drugs since retreatment should generally employ at least two new drugs. The risk of isoniazid hepatitis increases with age. Although it usually occurs within the first few weeks of treatment, it may occur at any time. Therefore, monitoring for signs and symptoms of INH toxicity (anorexia, nausea, vomiting, jaundice) should continue

Table 8 Surveillance of Tuberculosis in Nursing Home Patients All new residents should have two-step tuberculin testing. Repeat in 7–10 days if the first test result is negative (see Chapter 13, Figure 2). Chest radiography for all positive reactors. Annually retest all nonreactors (or retest whenever a case of active disease is diagnosed). Recent converters (an increase of >10 mm in duration) should receive therapy for latent infection. Anergy testing is not recommended.

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Table 9 Treatment for Tuberculosis Treatment for latent infection Isoniazida Treatment for active disease Isoniazid a Rifampin Pyrazinamide Ethambutal a

300 mg/day 300 mg/day 600 mg/day 25 mg/kg/day in two to three divided doses 25 mg/kg/day

Also use pyridoxine 25 mg/day.

throughout treatment. Most authorities do not recommend routine monitoring of liver enzymes because mild (less than five times the upper limit of normal) asymptomatic elevations are relatively common and are not a reason for changing therapy. If patients do not tolerate the first-line regimen, a pulmonary or infectious disease consultant may help in designing alternative regimens. 5 5.1

OTHER INFECTIONS IN THE ELDERLY Central Nervous System Infections

Alterations in consciousness may occur with any serious illness. Conversely, the classic presentation of bacterial meningitis including high fever, headache, and neck stiffness may be absent in the elderly. Time of year is important in determining the potential cause of meningitis. Viral meningitis from enteroviruses is more common in late summer and fall. Bacterial meningitis is more common in winter and early spring. It is most often caused by Streptococcus pneumoniae, Listeria monocytogenes, and less commonly aerobic organisms. Organisms that are more commonly seen in the elderly include Mycobacterium tuberculosis and Cryptococcus neoformans. Signs and symptoms of bacterial meningitis in elderly adults may be less prominent than in younger patients though cerebrospinal fluid (CSF) analysis findings are similar. The elderly confused patient with a stiff neck should be assumed to have meningitis until proved otherwise. Because of the concern of L. monocytogenes, the initial empirical antibiotics should include ampicillin (2 g q4h) in addition to ceftriaxone (2 g q12h). If penicillin-resistant pneumococcal infection is a possibility, vancomycin (15 mg/kg q12h) should be added. Arbovirus encephalitis is more common in late spring, summer, or early fall. St. Louis encephalitis (StLE) was first described in the 1930s and has occurred in both rural and urban areas all across the country. It is transmitted among wild birds by mosquitoes and is occasionally transmitted to humans. Whereas the infection may be asymptomatic in young adults, in the elderly adult symptomatic disease is more common, with altered mental status, fever, and a lymphocytic pleocytosis in the spinal fluid. West Nile virus (WNV) was unknown in the United States before the summer of 1999, when an outbreak was identified in New York City. The clinical manifestations were similar to those of StLE though some patients had a characteristic progressive paralysis. Seven fatalities were reported in New York City. The virus has been found in birds and/or mosquitoes in many parts of the Northeast and may have become more widespread. Treatment is primarily supportive although laboratory studies suggest a possible role for the antiviral drug ribavirin. If either StLE or WNV infection is suspected, blood and/or CSF specimens should be obtained and the local health department consulted urgently.

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Encephalitis due to herpes simplex type 1 (HSV-1) is the most common sporadic encephalitis. There are no seasonal peaks. There is a biphasic age distribution with the second peak in persons above 50 years. In this older population the encephalitis is most likely a reactivation of dormant HSV-1 infection. Patients have fever, altered mental status, focal neurological deficits, or seizures. Magnetic resonance imaging (MRI) scans show abnormalities characteristically in the temporal, parietal, and/or frontal lobes. The CSF shows a nonspecific lymphocytic pleocytosis. The diagnosis can be confirmed by demonstration of viral deoxyribonucleic acid (DNA) in the spinal fluid by polymerase chain reaction. It is the only potentially treatable viral encephalitis. Therapy with high-dose intravenous acyclovir (10 mg/kg q8h) may improve prognosis. Noninfectious causes of altered mental states should be considered for the confused elderly patient including stroke, systemic lupus erythematosus, sarcoidosis, vasculitis, and drugs. 5.2

Methicillin-Resistant Staphyloccus aureus in the Nursing Home

Methicillin-resistant S. aureus (MRSA) is well known to be a frequent cause of serious infection in hospitalized patients. The elderly are at greater risk of colonization and infection. The impact of MRSA on nursing home residents is less clear. MRSA colonization appears to be quite variable, having been found in from <10% to >50% in different surveys. Infection caused by MRSA has been documented much less frequently; it can cause skin and soft tissue infection, urinary tract infection, pneumonia, and septicemia. Treatment has been with intravenous vancomycin. Recently, two new agents have been approved for use—intravenous quinupristin; dalfopristin (Synercid), a streptogramin, and linezolid (Zyvox), an oxazolidinone—which can be taken either intravenously or orally (see Table 10). It is important but not always easy to distinguish colonization with MRSA from infection. Agents used to attempt eradication of colonization have included combinations of rifampin and either ciprofloxacin or trimethoprim-sulfamethoxazole. Intranasal 2% mupirocin cream has had success in eliminating nasal MRSA carriage. Relapse of colonization and bacterial resistance remain significant problems. Attempts to eradicate MRSA colonization are unlikely to be successful. Therefore, screening or surveillance cultures are generally not recommended; nor is elaborate environmental decontamination. The importance of regular hand washing after contact with patients who have MRSA cannot be overemphasized. 5.3

Malignant External Otitis

Malignant external otitis (MEO) is an infection of the external ear canal that invades the mastoid or temporal bones or base of the skull and adjacent tissues including cranial nerves. It is caused most commonly by Pseudomonas aeruginosa but can be caused by other bacteria, including staphylococci, and fungi, including Candida and Aspergillus species. It is called malignant because of the high mortality rate of invasive and subsequent central nervous system infection. MEO must be considered when patients do not rapidly respond to treatment of ear complaints. MEO occurs mostly in elderly diabetics. Ear pain is the most common symptom. It is typically severe and unrelenting. Purulent discharge is also usually present. Examination of the ear canal may show variable amounts of discharge, sometimes greenish, and the presence of granulation tissue. Swelling or erythema outside the ear canal should raise suspicion that the problem is more than superficial external otitis. Cranial nerve involve-

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Table 10 Treatment of Methicillin-Resistant Staphylococcus aureus Dosage a

Toxicity

Vancomycin

15 mg/kg IV q12h; Adjust for decreased renal function

Quinupristin; dalfopristin (Synercid)

5–7.5 mg/kg IV q8h

Linezolid (Zyvox)

600 mg PO or IV q12h g

Fever Phlebitis Redman syndrome c Auditory nerve damage Nephrotoxicity d Myalgia, arthralgia Phlebitis Nausea, vomiting Diarrhea Hypertension f Leukopenia Liver biochemical abnormalities Tongue discoloration

Drug

Cost for 10 days of therapy b $550

$4830 e

$800 $1440 (IV)

a

Assuming normal renal function. Average wholesale price. c Tingling, flushing, and redness of head, neck, and chest. d Now relatively uncommon. e For a 70-kg person. f Linezolid has monoamine oxidase inhibitory properties. It can raise blood pressure with certain drugs and tyramine-containing foods (see Chapter 3). g No adjustment for abnormal renal function is needed. b

ment, especially facial nerve weakness and involvement of nerves IX, X, and XII, should raise the possibility of MEO and be an indication for cranial imaging. Routine skull films or mastoid series may show bony involvement. Computed tomography (CT) is superior for evaluating the extent of bone involvement. MRI may give a better picture of soft tissue involvement. The erythrocyte sedimentation rate is typically elevated but is very nonspecific. Intravenous administration of an antipseudomonal antibiotic such as ceftazadime, cefepime, piperacillin, or ciprofloxacin should be started. Further therapy should be guided by culture results. Therapy should continue for 6 to 8 weeks. If the condition is improving, changing to oral ciprofloxacin can be considered. Surgical de´bridement of involved areas may be a useful adjunct. BIBLIOGRAPHY Ahronheim JC. Handbook of Prescribing Medications for Geriatric Patients. Boston: Little, Brown, 1992. Bentley DW, Bradley S, High K, et al. Practice guidelines for evaluation of fever and infection in long-term care facilities. Clin Infect Dis 31:640–653, 2000. Bergstrom N, Bennett MA, Carlson CE, et al. Treatment of pressure ulcers. Clinical Practice Guideline No. 15. AHCPR Publication No. 95-0652. Rockville, MD, U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1994. Dutt AK, Stead WW. Tuberculosis in the elderly. Med Clin North Am 77:1353–1368, 1993.

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Gleckman RA, Ganz NM, eds. Infection in the Elderly. Boston: Little, Brown, 1983. Metlay JP, Schulz R, Li Y, et al. Influence of age on symptoms at presentation in patients with community-acquired pneumonia. Arch Intern Med 157:1453–1459, 1997. Muder RR. Pneumonia in residents of long-term care facilities: Epidemiology, etiology, management and prevention. Am J Med 105:319–330, 1998. Nicolle LE. Urinary tract infection in long-term-care facility residents. Clin Infect Dis 31:757–761, 2000. Pressure ulcers in adults: Prediction and prevention. Clinical Practice Guideline No. 3. AHCPR Publication No. 92-0047. Rockville, MD, U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1992. Yoshikawa TT, Dean NC, eds. Infectious Disease in the Aging: A Clinical Handbook. Totowa, NJ: Humana Press, 2000. Yoshikawa TT, Norman DC, eds. Aging and Clinical Practice: Infectious Diseases: Diagnosis and Treatment. New York: Igaku-Shoin Medical, 1987, p 6.

42 Postexposure Prophylaxis Judith L. Steinberg Boston University, Boston, and Neponset Health Center, Dorchester, Massachusetts, U.S.A.

1

INTRODUCTION

The primary care physician may be called on to manage the care of health care workers or patients who have been exposed to potentially infectious blood and body fluids. Each incident needs to be analyzed individually as to the type of exposure, the history and risk factors of the source, and the medical history of the exposed. In the process, an assessment of risk is made. Exposures to blood and body fluids present risks for transmission of human immunodeficiency virus (HIV) as well as hepatitis B and C viruses. Thus, exposure episodes must be managed in a way that addresses each of these pathogens. When caring for patients who have sustained an occupational or nonoccupational exposure, it is important to utilize a clearly outlined exposure protocol for the following reasons: (1) comprehensive management must address all three viruses, each with its own set of guidelines; (2) an exposure episode is a stressful event for all involved that can lead to errors and confusion if a protocol is not followed; and (3) there may be potential legal issues. In addition to the administration of postexposure prophylaxis (PEP), such a protocol must include the counseling, support, and follow-up of exposed individuals. 2 2.1

HUMAN IMMUNODEFICIENCY VIRUS EXPOSURE Occupational Exposure

Occupational exposures to HIV-infected blood and body fluids in which PEP should be considered include percutaneous injury, contact with mucous membrane or nonintact skin with blood, tissue, or other potentially infectious body fluids; the latter include semen and vaginal secretions or other body fluids contaminated with visible blood. Cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluids should also be considered potentially infectious, although they pose an undetermined risk of transmission. Exposures to saliva, tears, sweat, breast milk, nasal secretions, sputum, vomitus, urine, or feces are not considered risks for HIV transmission when visible blood is not apparent in these fluids. Any direct contact with concentrated HIV from a laboratory setting is considered a significant exposure. Through prospective studies, the average risk of HIV transmission after percutaneous exposure to HIV-infected blood has been estimated to be 0.3%. After mucous membrane 787

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HUMAN IMMUNODEFICIENCY VIRUS POSTEXPOSURE PROPHYLAXIS Approach (see Figure 1) Risk of transmission dependent on type of exposure Occupational exposure Baseline human immunodeficiency virus (HIV) test Expert consultation suggested Determination of need for postexposure prophylaxis (PEP) Assessment of type of exposure (see Tables 1 and 2) Determination of HIV status of source (see Tables 1 and 2) PEP recommendations: dual or triple therapy; dual therapy warranted for most exposures Often not needed If PEP used Begin as soon as possible (ASAP) (<72 hours) Dual regimens: AZT/3TC or d4T/3TC or d4T/ddI Triple regimens: indinavir, nelfinavir, or efavirenz added to dual regimen or trizivir (AZT/3TC/abacavir) used 4 Weeks of therapy Frequent monitoring of physical and mental health needed Nonoccupational exposure PEP controversial Need to balance exposure risk (see Table 3) against drug toxicity, concern for viral resistance, costs Reinforcement of risk reduction behavior

exposure the risk has been calculated to be 0.09%. The risk of seroconversion after nonintact skin exposure is thought to be less than that of mucous membrane exposure. The transmission risk after exposure to body fluids other than blood has not been quantified but is thought to be significantly lower than that after blood exposures. Exposure to larger quantities of blood increases the risk of transmission. This increased risk may occur as a result of deep percutaneous injury, injury from needles visibly contaminated with HIV-infected blood or needles withdrawn from an HIV source patient’s vein or artery. Exposure to a source patient who has late-stage acquired immunodeficiency syndrome (AIDS) also increases the risk of transmission, presumably from increased viral titers in the patient’s blood and/or the presence of the more aggressive syncytial-inducing strains of HIV. Conversely, a lower or undetectable viral load in the source patient’s transmitted fluid probably reduces the risk of exposure. However, there have been documented cases of perinatal transmission and of one health care worker’s seroconversion from a source patient with undetectable viral loads. As of February 2002, 57 confirmed cases of health care worker seroconversions that followed a documented occupational exposure had been reported to the Centers for Disease Control (CDC). Twenty-six have developed AIDS. Modes of exposure were as follows: percutaneous (48), mucocutaneous (5), both (2), and unknown (2). An additional 137 possible cases of HIV transmission that followed occupational exposure have been reported.

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2.1.1

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Human Immunodeficiency Virus Postexposure Prophylaxis

Data in support of the use of PEP are from one retrospective case control study, animal studies, and extrapolation from the prevention of perinatal transmission. In the retrospective case control study of health care workers exposed to HIV-infected blood or body fluids, the use of zidovudine (azidothymidine, AZT) as PEP reduced the risk of transmission by 81% (95% CI = 43%–94%). Protocol 076, a randomized controlled prospective trial, showed that AZT administered during pregnancy, labor, and delivery and to the newborn could reduce the risk of perinatal transmission by 67%. More recent studies using AZT and lamivudine (3TC) or short-course nevirapine have also found in decreased perinatal transmission. Animal studies using zidovudine or other agents resulted in either prevention of infection or delayed onset, peak, and duration of viral antigenemia as well as reduction in viral titers after viral inoculation. Such studies have also demonstrated the adverse effect of larger viral inocula and decrease in the efficacy of PEP caused by delay of onset, shortening of duration, and reduction of dosage. The rationale for HIV PEP also stems from an understanding of the pathogenesis of HIV infection. In a primate model of infection; systemic spread does not occur until 5 days post inoculation. Within the first 24 hours of infection, virus replicates in dendritelike cells. These cells then migrate to regional lymph nodes by 24–48 hours. Thus, there is a theoretical window of opportunity to prevent systemic infection by initiating PEP soon after exposure. The current recommendation for HIV PEP is combination therapy with two or three antiretroviral agents, depending on the exposure risk. Data supporting the use of combination therapy for HIV PEP are extrapolated from clinical trials of HIV-infected patients in which combination regimens have been shown to be more efficacious than monotherapy. At least 21 failures of HIV PEP have been reported. Failures have been associated with antiretroviral resistance in several cases. Other possible factors include high titer or large inoculum exposures, delay in initiation or short duration of PEP, and factors related to the hosts’ cellular immunity and/or the sources’ virus (e.g., syncytial producing strains). A review of calls to the San Francisco PEP hotline has revealed that in over 50% of cases, hotline recommendations were either not to use HIV PEP, to stop using PEP that had already been started, or to decrease the number of drugs being used. This review indicates that PEP is often overused. In addition, there have been at least two case reports of acute liver failure with the use of neviripine for PEP, one requiring liver transplantation. These reports are a reminder that the PEP regimens can be toxic and should be used with caution. New Centers for Disease Control and Prevention (CDC) guidelines emphasize that the two-drug regimen is appropriate for the majority of exposures in which PEP is indicated and the three-drug regimen should be reserved for the more rare, highest risk exposures. 2.1.2

Recommendations for Management

The U.S. Public Health Service has issued the following guidelines for the management of health care worker exposures to hepatitis B virus (HBV), HCV, and HIV and recommendations for postexposure prophylaxis (CDC 2001): A System Should Be in Place for the Timely and Efficient Management of Health Care Worker and Other Occupational Exposures. This should include a written protocol and provider training of the protocol, 24-hour/7-day-a-week availability of care through this protocol, and access to experts for consultation and guidance, timely availability of

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at least starter sets of medications for PEP, and supportive counseling for the exposed worker. Exposure Report. The date, time, type of exposure, and conditions that led to the exposure should be documented on an exposure report form, which is specifically developed for this purpose. The type of exposure may include puncture, laceration, abrasion, mucous membrane, nonintact skin contamination, or bite. Details about the implicated device, such as the type of needle (solid vs. hollow) and gauge suggest the volume of blood or body fluid involved in the exposure. The depth of instrument penetration also adds to risk determination. Documentation of barrier use such as gloves, eye protection, and masks may indicate deficiencies that should be addressed to prevent future exposures. Similarly, the circumstances of the exposure, including the time of day, staffing, number of consecutive hours worked by the exposed, and whether the procedure was an emergency, should be documented. Areas that require improved infection control efforts should be indicated. The management of the exposure should be documented on this form, including the evaluation of both the exposure source and the exposed individual as well as details about counseling, PEP management, and follow-up. Confidentiality of the employee’s health records, laboratory tests, and test results must be ensured. Treatment of Exposure Site. Wash wounds with soap and water. Mucous membranes should be flushed with water. Antiseptics may be used, but there are no data supporting their efficacy in this setting. Bleach or other caustic agents should not be used. Evaluation of Exposure Source. HIV testing should be performed if a documented positive test result is not available. A U.S. Food and Drug Administration– (FDA)-approved rapid HIV antibody kit is preferable, because it provides results in <10 minutes. Alternatively, enzyme-linked immunoassay (ELISA) results can be used if available within 24– 48 hours. Repeatedly reactive ELISA or rapid HIV-antibody test results are highly suggestive of infection, whereas negative results produced by these methods are adequate to support a decision to discontinue PEP. Confirmation with Western blot is not necessary. If the HIV status of the source is unknown, review HIV risks, including injection drug use, high-risk sexual exposures (heterosexual and homosexual), history of blood transfusion before 1985, or origination from a country endemic for HIV infection. Clinical symptoms suggestive of acute retroviral syndrome or immunodeficiency should be reviewed. If symptoms suggest the acute retroviral syndrome, obtain a HIV viral load test. Review the medical history of HIV infection, including CD4 count, HIV viral load, and antiretroviral treatment history and the results of genotype or phenotype viral resistance testing. Review the history of hepatitis B and C virus infections, including serological status. If none is documented, obtain hepatitis serological tests including, hepatitis B surface antigen (HBsAg) and antibody to HCV. If the exposure source is unknown, estimate the prevalence of HIV in the exposure setting. A needle-stick injury that occurred on an AIDS unit or in an area with a high prevalence of injecting drug users would be a higher-risk exposure. If the exposure source is not infected with HIV, HBV, or HCV, then baseline testing or further follow-up of the exposed individual is not necessary.

Postexposure Prophylaxis

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Evaluation of the Exposed Individual. Review of HIV status and HIV risks factors. Review of prior HIV test results and dates. Evaluation of baseline HIV serological status. Review of hepatitis history, including serological status and vaccination history with resultant hepatitis B surface antibody titer. Evaluation of baseline hepatitis B and C virus serological status, if not documented. Review of the medical history, including underlying medical conditions such as renal or hepatic disease, immunosuppression, medications, pregnancy, and breastfeeding status. Evaluation of baseline pregnancy test, if history indicates, and testing for complete blood count, electrolytes, glucose level, and renal and liver function if HIV PEP is to be administered. Assessment of Human Immunodeficiency Virus Infection Risk and Determination of Human Immunodeficiency Virus Postexposure Prophylaxis. The risk of infection is determined by assessing (1) the type of injury or exposure and (2) the HIV status of the source. Less severe percutaneous exposures are those caused by a solid needle or resulting in a superficial injury. More severe exposures may involve a large-bore needle, deep puncture, visible blood on the device, or needle use in a patient’s artery or vein. A lowerrisk source (denoted class 1) is one with asymptomatic HIV infection or known low viral load (<1500 copies/mL). A higher-risk source (denoted class 2) may have symptomatic HIV infection, AIDS, acute seroconversion, or a known high viral load. A two-tiered recommendation for PEP is used. Dual therapy is recommended for lower-risk exposures and triple therapy for higher-risk exposures. Most HIV exposures warrant dual therapy (see Tables 1 and 2). Human Immunodeficiency Virus Postexposure Prophylaxis Regimens. Recommended dual regimens include zidovudine (AZT)/lamivudine (3TC), stavudine (d4T)/3TC, or d4T/didanosine (ddI). AZT/3TC might be considered first-line, since it is conveniently administered as one pill twice a day and it has the longest history of use in this setting. The other dual regimens should be considered if resistance to these antiretroviral agents is a possibility or if side effects or potential side effects are deemed intolerable. Triple therapy consists of a dual regimen with the addition of indinavir, nelfinavir, or efavirenz. Another expanded, triple-therapy option is the addition of abacavir to AZT/ 3TC (trizivir). Other antiretroviral agents may be considered for use in PEP regimens on the basis of the source’s treatment history and viral resistance testing results. PEP should not be delayed, however, pending this information. It can be initiated and later modified, if indicated. Neviripine is not recommended for HIV PEP because of reports of severe hepatotoxicity associated with its use. Consultation with an expert is advised. The exposed individual should be advised of the rationale behind PEP and its risks and benefits. The patient’s informed consent should be obtained. Timing of PEP initiation: Therapy should be commenced as soon as possible, ideally within 1–2 hours of the exposure. Animal studies suggest no benefit from PEP when commenced 24–36 hours after exposure, but the interval after which there is no benefit from PEP for humans is not defined. Therefore, if unavoidable, PEP should be considered even after this time frame if the exposure warrants it.

d

Recommend expanded threedrug PEP

Recommend basic two-drug PEP

HIV-positive class 1a

Recommend expanded three-drug PEP

Recommend expanded three-drug PEP

HIV-positive class 2a

Generally, no PEP warranted; basic two-drug PEPe considered for source with HIV risk factorsf

Generally, no PEP warranted; basic two-drug PEPe considered for source with HIV risk factorsf

Source of unknown HIV statusb

Generally, no PEP warranted; basic two-drug PEPe considered in settings of likely exposure to HIV-infected persons Generally, no PEP warranted; basic two-drug PEPe considered in settings of likely exposure to HIV-infected persons

Unknown sourcec

No PEP warranted

No PEP warranted

HIV-negative

HIV-positive, class 1: asymptomatic HIV infection or known low viral load (e.g., <1500 RNA copies/mL); HIV-positive, class 2: symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load. If drug resistance is a concern, obtain expert consultation. Initiation of PEP should not be delayed pending expert consultation, and, because expert consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. PEP, postexposure prophylaxis; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; RNA, ribonucleic acid. b Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). c Unknown source (e.g., a needle from a sharps disposal container). d Less severe (e.g., solid needle and superficial injury). e The designation ‘‘consider PEP’’ indicates that PEP is optional and should be based on an individualized decision of the exposed person and the treating clinician. f If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued. g More severe (e.g., large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient’s artery or vein). Source: CDC 2001.

a

More severeg

Less severe

Exposure type

Infection status of source

Table 1 Recommended Human Immunodeficiency Virus Postexposure Prophylaxis for Percutaneous Injuries

792 Steinberg

Basic two-drug PEP recommended

Large volumei

Generally, no PEP warranted; basic two-drug PEPa considered for source with HIV risk factorsh Generally, no PEP warranted; basic two-drug PEPg considered for source with HIV risk factorsh

Source of unknown HIV statusc d

Generally, no PEP warranted; basic two-drug PEPg considered in settings of likely exposure to HIV-infected persons Generally, no PEP warranted; basic two-drug PEPg considered in settings of likely exposure to HIV-infected persons

Unknown source

No PEP warranted

No PEP warranted

HIV-negative

For skin exposures, follow-up is indicated only if there is evidence of compromised skin integrity (e.g., dermatitis, abrasion, or open wound). HIV, human immunodeficiency virus; PEP, postexposure prophylaxis; RNA, ribonucleic acid; AIDS, acquired immunodeficiency virus. b HIV-positive, class 1: asymptomatic HIV infection or known low viral load (e.g., <1500 RNA copies/mL); HIV-positive, class 2: symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load. If drug resistance is a concern, obtain expert consultation. Initiation of PEP should not be delayed pending expert consultation, and, because expert consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. c Source of unknown HIV status (e.g., deceased source person with no samples available for HIV testing). d Unknown source (e.g., splash from inappropriately disposed blood). e Small volume (i.e., a few drops). f The designation ‘‘consider PEP’’ indicates that PEP is optional and should be based on an individualized decision of the exposed person and the treating clinician. g If PEP is offered and taken and the source is later determined to be HIV-negative, PEP should be discontinued. h Large volume (i.e., major blood splash). Source: CDC 2001.

a

Basic two-drug PEP recommended

Basic two-drug PEPf considered

Small volumee

Expanded three-drug PEP recommended

HIV-positive class 2b

HIV-positive class 1b

Exposure type

Infection status of source

Table 2 Recommended Human Immunodeficiency Virus Postexposure Prophylaxis for Mucous Membrane and Nonintact Skin Exposures

Postexposure Prophylaxis 793

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Duration is 4 weeks. Dosage. –AZT: 200 mg PO tid or 300 mg bid. –3TC: 150 mg PO bid. –d4T: 40 mg PO bid (if body weight is <60 kg, 30 mg PO bid). –ddI: 400 mg once daily by Videx EC or buffered tablet (chewable or dispersable) (if body weight is <60 kg, 125 mg PO bid) on an empty stomach. –Indinavir: 800 mg (two 400-mg tablets) PO q8h 1 hour before meals or 2 hours after meals or with a low-fat snack and taken with 1.5 qt. of water per day. –Nelfinavir: 750 mg (three 250-mg tablets) PO q8h or 1250 mg (five 250-mg tablets) PO bid, taken with a meal or snack. –Efavirenz: 600 mg (three 200-mg tablets) PO qhs. –Abacavir: 300 mg PO bid. –Trizivir (combination AZT, 3TC, abacavir): one tablet PO bid. Side effects. –AZT: nausea, vomiting, headache, insomnia, myalgia, bone marrow suppression. –3TC: usually well tolerated, although rare instances of gastrointestinal intolerance and bone marrow suppression have been reported. –ddI: neuropathy, pancreatitis, hepatitis, and gastrointestinal (GI) upset. –d4T: neuropathy, hepatitis. Combination ddI/d4T may increase the risk of pancreatitis, neuropathy, lactic acidosis, and hepatitis. –Abacavir (component of trizivir, a triple-nucleoside combination): potential for severe hypersensitivity reaction, usually within the first 6 weeks: fever, rash, GI upset, respiratory symptoms. Fatal cases described, including on rechallenge. –Nucleoside class adverse effect: lactic acidosis and hepatic steatosis. –Indinavir: nephrolithiasis, nephrotoxicity, gastrointestinal intolerance, hepatitis, glucose intolerance/diabetes. –Nelfinavir: diarrhea, glucose intolerance/diabetes. –Efavirenz: rash (including Stevens-Johnson syndrome), nervous system side effects: dizziness, ‘‘disconnectedness,’’ somnolence, insomnia, and/or abnormal dreaming. Psychiatric symptoms, including depression, can occur. Teratogenicity. Counseling the Exposed Individual. Exposure to possible blood-borne pathogens is a stressful, anxiety-provoking event. The exposed individual needs counseling regarding the risks of the exposure and access to a provider who is an expert in the field to provide thoughtful answers. Psychological and/or psychiatric consultation and follow-up may also be necessary. The exposed individual must also be advised either to use condoms or to practice abstinence during the follow-up period, especially during the first 6–12 weeks after the exposure. In addition, women should be advised to prevent pregnancy and to consider discontinuing breast-feeding since HIV may be transmitted to infants through breast milk. Exposed individuals should not donate blood, plasma, organs, tissue, or semen during the follow-up period. However, if the exposed individual is a health care worker, his or her work responsibilities need no modification to prevent transmission to patients. Exposed individuals should also be advised of the signs and symptoms of the acute retroviral syndrome (see Chapter 25, Table 2) and to seek medical evaluation if these should occur. If the individual is taking PEP, he or she should be counseled on the dosage

Postexposure Prophylaxis

795

and administration of the medications as well as the importance of strict adherence to the regimen and completion of the 4-week course of therapy. With a health care provider, an individualized adherence plan should be developed to address the individuals’ specific barriers to adherence. Drug interactions and side effects as well as their management should also be reviewed. Monitoring and Follow-up. Reevaluation of the exposed individual is recommended at 72 hours post exposure. At this time, test results from the source and exposed individuals can be reviewed and a reassessment of PEP made. For example, if the source is found to be HIV-negative, PEP can be discontinued. All exposed individuals (with or without PEP) should receive follow-up counseling, medical evaluation, and postexposure testing. Follow-up HIV serological tests should be performed at 6 and 12 weeks and 6 months. There have been rare cases of documented seroconversion past 6 months. Individualized decisions should be made about the need for repeat testing at 12 months. There have been case reports of delayed seroconversion to HIV when HIV and hepatitis C virus were cotransmitted. Therefore, a 12-month follow-up HIV serological test should be performed if seroconversion to hepatitis C is documented. HIV viral load tests should not be used to detect infection because they have an unacceptably high false-positive rate (3%–5%). HIV viral load and antibody testing are indicated if the exposed individual has findings compatible with the acute retroviral syndrome (usually 2–6 weeks after exposure if seroconversion is to occur). The diagnosis of primary HIV infection is based on clinical findings, a high viral load, and a negative or indeterminate HIV serological test finding. For individuals treated with HIV PEP, ongoing adherence counseling and support are needed. Adherence monitoring should be done at least weekly and counseling frequency should be dependent on the exposed person’s psychological reaction to the event. Follow-up evaluations should be performed at 2 and 4 weeks. These evaluations should include a full medical assessment and review of symptoms for drug side effects or the acute retroviral syndrome. The laboratory evaluation should include a complete blood count, electrolytes, glucose level (if protease inhibitor is used), hepatic and renal function tests, and urinalysis (if indinavir is used). Side effects are the major reasons exposed individuals may not complete the 4-week course of therapy. These can be managed through the use of antiemetics, analgesics, and antidiarrheal agents. If the side effect occurs with each dose, these supportive medicines may be taken prophylactically with or just before the antiretroviral doses. Tolerance to AZT can be improved by reducing the dosage and administering it at more frequent intervals (100 mg q4h while awake). If a patient is unable to tolerate AZT, d4T may be substituted. Gastrointestinal side effects of indinavir can be reduced by taking the dose with a light, low-fat snack. If nephrolithiasis occurs, fluid intake should be increased or the third agent switched to nelfinavir, efavirenz, or abacavir (used with AZT/3TC). Special Situations. Pregnant women should be offered PEP as indicated. These women should also be advised of the risks of perinatal transmission of HIV and be apprised of what

796

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is known and not known about the risks of these medications to the fetus. The tolerability of the PEP medications during pregnancy should also be discussed. The exposed pregnant individual should then make an informed decision regarding PEP in consultation with her obstetrician. There are specific antiretroviral medications or combinations that should be avoided in pregnancy: efavirenz may be a teratogen and reports of fatal lactic acidosis in pregnant women have been associated with the use of the d4T/ddI combination. Indinavir, which may cause an indirect hyperbilirubinemia, should not be used close to delivery because of the risk to newborns. Transmission of resistant virus has been documented. The source patient’s antiretroviral history, most recent CD4 count, and particularly viral load tests should be considered. If the source has a detectable viral load with highly active antiretroviral therapy (HAART) administration, antiretroviral resistance must be presumed. If the source patient is currently not being treated with antiretrovirals, his or her prior treatment history should be considered. Resistance testing is not helpful at the time of the exposure since results of genotype or phenotype assays are not readily available. If resistance is suspected and PEP indicated, a PEP regimen should be devised in consultation with an expert. The regimen should include drugs from classes of antiretrovirals not previously used or drugs to which significant cross-resistance is not expected. Postexposure Registries and Resources. Health care workers who receive PEP should be enrolled in the confidential HIV PEP Registry: (888) PEP-4HIV. The National Clinicians’ Post-Exposure Prophylaxis Hotline (PEP-Line) can be accessed to obtain expert consultation on postexposure prophylaxis: (888) 448– 4911. To report occupationally acquired HIV infections and failures of PEP, call: (800) 893-0485. 2.2

Nonoccupational Exposure

Patients may request preventative therapy from their primary care provider after a highrisk exposure such as unprotected sex or needle sharing. With the advent of combination therapy that is effective in reducing the mortality rate, extrapolation from occupational exposure PEP, as well as data supporting the prevention of perinatal transmission, this form of prophylaxis has been under consideration and often prescribed. The United States Public Health Service (USPHS) has concluded that it ‘‘cannot definitively recommend for or against anti-retroviral agents in these situations because of the lack of efficacy data.’’ However, guidelines for the use of antiretroviral agents in these situations are provided by the USPHS. Prevention of HIV infection is best performed by practicing safe behavior. PEP for nonoccupational exposures should not supplant this behavior and should be reserved for accidental high-risk exposures among individuals who are otherwise practicing safe behavior. The decision to provide PEP for nonoccupational exposures should be based on the following considerations: (1) the transmission risk of the exposure (see Table 3), (2) the routine behavior of the exposed individual (is this a one-time accidental occurrence of a high-risk exposure?), and (3) the risks and costs of PEP (see Table 4).

Postexposure Prophylaxis

797

Table 3 Probability of Transmission from One Human Immunodeficiency Virus Exposure Type of exposure

Estimated risk

Intravenous needle or syringe exposure Percutaneous exposure (needlestick) Receptive anal intercourse Insertive anal intercourse Receptive vaginal intercourse Insertive vaginal intercourse Receptive oral exposure

0.67% 0.3%–0.4% 0.1%–0.3% 0.03% 0.1%–0.2% 0.03%–0.09% a

a

There are no published estimates of the risk of transmission from receptive oral exposure but instances of transmission have been reported. Source: CDC 1998b.

There has been much debate in the medical literature regarding the use of HIV PEP for nonoccupational exposures. Concern has been raised that there may be an increase in high-risk exposures as a result of reliance on the protective effects of HIV PEP. This has been countered by the lack of evidence that the availability of the ‘‘morning after pill’’ for emergency contraception has resulted in any behavior change. On the other hand, recent reports of a resurgence in high-risk homosexual activity in San Francisco and other areas are of concern. Ideally this can be counteracted by making it clear that the use of HIV PEP is only a small part of HIV prevention. Prevention primarily depends on abstinence or mutually monogamous relationships and nonuse of injection of drugs. Safe sex and needle use practices are encouraged. PEP is the last resort for certain high-risk exposures. Economic concerns have also been raised. Although HIV PEP for certain nonoccupational exposures has been determined to be cost-effective, especially if a two-drug regimen is used, the overall costs may be great, given the potentially large number of exposures. This could significantly impact community health resources. Also, the logistics of providing timely access to HIV PEP for nonoccupational exposures may prove costly. Finally, insurers may not cover this treatment. Patients need to be made aware that this may be an out-of-pocket expense. 2.2.1

Recommendations for Management

A Protocol Should Be Established. Health care providers should be trained in the prompt and efficient management of nonoccupational exposures to HIV by a protocol and follow for baseline testing and prompt administration of medications.

Table 4 Possible Risks and Costs of Postexposure Prophylaxis Drug toxicity Reduced effectiveness of behavioral human immunodeficiency virus (HIV) prevention measures Acquisition of antiretroviral-resistant HIV strains High costs of medications that may not be covered by insurers ($600–$1000) plus the costs of initial and follow-up visits and laboratory evaluations (about $600)

798

Steinberg

Evaluate the Exposure Source. The HIV status and the risk behavior of the source, as well as the hepatitis B and C viral status of that person, should be assessed (see the discussion of evaluation of the exposure source under section 2.1.2). Evaluate the Exposed. Evaluate the HIV status and risk behavior of the exposed individual, including the frequency of HIV exposure. Determine whether and when the patient was HIVtested. Review the medical history, including underlying medical conditions such as renal or hepatic disease, medications, pregnancy, and breast-feeding status. Review the hepatitis history, including serological status and vaccination history with resultant hepatitis B surface antibody titer. Obtain baseline HIV and hepatitis B and C virus serological tests if not documented. Obtain a baseline pregnancy test if the history indicates. Obtain complete blood count, chemical tests, glucose level, and renal and hepatic function tests if PEP is to be administered. Provide Medical Care to the Exposed. Medical care includes sexually transmitted disease (STD) screening. Women at risk for unintended pregnancies should be offered emergency contraception. Evaluate the Risk for Transmission. Determine the circumstances of the exposure and factors that may increase the risk of transmission, such as genital ulcers or tears or other active STDs. Determine When the Exposure Occurred. Animal studies suggest that postexposure antiretroviral therapy is most effective within 1–2 hours of exposure and probably not effective after 24–36 hours. However, there are no human studies that define the exact interval. The San Francisco Department of Public Health and University of California at San Francisco (UCSF) guidelines for nonoccupational PEP use an interval of ⱕ72 hours. Determine Whether Postexposure Prophylaxis Is indicated. Consider PEP if the following criteria are met: (1) high-risk exposure, i.e., unprotected sex or needle exposure; (2) source known to have HIV or at high risk for HIV infection; (3) exposed individual unlikely to be HIV-positive; (4) exposure that is an isolated event in a patient who otherwise practices safe sex or needle use behavior; (5) exposure that occurred ⱕ72 hours before presentation. The San Francisco Department of Health and University of California at San Francisco protocol specifies high-risk sexual exposures as unprotected receptive anal intercourse, receptive vaginal intercourse, insertive vaginal intercourse, insertive anal intercourse, and receptive fellatio with ejaculation. Provide Counseling and Informed Consent. PEP for nonoccupational exposure is considered an experimental therapy. Therefore, informed consent for it should be obtained (see the discussion of counseling the exposed individual under section 2.1.2). PEP Regimens. AZT/3TC (Combivir), d4T/3TC, or ddI/d4T: For dosage see the discusssion of determination of whether PEP is indicated under section 2.1.2.

Postexposure Prophylaxis

799

Add nelfinavir, indinavir, or efavirenz, or add abacavir to AZT/3TC (trizivir) for higher-risk exposure (source patient has high viral load or advanced HIV disease). For dosage see the discussion of indications for PEP. Adjust the regimen with consultation of an expert if source HIV is suspected of harboring antiretroviral resistance. Continue PEP for 4 weeks. Provide Risk Reduction Counseling. An accidental exposure can serve as an effective teaching moment. Risk reduction counseling should be provided to all patients and should focus on the patient’s specific behavior patterns and barriers to safe sex and/or needleusing practices. Counseling should emphasize skill building to overcome these barriers. Ongoing prevention counseling is more effective than a single session; thus patients should be referred to multisession programs, and risk reduction counseling should be included in the follow-up and monitoring schedule noted later. Substance abusers should be referred to treatment and/or needle exchange programs (if available). Provide Counseling. tion 2.1.2.

See the discussion of counseling and informed consent under sec-

Monitoring Follow-up. 3

See monitoring and follow-up under section 2.1.2.

HEPATITIS B VIRUS

Exposure to hepatitis B virus– (HBV)-infected blood is a significant occupational risk to health care workers. Before the use of HBV vaccine such exposures resulted in 12,000 health care worker infections per year. Two hundred fifty of these infected individuals died of either acute fulminant hepatitis or chronic liver disease/cancer. Since 1985, there has been a 90% decline in occupationally acquired HBV infection as a result of the use of both HBV vaccine and universal precautions. HBV is transmitted in the occupational setting through percutaneous exposure to infected blood or bloody body fluids. Transmission can also occur through contact of open skin or mucous membranes with infected blood or bloody body fluids. This may include dried blood on environmental surfaces, for HBV can survive in dried blood at room temperature for at least 1 week. The risk of transmission after a percutaneous exposure to HEPATITUS B AND C VIRUS POSTEXPOSURE PROPHYLAXIS Approach (see Figure 1) Hepatitus B virus (HBV) HBV vaccine protective; required for all health care workers to prevent infection Percutaneous exposure risk for nonimmune persons: 6%–30% Possible transmission via mucous membranes and open skin Occupational exposure postexposure prophylaxis (PEP) (see Table 5) Nonoccupational exposure If exposed person nonimmune, hepatitus B immune globulin (HBIG) and vaccine Hepatitis C virus No vaccine Immunoglobulin not effective

800

Steinberg

hepatitis B surface antigen– (HBsAg)-positive blood is 6%–30% with an overall risk of approximately 26%. If the source blood is hepatitis B e antigen– (HBeAg)-positive, the transmission risk can approach 60%. Note that these rates are significantly higher than the transmission risk of HIV. Semen and saliva may contain HBV, but at titers 1000–10,000 fold lower than in the blood. Mucosal exposure to saliva does not pose a significant risk, but HBV can be transmitted through bite wounds. Other body fluids, including breast milk, bile, cerebrospinal fluid, feces, nasopharyngeal washings, sweat, and synovial fluid, may contain HbsAg, but because they have low quantities of infectious HBV, they transmit the virus inefficiently. HBV deoxyribonucleic acid (DNA) is undetectable in urine. The rate of HBsAg seropositivity in the general population is 1–3/1000. Groups at high risk for HBV infection (5%–15% seropositivity rates) are immigrants from endemic areas (China, Southeast Asia, Sub-Saharan Africa, Pacific Islands, and Amazon Basin), institutionalized individuals, injection drug users, gay men, and household contacts of HBV carriers. The natural history of HBV infection ranges from asymptomatic infection to chronic hepatitis and cirrhosis (see Chapter 23). 3.1 3.1.1

Occupational Exposure to Hepatitis B Virus Preexposure Prophylaxis

Preexposure prophylaxis through vaccination against HBV infection has been an essential component of prevention of occupationally acquired disease. The HBV vaccination series is required for individuals regularly exposed to blood and other potentially infectious body fluids. Ninety percent of individuals who receive the three-dose series achieve protective immunity, the duration of which is at least 9 years. Vaccine nonresponse has been associated with immunosuppression, obesity, age >50, and smoking. Health care workers should have hepatitis B surface antibody (HBsAb) titers checked 1–2 months after completion of the vaccine series. Those with titers <10 mIU/mL should be revaccinated. After a subsequent three-dose series, 30%–50% of initial nonresponders achieve protective immunity. Although antibody titers wane over time, an amnestic response occurs. Routine booster doses are not recommended. The most frequent side effects of the vaccination series are fever and pain at the injection site. There have been 45 case reports of alopecia associated with hepatitis B vaccination, but an epidemiological study did not find a statistical association between the two in children. Case reports have also raised the concern of an association between multiple sclerosis and hepatitis B vaccination. However, this has not been substantiated in recent case control studies, and an expert panel concluded that available data do not support a link between hepatitis B vaccination and demyelinating diseases. 3.1.2

Postexposure Prophylaxis

Postexposure prophylaxis for HBV involves evaluation of both the source and the exposed individual to determine the risk of transmission, as is the case for exposure to other pathogens. A determination is made as to whether the source is HBsAg-positive, and for the exposed, the past medical and vaccination history, including documentation of response, is considered. HBV vaccine is administered after an exposure to an HBsAg-positive source if the exposed (1) has not been vaccinated, (2) had an unknown vaccine response, or (3) is a known vaccine nonresponder. For individuals with a known response to vaccine, PEP recommendations changed as of 1998; no treatment is indicated since an amnestic response occurs.

Postexposure Prophylaxis

801

Administration of hepatitis B immune globulin (HBIG) is another important strategy in HBV PEP. HBIG contains a high titer of antibody against HBsAg but provides only temporary protection against infection (i.e., 3–6 months). Although prepared from pooled plasma, HBIG poses no risk of HIV, hepatitis B, and hepatitis C transmission since the plasma is screened for antibodies to these pathogens and the process by which it is prepared destroys these and other viruses. The efficacy of HBIG is greatest within 3 days of the exposure; efficacy after 7 days is not known. HBIG and HBV vaccine are administered simultaneously but at separate sites and the vaccine administered in the deltoid for adults. Both hepatitis B vaccine and HBIG may be administered to pregnant or lactating women. Although there are no formal recommendations regarding HBV PEP for vaccinated immunosuppressed individuals, it would be reasonable to test the exposed for HBsAb. If there are inadequate antibody levels, HBIG and a booster dose of vaccine should be administered. 3.1.3

Management of Exposures

Wound Management and Documentation of Injury. See the discussions of the exposure report and treatment of the exposure site under section 2.1.2. Evaluate the Source. Evaluate risk factors for hepatitis B and hepatitis HBsAg (see the discussion of evaluation of the exposure source under section 2.1.2). Evaluate the Exposed. History of HBV infection or HBV vaccination and response should be documented (see the discussion of evaluation of exposed individuals under section 2.1.2). Postexposure Prophylaxis.

See Table 5.

Monitoring and Follow-up. Follow-up should occur at 48–72 hours to review the results of serological testing and refine management according to the protocol in Table 5. Ongoing support and counseling may be necessary and should be provided. For individuals who are vaccinated after exposure, HBsAb should be tested at 1–2 months after completion of the series. With appropriate prophylaxis, failure rates are negligible. Further monitoring of liver function tests and HBV serological tests is not recommended. Exposed individuals do not need to take any special precautions about household or sexual contacts or patient care. 3.2

Nonoccupational Exposures to Hepatitis B Virus

Sexual partners of HBsAg-positive individuals are at increased risk of infection. HBIG is 75% effective in preventing infection in these individuals. Although the maximal duration of interval after sexual exposure at which HBIG is still effective is not known, administering HBIG as soon as possible and within 14 days of exposure is recommended. The exposed individual should be tested for susceptibility to infection by checking for HBsAg, antibody to hepatitis B core antigen (HBcAb), and antibody to hepatitis B surface antigen. If results of all tests are negative, then the exposed individual is susceptible. A single dose of HBIG should be given along with the initiation of the vaccine series within 14 days of the last sexual contact or if sexual contact with the source will continue. Alternatively, if the exposed person is not in a high-risk group and the source has acute HBV infection, one dose of HBIG can be administered without vaccine. The source should be retested for HBsAg at 3 months. If the source is seronegative, the exposed person requires no

802

Steinberg

Table 5 Postexposure Prophylaxis for Hepatitis B Virus Infection Treatment of exposed when source is Exposed person is

HBsAg-positive

HBIG ⫻ 1 and HBV vaccine series Did not complete vaccine HBIG ⫻ 1 and complete series vaccine series as scheduled Unvaccinated

Previously vaccinated: Known responderb Known nonresponderc

Response unknown

a

HBsAg-negative

Unknown or not tested

HBV vaccine HBV vaccine series series Complete vaccine Complete vaccine series; if series as schedhigh-risk source, consider uled treatment as if HBsAg-positive source

No treatment No treatment No treatment HBIG ⫻ 1 and revaccination or if nonresponse after previously completing a second three-dose vaccine series, HBIG ⫻ 2 one month apart No treatment Exposed person tested for HBsAb If adequate, no treatment If inadequate, HBIG ⫻ 1 and vaccine booster

No treatment If known high-risk source, treatment as HBsAg-positive source

Exposed person tested for HBsAb If adequate, no treatment If inadequate, vaccine booster and titer checked in 1–2 months If high-risk source, administration of HBIG (treatment as if HBsAg-positive) source

a

HBIG dose 0.06 mg/kg IM. HBsAg, hepatitus B surface antigen; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HBsAb, hepatitis B surface antibody. b Adequate response or responder: HBsAb titer ⱖ10 mIU/mL. c Inadequate response or nonresponder: HBsAb titer <10 mIU/mL. Source: Adapted from CDC 2001.

further treatment. If the source is seropositive, a second dose of HBIG should be administered and the HBV vaccine series initiated in the exposed individual. Household contacts do not require prophylaxis unless there is an identifiable blood exposure to an HBsAg-positive source. If there is such an exposure, prophylaxis should be administered as described for sexual exposure. If the source patient is or becomes chronically infected with HBV, all household contacts should be vaccinated. 4

EXPOSURES TO HEPATITIS C VIRUS

Hepatitis C virus (HCV) is a blood-borne pathogen that causes chronic infection in the majority of hosts. Among infected individuals, chronic liver disease occurs in 60%–70%, cirrhosis in 10%–20%, and hepatocellular carcinoma in 1%–5%. The prevalence of HCV infection in the general population is 1%–2 %, 10 times higher than that of HBV infection. Transmission occurs primarily through blood exposure. Sexual transmission occurs, albeit in a less efficient manner. In addition, HCV may be transmitted perinatally at a rate of 5%–6%. Populations at high risk for HCV infection include hemophiliacs, injection drug

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users, long-term hemodialysis patients, persons with multiple sex partners and histories of STDs, and persons who received a blood transfusion before 1990. The risk of seroconversion after occupationally associated percutaneous exposure to HCV-positive blood is 1.8% (range 0%–7%). However, the transmission rate may be as high as 10% according to one study that used HCV polymerase chain reaction (PCR) to detect infection. Transmission after mucous membrane exposure occurs rarely, and there have been no reports of transmission after blood exposures on intact or nonintact skin. Transmission after blood splashes to the conjunctiva has been described. Also reported is transmission of HCV after human bites. HCV has not been detected in urine, feces, saliva, vaginal secretions, or semen of patients with chronic HCV. 4.1 4.1.1

Management After Percutaneous Exposures Wound Care and Documentation of Episode

See the discussions of the exposure report and treatment of the exposure site (under section 2.1.2). 4.1.2

Evaluation of the Source Patient

Risk factors for HCV and HCV antibody test results (enzyme immunoassay [EIA]) should be assessed. Confirmation of positive EIA test results should be obtained by using a supplemental assay, such as the recombinant immunoblot assay (RIBA). Direct virus assays for hepatitis C ribonucleic acid (RNA) should not be used (see the discussion of evaluation of the exposure source under section 2.1.2). 4.1.3

Evaluation of the Exposed Patient

HCV antibody testing and baseline liver function tests should be performed. (see the discussion of evaluation of exposed individuals under section 2.1.2). 4.1.4

Postexposure Prophylaxis

There is currently no approved prophylactic treatment after exposure to HCV. Immunoglobulin (IgG) is not effective and therefore not indicated. There are no data on the use of interferon or other antiviral agents as PEP. However, there are a few uncontrolled trials on the use of interferon and ribavirin or interferon and lamivudine as preemptive treatment after acute infection. Such treatment is not generally recommended at this time. 4.1.5

Monitoring and Follow-up

Recheck anti-HCV and liver function test results at 4–6 months. Confirm a positive test result (seroconversion) with a supplemental test for HCV, such as RIBA. If an earlier diagnosis is desired, testing for HCV RNA can be performed at 4–6 weeks. If infection occurs, antibody can be detected within 15 weeks of exposure in 80% and by 6 months after exposure in 97%. Individuals exposed to HCV need not change their sexual behavior during the monitoring period, and modifications to patient care activities (if the exposed is a health care worker) are not necessary. If HCV infection is identified during the followup period, the exposed individual should be referred to a hepatic or infectious disease specialist. 4.2

Management After Sexual Exposures

The risk of transmission after sexual exposure is low, lower than that of percutaneous exposure. The average prevalence of HCV infection among sex partners of patients with

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chronic infection is 1.5%, similar to the prevalence rate in the general population. This and the fact that there is no postexposure prophylaxis for HCV make monitoring and follow-up the mainstay of management. 5

SUMMARY

Exposures to potentially infectious blood or body fluids may place the exposed individual at risk for infection with HIV, HBV, and HCV. Figure 1 provides a flow diagram for the management of exposures, addressing all three pathogens.

Figure 1 Management of occupational exposure to blood or body fluid. HIV, human immunodeficiency virus; RNA, ribonuleic acid; PEP, postexposure prophylaxis; CBC, complete blood count.

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There are several key messages in the management of exposures to blood-borne viruses. First, it is essential that an exposure protocol be established, staff educated about this protocol, and the protocol followed when an exposure episode occurs. The protocol guides the health care provider to an assessment of infection risk, and the choice of postexposure prophylaxis follows accordingly. Second, timely access to care, which includes not only medical management but also psychosocial counseling, is critical. Also important is a plan and visit schedule for ongoing support, monitoring, and follow-up testing. In the case of HIV PEP, this must include counseling and monitoring about adherence to the PEP regimen and management of side effects. It is important to remember that HIV PEP can be associated with significant side effects (which in some cases have been fatal), and, therefore, overtreatment should be avoided. Finally, advice of an expert should be sought, especially for complicated HIV PEP cases. The National Clinicians’ Post-Exposure Prophylaxis Hotline (PEP-Line) can serve as an excellent resource for expert guidance.

BIBLIOGRAPHY Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med 337:1485–1490, 1997. CDC. Hepatitis B Virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 40(no. RR-13):1–19, 1991. CDC. Case-control study of HIV seroconversion in health-care workers after percutaneous exposure to HIV-infected blood- France, United Kingdom and United States, January 1988–August 1994. MMWR Morb Mortal Wkly Rep 44:929–933, 1995. CDC. Guideline for infection control in health care personnel, 1998. Am J Infect Control 26:289– 354, 1998a. CDC. Management of possible sexual, injecting drug-use, or other non-occupational exposure to HIV, including considerations related to antiretroviral therapy Public Health Service statement. MMWR Morb Mortal Wkly Rep 47(no. RR-17):1–14, 1998b. CDC. Public Health Service guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep 47(no. RR-7), 1998c. CDC. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep 50(no. RR-11), 2001. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 331:1173–1180, 1994. Gerberding JL. Management of occupational exposures to blood-borne viruses. N Engl J Med 332: 444–451, 1995. Gerberding JL, Henderson DK. Management of occupational exposures to bloodborne pathogens: Hepatitis B virus, hepatitis C virus and human immunodeficiency virus. Clin Infect Dis 14: 1179–1185, 1992. Henderson, DK. Postexposure chemoprophylaxis for occupational exposures to the human immunodeficiency virus. JAMA 289(10):931–936, 1999. Katz MH, Gerberding JL. Postexposure treatment of people exposed to the human immunodeficiency virus through sexual contact or injection-drug use. N Engl J Med 336:1097–1099, 1997. Katz MH, Gerberding JL. The care of persons with recent sexual exposure to HIV. Ann Intern Med 128:306–312, 1998.

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Lurie P, Miller S, Hecht F, Chesney M, Lo Bernard. Postexposure prophylaxis after nonoccupational HIV exposure: Clinical, ethical and policy considerations. JAMA 280(20):1769–1773, 1998. Moran, GJ. Emergency department management of blood and body fluid exposures (state of the art). Ann Emerg Med 35(1):47–62, 2000. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 47(no. RR-19):1–39, 1998.

43 Adult Immunization W. Kemper Alston University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

This chapter summarizes adult vaccination. The administration of a product, either natural or synthetic, for the purpose of stimulating immunity to infection has been one of the milestones of medical progress. Such immunity may be active or passive and may in some cases be effective before or after exposure to the infectious agent. Although the development of antibiotics followed by their inevitable overuse, commercialization, and emergence of resistance has dominated both the public and professional perspective on adult infectious diseases, vaccination and sanitation have had the greatest impact on our health. Only the smallpox vaccine has successfully eradicated an infectious disease; however, several other infections have come under control in many parts of the world largely as a result of vaccination. As we confront multidrug-resistant malaria, tuberculosis, and human immunodeficiency virus (HIV) as well as the threat of bioterrorism, the practice of vaccination will undoubtedly remain a key to improving human health. An overview of vaccination is followed by a practical review of selected agents and special hosts. There are licensed vaccines for 25 infectious diseases and immune globulins for several others. Primarily pediatric vaccines (diphtheria, Haemophilus influenzae, rotavirus, and pertussis) and uncommonly used vaccines (anthrax, cholera, plague, and bacille Calmette Gue´rin [BCG]) are not covered. Although usually administered to children, measles, mumps, and rubella (MMR) and polio vaccines are discussed, since they are occasionally indicated for adults.

2

BRIEF HISTORY

Although Edward Jenner is considered the father of vaccination in the Western world, attempts at variolation in China and India date at least to the 16th century. Jenner was the first who systematically inoculated humans with cowpox as a means of preventing smallpox. The term vaccination is derived from the Latin vacca, meaning ‘‘cow.’’ During the late 19th century, Louis Pasteur, Robert Koch, and many others achieved remarkable progress in vaccination and immunology. Rabies, cholera, anthrax, plague, and typhoid were targets of vaccine development 50 years before the antibiotic era began. The early 20th century witnessed the discovery of neutralizing antibodies against toxins (antitoxins) 807

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and the use of inactivated toxins (toxoids) that stimulate neutralizing antibodies for protection against illnesses such as diphtheria and tetanus. In 1950, a live vaccine for tuberculosis (bacille Calmette Gue´rin [BCG]) was licensed. The modern vaccine era began in the 1950s with the cultivation of viruses in cell culture, which made possible the development of polio and measles, mumps, and rubella (MMR) vaccines. Jonas Salk and colleagues developed an inactivated polio vaccine in the 1950s that led to a dramatic decline in paralytic polio worldwide. Bacterial vaccines using purified capsular polysaccharide (Neisseria meningitidis, Streptococcus pneumoniae, and H. influenzae) were developed during the 1970s and 1980s. Since the late 1980s conjugated polysaccharide vaccines (H. influenzae and S. pneumoniae) and recombinant vaccines (hepatitis B virus and Lyme disease) have been licensed. The future holds the promise of exciting new technologies that will make possible safe and effective vaccines against both emerging pathogens and old foes alike. 3

THE FUNDAMENTALS

Immunization may be described as active when an agent stimulates the host’s own cellular or humoral immune system to produce immunity, which is generally long-lasting. Active immunization may take the form of live (attenuated) or inactivated (killed) products. Inactivated vaccines may be whole cell or purified fractions (split), including protein, polysaccharide, or a combination (conjugate) of polysaccharide and protein. Viral or bacterial proteins or polysaccharides can also be made with recombinant technology for vaccine use (hepatitis B virus vaccine and Lyme vaccine). Inactivated vaccines are not as immunogenic as live attenuated vaccines and usually require multiple dosage to induce immunity and repeated dosage over time to maintain protection. Polysaccharide vaccines such as the pneumoccocal vaccine stimulate T-cell-independent immunity. These vaccines usually do not produce booster responses on repeated injections. Protein-derived vaccines produce Tcell-dependent immune responses that provide immunological memory and response to booster injections. Conjugate vaccines such as the Haemophilus influenzae type B and pneumococcal vaccines for children link a polysaccharide to a protein that enhances immunogenicity. Passive immunity occurs when a substance is simply transferred from another human or animal to provide short-term protection. Examples include transplacental maternal antibody, transfusion of blood products, and administration of pooled or hyperimmune globulins. The host’s immune response is complex and depends on both vaccine characteristics (specific antigen and dosage, route of administration, and use of adjuvants) and host factors (preexisting antibody, age, immune competence, nutrition, medical comorbidities, and genetics). Live vaccines, whether viral (measles, mumps, rubella) or bacterial (BCG, oral typhoid), replicate in the host and simulate natural infection. The benefits of this approach include a more durable response from a single dose. Potential pitfalls include their inherent instability, requiring careful storage, potential for vaccine-associated disease in immunocompromised hosts, revision of the vaccine strain to the wild type, and risk of interference from host antibody. Conversely, inactivated vaccines take many forms but share several characteristics. There is no replication or fear of infection, and there is no interference from antibody. However, multiple dosage is generally required to stimulate immunity, which may wane with time and require boosting. Adverse reactions to immunization include local, systemic, and allergic responses. Local reactions are quite common but fortunately are typically mild; they include discom-

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fort, swelling, and redness at the injection site. Systemic reactions are common with some vaccines (whole-cell pertussis); they include fever, fatigue, joint pain, and headache. Allergic reactions either to the antigen or to another ingredient in the vaccine preparation are rare but potentially severe. Adverse events that occur within 30 days of vaccine administration should be reported to the Vaccine Adverse Events Reporting System (VAERS, 800-822-7967). Recent controversy has focused on the mercury-based preservative thimerosal. Concern has been raised that repetitive dosage of thimerosal-preserved vaccines potentially exposes the individual to harmful levels of mercury. To date, there is no convincing evidence that thimerosol is harmful. Contraindications to vaccination include host factors that significantly increase the risk of an adverse reaction to a specific vaccine (e.g., an egg allergy and influenza vaccination). Contraindications may be permanent (severe allergy) or temporary (pregnancy). One obstacle to vaccination has been inappropriate concern about host factors that do not significantly increase risk. Examples of these invalid contraindications include a mild concurrent illness (upper respiratory infection), antibiotic use, household pregnancy, breastfeeding, unrelated allergies, or the need for multiple vaccines. Precautions include host factors that may increase the risk or decrease the response to vaccination, but for which the potential benefit may outweigh the risk. Temporary precautions may include moderate to severe concurrent illness or recent blood product administration that may interfere with the MMR or varicella vaccine (see Table 1).

4 4.1

ADULT VACCINES Pneumococcal Vaccine

Streptococcus pneumoniae remains a potent pathogen around the world. It kills more Americans each year than all other vaccine-preventable infections combined. Pneumococcal pneumonia, bacteremia, and meningitis are common in adults. The evolution of broad antibiotic resistance among pneumococci (drug-resistant Streptococcus pneumoniae [DRSP]) in recent years has refocused attention on vaccine strategies. The pneumococcal polysaccharide vaccine (PPV) consists of 23 different capsular polysaccharide types, accounting for the majority of invasive types. Two polysaccharide vaccines are available in the United States (Pneumovax 23 and Pnu-Imune 23). The vaccine should be administered as a 0.5-mL injection either intramuscularly or subcutaneously. Each dose contains 25 ␮g of each antigen with a preservative. The immunogenicity of the polysaccharide vaccine depends to a great extent on host factors. Those patients at greatest risk of invasive pneumococcal disease (hypogammaglobulinemia and asplenia) are the least likely to respond. Although the efficacy of this vaccine remains quite controversial, most agree that the benefit of vaccinating the elderly and those with high-risk medical conditions justifies the cost. The PPV is recommended for all adults who are 65 years and older as well as all adults who have chronic diseases (cardiopulmonary, hepatic, diabetes mellitus, alcoholism, or cerebrospinal fluid leaks) and immunocompromise (asplenia, hematological malignancies, human immunodeficiency virus [HIV] infection, organ transplantation, chemotherapy, or nephrotic syndrome). The pneumococcal vaccine should be administered 2 weeks before elective splenectomy. This vaccine has been underutilized in the elderly. Patients with unknown vaccine histories should receive the pneumococcal vaccine. Revaccination is not routinely recommended for healthy adults. Because antibody titers wane with time, a single repeat dose is recommended for high-risk patients. The

Two type A and one type B inactivated whole cell or disrupted influenza virus

Influenza

Tetanus

Inactivated toxin (toxoid)

Hepatitis A virus Whole inactivated virus

Hepatitis B virus Recombinant surface antigen expressed in yeast cells

23 Capsular polysaccharide types

Vaccine makeup

Pneumococcal

Vaccine

Table 1 Adult Vaccines a

$60.00 per dose

$4.70

IM

IM

IM

One dose at times 0, 4 wk and 4–6 mo

Initial dose followed by second dose after 6–12 mo Primary series with vaccination At 0, 4 wk and 6–12 mo Booster every 10 yr

$65.00 per dose

$5.00

IM

Yearly in fall

$18.80

IM or SQ

Repeat after 5 yr for high-risk persons c

Cost b

Adults ⱖ65 yr Chronic diseases c Immune-suppressed d Adults ⱖ50 yr Chronic illness c Immune-suppressed d Pregnant women in second or third trimester Resident of long-term care facilities HCW Household contacts of chronically ill HCW Multiple sex partners and persons with sexually transmitted diseases MSM IDU and prisoners Dialysis patients Close contact with chronic HBsAg carriers Residents of long-tern care facilities Travelers to developing countries MSM IDU Patients with chronic liver disease Primary series if not vaccinated during childhood All adults every 10 yr If last booster >5 yr, repeated for persons with dirty, contaminated wounds; burns; crush injuries

Route of administration

Frequency

Indications

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Inactivated virus grown in tis- Preexposure prophylaxis for veterinarisue culture ans, animal laboratory workers, high-risk travelers, spelunkers Postexposure prophylaxis (see Chapter 37, Figure 2 and Table 3) Recombinant OspA of spiro- Persons who live in high-risk areas chete such as the northeastern U.S. coast and Midwest Live attenuated virus Postexposure prophylaxis for those at risk All adults without history of chickenpox or antibody titer to varicella, especially HCW, nonpregnant women of childbearing age, and international travelers Inactivated polysaccharide, Adults during a meningococcal outtypes A, C, Y, and W-135 break Military recruits College students e High-risk travelers Persons with asplenia, complement deficiencies Live attenuated vaccine Adults born after 1957 who have not received one dose of vaccine or have no serological evidence of past infection HCW without serological evidence of past infection SQ

Two doses at least 1 mo apart

$40.00 per dose

$75.00

$60.00 per dose

SQ

SQ

$61.00 per dose

$90.00–$150.00 per dose, depending on manufacturer

IM

IM or ID

Booster every 3–5 yr as needed

Within 3 days of exposure two doses 4–8 wk apart

Vaccinations at days 0, 3, 7, 14, 28 Day 0, 1 mo, and 12 mo

Days 0, 7, and 21 or 28

HCW, health care worker; IDU, injection drug user; STD, sexually transmitted disease; MSM, men who have sex with men; OspA, outer surface protein A; MMR, measles, mumps, rubella; IM, intramuscular; SQ, subcutaneous; ID, intradermal; HBsAg, hepatitis B surface antigen. b Average wholesale price, 2000 Drug Topics, Redbook. c Persons who have chronic pulmonary, cardiac, or liver disease; alcoholism; diabetes mellitus; and cerebrospinal fluid leaks. d Immune-suppressed persons such as those with HIV, asplenia, organ transplantation, and nephrotic syndrome who are receiving chemotherapy. e Highest risk is among freshman students living in dormitories.

a

MMR

Meningococcal

Varicella

Lyme disease

Rabies

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second dose may be given 5 years or more after the initial vaccination. Contraindications include serious allergic reactions, pregnancy, and moderate or severe acute illness. Local adverse reactions are common, whereas systemic and allergic reactions are rare. The vaccine should be refrigerated (25⬚F–46⬚F). A new seven-valent polysaccharide conjugate vaccine (Prevnar) was approved in February 2000. It is currently recommended only for use in toddlers and children. 4.2

Influenza Vaccine

The influenza viruses A and B cause yearly epidemics (see Chapter 14). Type A can undergo antigenic shifts that have the potential to cause catastrophic pandemics as occurred in 1918. Influenza epidemics are a frequent cause of hospitalization and death among the elderly, typically complicated by pneumonia. Currently approved influenza vaccines in the United States consist of inactivated trivalent antigen. Each year the Food and Drug Administration and the World Health Organization choose which types to include. Typically two type A hemagglutinin antigens and one type B are included. Both whole (Fluzone) and split virus (Fluvirin) vaccines are produced. The vaccine should be administered as 0.5 mL intramuscularly. Each dose contains 15 ␮g of each antigen. A single dose should be administered each year, beginning in September. The influenza vaccine is unique in that the efficacy of vaccination each year depends not only on the usual host factors, but also on precisely which strains are circulating in the community and the degree to which they resemble the vaccine strains. The vaccine protects against influenza and reduces complications, fatalities, and hospitalizations related to influenza. Efficacy may range from 30% to 90%. Protection may be considered to last 1 year. The influenza vaccine is recommended for all adults 50 years and older, patients with chronic illnesses (cardiopulmonary disease, diabetes mellitus, renal failure, and immunocompromised state, including human immunodeficiency virus [HIV] infection), pregnant women in the second and third trimesters, and residents of long-term care facilities. In addition, vaccination should be encouraged for those living or working with high-risk persons such as health care workers and household members of those with chronic disease. Finally, students and foreign travelers may be considered for vaccination. Individuals with a history of significant reactions to previous influenza vaccination, egg allergy, or moderate to severe acute illness should not be vaccinated. Typical local reactions are common. Immediate allergic reactions are rare. The vaccine should be stored in the refrigerator and not frozen. 4.3

Hepatitis B Virus Vaccine

Hepatitis B virus (HBV) remains a common cause of acute and chronic viral hepatitis in the United States, with an estimated 1 million chronic carriers and several thousand deaths per year (see Chapters 23 and 42). Both acute and chronic infections follow sexual and blood-borne transmission, providing the vaccine with a unique role in the prevention of sexually transmitted disease, cirrhosis, and hepatocellular carcinoma. A recombinant hepatitis B surface antigen (HBsAg) vaccine has been available since 1986, replacing the plasma-derived vaccine. Currently two preparations (Recombivax HB and Engerix-B) are licensed in the United States. The purified antigen is expressed in yeast cells. One milliliter (1 mL) of vaccine (10–20 ␮g antigen) should be given intramuscularly in the deltoid muscle. The routine schedule for an adult includes three doses over 6 months

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(the second dose is given 4 weeks after the first, followed by the third dose in 4 to 6 months). Dialysis patients should receive a higher dosage, as outlined in the manufacturer’s instructions. As with most vaccines, the response rate declines with age. In 90% of healthy adults protective surface antibody develops after a complete series. Although antibody titers wane with time, there is an anamnestic response to subsequent exposure, and those individuals who initially respond to the vaccine are considered protected. Therefore, booster dosage is not routinely recommended. Adults at risk for HBV should be vaccinated. Individuals with multiple sexual partners including commercial sex workers, men who have sex with men, those with sexually transmitted diseases, intravenous drug users, prisoners and residents of institutions, health care workers, dialysis patients and those dependent on blood products, and close contacts of carriers should be offered the hepatitis B vaccine. Screening for evidence of previous HBV infection before vaccination may be costeffective for certain high-risk populations. Routine serological testing is not required after vaccination. Because knowledge of serological response is important for managing any subsequent blood-borne exposures, health care workers should have their surface antibody titer checked 1 to 2 months after the completion of vaccination. Responders may be considered protected against future HBV exposures, whereas nonresponders should be tested for active hepatitis B and then receive a second series (not a single booster). HBV immune globulin is available for exposed persons who have not been vaccinated or did not respond to vaccination. Contraindications to vaccination include a significant allergic reaction to a prior dose of vaccine and moderate to severe acute illness. Local reactions that consist primarily of pain are common after vaccination. The vaccine should be stored in the refrigerator. 4.4

Hepatitis A Virus Vaccine

Hepatitis A virus (HAV) is spread via the fecal-oral route around the world (see Chapter 23). Contaminated food and water and person-to-person transmission place susceptible persons at risk. It is difficult to determine precisely the number of acute HAV cases in the United States because of underreporting and asymptomatic cases. Approximately 30,000 cases are reported per year. HAV vaccines consist of whole-inactivated virus. There are currently two licensed vaccines in the United States (Havrix and VAQTA). One milliliter (1 mL) of vaccine should be administered intramuscularly in the deltoid. A second booster dose is indicated at 6 to 12 months. The response rate to a single dose is rapid (95% within 2 weeks) and complete (100% after second dose). The duration of protection remains to be determined. Those at risk for HAV or complications from acute hepatitis include all travelers to developing countries, men who have sex with men, intravenous drug users, patients dependent on blood products, persons working with primates, and patients with chronic liver disease. Screening for evidence of previous hepatitis A infection may be cost-effective for certain high-risk populations. Routine serological testing is not required after vaccination. A significant allergic reaction to a prior dose of vaccine or moderate to severe acute illness is a contraindication. Mild local reactions with pain and swelling are common. The vaccine should be stored in the refrigerator. 4.5

Tetanus Toxoid

Toxin-mediated disease caused by Clostridium tetani occurs worldwide as a result of contaminated wounds. The occurrence of tetanus continues to decline in the United States,

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as fewer than 50 cases are reported per year. Tetanus toxoid consists of inactivated toxin. Adult formulations include the tetanus toxoid alone or combined with diphtheria toxoid (Td). After primary vaccination during childhood, booster doses are recommended every 10 years. A primary series can be administered to adults as three doses of Td at 0 week, 4 weeks, and 6 to 12 months. Toxoid is administered intramuscularly. Antitoxin levels are protective after the primary series and then wane with time. A booster is recommended as part of routine management of contaminated wounds if 5 years has elapsed since the last dose. All adults who have received a primary series should receive a booster dose of toxoid every 10 years. A severe allergic reaction to a prior dose of toxoid and moderate to severe acute illness are contraindications. Local reactions are common with pain and swelling. More severe arthus-like reactions are less common. Rare neurological and systemic reactions have been attributed to tetanus toxoid. The vaccine should be stored in the refrigerator. 4.6

Rabies Vaccine

Although human rabies remains a significant public health problem in many areas of the world, only 22 human deaths due to rabies occurred in the United States between 1990 and 1996 (see Chapter 37). Animal rabies remains quite common in the United States, especially among raccoons, bats, and skunks, and therefore the risk of human exposure persists. There are three rabies vaccines approved for human use in the United States (Imovax, rabies vaccine adsorbed [RVA], and RabAvert). All three consist of inactivated virus grown in tissue culture. For individuals at risk of rabies exposure, preexposure prophylaxis consists of a series of three intramuscular or intradermal injections given on days 0, 7, and 21 or 28 (see the manufacturer’s instructions). Booster doses may be considered every 2 to 3 years. Postexposure treatment includes vaccine administration on days 0, 3, 7, 14, and 28 as well as rabies immune globulin. For those already vaccinated before an exposure, booster doses may be given on days 0 and 3. Wound care, vaccine, and rabies immune globulin must be provided as soon as possible after a susceptible individual is exposed to rabies. Treatment failures have been described when treatment has been incomplete or incorrectly administered. Candidates for preexposure prophylaxis with rabies vaccine include veterinarians, other animal or laboratory workers at risk, and high-risk travelers including spelunkers. Individuals bitten or exposed to the saliva of a potentially rabid animal should receive complete postexposure therapy. Domesticated animals may be observed for 10 days for evidence of illness. Bats, foxes, raccoons, and skunks should be regarded as potentially rabid unless the animal is available for laboratory testing. Detailed recommendations can be obtained form local public health officials (see Chapter 37, Figure 2 and Table 3). Since rabies is invariably fatal, there are no contraindications to postexposure treatment. Local reactions are common. Severe allergic and neuroparalytic reactions have been rarely reported. The vaccine should be stored in the refrigerator. 4.7

Lyme Disease Vaccine

Lyme disease is the most common tick-borne illness in the United States with over 12,000 reported cases per year (see Chapter 30). Although it is typically an uncomplicated infection, in some patients serious neurological, cardiac, and arthritic complications develop. The Lyme disease vaccine (LYMErix) was approved in December 1998. It consists of a recombinant outer surface lipoprotein (OspA) of the Lyme spirochete, Borrelia burgdorferi, with a unique mode of action. When a tick harboring the spirochete bites a human,

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it ingests blood with antibody into its midgut. The OspA antibodies neutralize the spirochete in the tick midgut before the organism enters the human host. The vaccine should be administered as 0.5 mL (30 ␮g) intramuscularly at 0, 1, and 12 months. The vaccine has provided 78% protection against definite Lyme disease after the third dose. Lyme vaccine should be considered for those persons aged 15 to 70 who live, work, or spend time in geographical areas of high or moderate risk and have frequent exposure to ticks. Those with a history of uncomplicated Lyme disease who remain at risk may also be considered for vaccination. The Lyme vaccine is contraindicated for those with a history of allergy to prior doses or a component of the vaccine. Local redness, soreness, and swelling as well as systemic symptoms such as arthralgias and fatigue were reported more often after vaccination than with placebo. The vaccine should be stored in the refrigerator. 4.8

Varicella Vaccine

Susceptible adults are at risk of significant complications from varicella. The varicella vaccine is indicated for adults without a history of chickenpox or a positive antibody titer finding. These indications especially apply to health care workers, school teachers, military and prison personnel, family contacts of high-risk persons, nonpregnant women of childbearing age, and international travelers. A live attenuated vaccine (Varivax) is administered as two subcutaneous doses 4 to 8 weeks apart. The varicella vaccine has been recommended for postexposure prophylaxis for nonimmune persons. It may be less successful in adults than in children since two doses are needed. The first dose should be given within 3 days of exposure. The varicella vaccine is contraindicated for immune-compromised persons and pregnant women. Pain at the injection site and fever can occasionally occur. The vaccine should be stored in the refrigerator. 4.9

Meningococcal Vaccine

There are as many as 3000 cases of invasive meningococcal disease per year in the United States with a mortality rate of 10%–15%. There are 13 serotypes of Neisseria meningiditis; types B and C predominate the United States and Europe, whereas A and C are most common in Asia and Africa. A quadrivalent polysaccharide vaccine is available for N. meningitidis types A, C, Y, and W-135 (Menomune-A/C/Y/W-135). The vaccine may protect against secondary transmission during outbreaks, but these cases account for only 5% of infections in the United States. The vaccine does not provide protection against serotype B, which accounts for approximately 30% of cases in the United States. The meningococcal vaccine is administered as a single 0.5-mL subcutaneous dose. It may be indicated for adults during an outbreak and for those with terminal complement deficiencies, asplenia, or occupational exposure and for military recruits and high-risk travelers. College students, especially freshmen living in dormitories and household contacts of cases, may be considered for vaccination. The vaccine is generally well tolerated. Adverse reactions include pain and erythema at the injection site in more than 40% of recipients. The vaccine should be stored in the refrigerator. 4.10

Measles, Mumps, and Rubella Vaccines

For the purposes of vaccination, there is only one type of measles virus. A live attenuated vaccine was licensed in 1963. Susceptible adults, including pregnant women, are at in-

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creased risk for complications. Adults who received the inactivated vaccine between 1963 and 1967 are at risk for atypical measles with fever, rash, and pneumonia. In 1998 there were 100 reported cases of measles in the United States, 32% in adults. The current live attenuated measles vaccine may be administered alone, with rubella vaccine, or with rubella and mumps (MMR). Measles vaccine is indicated for all susceptible adults, including those born in 1957 or later, unless they have documented evidence of at least one dose of vaccine, a history of physician-diagnosed measles, or a positive serological test. In general, those born before 1957 are considered immune. Health care workers, college students, and international travelers are considered to be at high risk. These individuals should have documentation of two doses of live measles vaccine no earlier than the first birthday unless there is evidence of immunity, as described. The number of cases of mumps each year in the United States fell through the 1990s. At least 80% of adults are considered immune. The mumps vaccine is also a live attenuated virus. Similarly to immunity to measles, adults may be considered immune to mumps if they were born before 1957, have had a physician-diagnosed case, a positive serological test, or at least one dose of MMR. Rubella is notable for its complications, which occur more commonly in adults than in children. Arthritis, encephalitis, thrombocytopenia, and the congenital rubella syndrome (CRS) are important complications associated with rubella in adults. Rubella infection of pregnant women during the first trimester may have calamitous consequences. A complete discussion of CRS is beyond the scope of this chapter. The rubella vaccine is a live attenuated virus. The vaccine is typically administered as MMR. Those adults who have had at least one dose of MMR, were born before 1957 (unless still of childbearing age or a health care worker), or have a positive serological result are considered immune. The most common adverse reaction after MMR is fever. There is no increased risk of adverse reactions in those already immune. Rash, thrombocytopenia, lymphadenopathy, or arthralgia may occur. Contraindications include a severe allergic reaction to a prior dose, pregnancy (which should be prevented for 3 months after vaccination), immunosuppression (including HIV infection with severe immunosuppression or AIDS), moderate to severe acute illness, recent receipt of a blood product (especially immune globulin), and thrombocytopenia. MMR is not contraindicated for those allergic to eggs or penicillin. Of note, measles vaccine may inhibit the response to skin testing for tuberculosis (purified protein derivative [PPD]), and such testing should be done before vaccination or delayed for 6 weeks. The MMR vaccine is administered subcutaneously. It must be refrigerated.

5

INTERNATIONAL TRAVEL

Specific, up-to-date recommendations for travelers may be obtained from the Centers for Disease Control and Prevention (CDC) (see the Bibliography; also see Chapter 40). 5.1

Japanese Encephalitis Vaccine

Mosquitoes throughout Asia transmit Japanese encephalitis (JE). The JE vaccine (JE-VAX) is a purified inactivated viral vaccine. It is administered subcutaneously on days 0, 7, and 30. Local and mild systemic side effects are quite common. More significant events such as angioedema and urticaria have been reported. The vaccine is recommended for those spending a month or more in countries with endemic or epidemic JE. Those traveling to rural areas during transmission seasons are at greatest risk.

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VACCINES FOR SPECIAL HOSTS International travel vaccines (see Chapter 40) Hepatitis A virus Japanese encephalitis virus Yellow fever Meningococcal Polio Varicella (if not immune) Health care worker Hepatitis B virus Influenza Measles mumps rubella (MMR) (if not immune) Varicella (if not immune) Immune-compromised host Live vaccines avoided Pregnancy (see Chapter 33) No vaccines though inactivated vaccines considered safe Deferral of live vaccines Should be immune to tetanus Influenza during second or third trimester

5.2

Meningococcal Vaccine

The meningococcal vaccine should be given to those traveling to (1) sub-Sahara Africa during the dry season (December–June); (2) Mecca, Saudi Aradia, during the annual hadj; and (3) any country with epidemic disease due to types A, C, Y, and W-135 (see Sec. 4.9). Antibody titers decline after 2–3 years. Those travelers with repeated trips to highrisk areas should be revaccinated every 3–5 years. 5.3

Typhoid Fever Vaccine

There are three products approved for use in travelers: an oral live attenuated vaccine (Vivotif Berna), an intramuscular polysaccharide vaccine (Typhim Vi), and a subcutaneous killed vaccine (Typhoid Vaccine [AKD]). Although not required for international travel, these vaccines may provide substantial protection (approximately 75%) against typhoid fever. Travelers to developing countries, especially those who plan to stay more than 3 weeks or visit rural areas, should consider vaccination. In general, the newer oral vaccine and injectable polysaccharide (Typhim Vi) have a lower incidence of side effects than the heat killed preparation. Pros and cons exist for a series of four oral doses versus a single intramuscular dose in terms of tolerability and compliance. Protection may wane after a few years. Vaccination is not a substitute for appropriate precautions with regard to food and water. 5.4

Yellow Fever Vaccine

Yellow fever is transmitted by mosquitoes in sub-Saharan Africa and South America. A live attenuated viral vaccine can be administered as a single subcutaneous dose. The vaccine is 95% effective and provides durable protection. The yellow fever vaccine may

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be required for entering certain countries, especially when travelers arrive from endemic areas. Certificates are provided by designated providers and public health departments and are valid for 10 years. Physicians should carefully review any country-specific yellow fever vaccine requirements (which are available from the CDC). 5.5

Polio Vaccine

Paralytic poliomyelitis is caused by the poliovirus. It has been eradicated from the United States, although cases continue to occur in underdeveloped countries. There are two vaccine preparations: oral polio vaccine (OPV) and inactivated polio vaccine (IPV). The OPV form has been associated with rare cases of paralytic polio; therefore, the IPV formulation is preferred for adults. Previously unvaccinated adults traveling to polio-endemic countries should receive two doses of IPV 4–8 weeks apart and a third dose after 6–12 months. Those with previous IPV or OPV vaccination during childhood traveling to polio-endemic areas should receive a single booster of either the OPV or IPV. 6

HEALTH CARE WORKERS

Vaccination is of particular importance to health care providers, to protect both themselves and their patients. Administrative programs must ensure that all health care workers are appropriately screened and vaccinated. 6.1

Hepatitis B Virus Vaccine

Health care workers remain at high risk of hepatitis B virus through blood-borne exposure. The Occupational Safety and Health Administration (OSHA) mandates that employers provide preexposure hepatitis B vaccine to all of their employees who are at risk. Guidelines exist for managing exposed health care workers on the basis of their vaccine history (see Chapter 42). 6.2

Influenza Vaccine

Annual influenza vaccination is recommended for all health care workers with patient contact. 6.3

Measles Vaccine

Health care workers should be considered for vaccination if they have not had two documented doses of vaccine, physician-diagnosed measles, or serological evidence of immunity (see Sec. 4.10). Most individuals born before 1957 are immune. 6.4

Mumps Vaccine

Immunity to mumps can be assumed for those who have been vaccinated, had a physician diagnosis, or have a positive antibody titer finding and for persons born before 1957 (see Sec. 4.10). 6.5

Rubella Vaccine

Health care workers who do not have a positive antibody titer or history of vaccination should be immunized (see Sec. 4.10).

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Varicella Vaccine

Susceptible adults are at risk of significant complications from varicella (see Sec. 4.8). They may play an important role in nosocomial transmission. The varicella vaccine is indicated for health care workers with no history of chickenpox or a positive antibody titer result. 7

IMMUNOCOMPROMISED HOSTS

In general, live vaccines may be hazardous to patients who have significant immune suppression, whether congenital, acquired, or iatrogenic. Malignancy (especially hematological or metastatic), systemic steroids, HIV infection, chemotherapy, and radiation therapy are examples. The oral polio; measles, mumps, rubella; smallpox; varicella; BCG; and yellow fever vaccines are all live. Compromised hosts may not respond adequately to vaccination, and consideration may be given to deferring immunization in cases of temporary or reversible immunosuppression. 8

PREGNANCY

In general, vaccination during pregnancy should be avoided. However, the risks of maternal vaccination to the fetus are hypothetical. No vaccines, whether live or inactivated, are known to cause birth defects. Inactivated vaccines are considered safe during pregnancy. Pregnant women should certainly be immune to tetanus and can receive the annual influenza vaccine during the second or third trimester. As a matter of caution, live vaccines are withheld until after pregnancy. BIBLIOGRAPHY CDC. Immunization of healthcare workers. MMWR Morb Mortal Wkly Rep 46(RR-18):1–42, 1997. CDC. Human rabies prevention—United States, 1999: Recommendation of the ACIP. MMWR Morb Mortal Wkly Rep 48(RR-1):1–21, 1999. CDC. Prevention of hepatitis A through active or passive immunization: Recommendation of the ACIP. MMWR Morb Mortal Wkly Rep 48(RR-12):1–37, 1999. CDC. Prevention of varicella: Updated recommendation of the ACIP. MMWR Morb Mortal Wkly Rep 48(RR-6):1–5, 1999. CDC. Recommendation for the use of Lyme disease vaccine: Recommendation of the ACIP. MMWR Morbid Mortal Wkly Rep 48(RR-7):1–17, 1999. CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. 6th ed. Department of Health and Human Services, 2000. CDC. Prevention and control of influenza: Recommendation of the ACIP. MMWR Morb Mortal Wkly Rep 49(RR-3):1–38, 2000. CDC. Available at: www.cdc.gov CDC. Travel. Available at: www.cdc.gov/travel/ Gardner P, Eickhoff T, Poland GA, Gross P, Griffin M, LaForce FM, Schaffner W, Strikas R. Adult immunizations. Ann Intern Med 124:35–40, 1996. Lemon SM, Thomas DL. Vaccines to prevent viral hepatitis. N Engl J Med 336:196–204, 1997. Morbidity and Mortality World Report. Advisory Committee on Immunization Practices (ACIP) Statements. Available at: www.cdc.gov/mmwr/ National Immunization Program. Available at: www.cdc.gov/nip/ Orenstein WA, Wharton M, Bart KJ, Hinman AR. Immunization. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 5th ed. Philadelphia: Churchill Livingstone, 2000, 3207–3234. Plotkin SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia: WB Saunders, Co 1999. 2000 Drug Topics Red Book. Montvale, NJ: Medical Economics, 2000.

44 Bioterrorism Christopher J. Grace University of Vermont, Burlington, Vermont, U.S.A.

1

INTRODUCTION

Bioterrorism in the United States is no longer a theoretical concern. The anthrax attacks in the fall of 2001 have shaken our sense of national security and have made it terrifyingly clear that we as a nation, and as individuals, are at risk for being injured or killed by the deliberate release of pathogenic microorganisms. The potential for mass casualties caused by many of these biological agents eclipses that of conventional and some nuclear weapons. Many experts in the field feel it is not so much a matter of whether a larger biological attack will occur or not, as of when and where. The agents most likely to be used as biological weapons produce illnesses that have not been commonly seen in the United States in the past 40 or more years. Therefore, educating primary care providers to recognize these rare and at times difficult to diagnose illnesses is paramount. This requires a philosophical shift to thinking of ‘‘horses and zebras’’ when we hear hoofbeats. Most of these agents begin as nonspecific illness that may be confused with common infections seen on a daily basis. Recognition of a biological attack will depend on identification of unusual pathogens or large numbers of patients who present similar and often life-threatening infections. This chapter reviews the background of the current concerns of bioterrorism, the pathogens most likely to be used in an attack, and safety issues for health care workers. Internet resources to help the clinician stay current are listed in Table 1. 1.1

Definition and History

Bioterrorism is defined as the intentional use of microorganisms or biological toxins to kill or incapacitate people, animals, or crops. The intent is not only to cause large numbers of illnesses and deaths but also to spread terror and panic throughout the population. Combating an invisible, difficult to detect weapon that may be contagious has potential to paralyze and incapacitate governmental and societal functioning. Biological weapons are comparatively inexpensive to produce and easy to conceal, transport, and deploy compared to toxins and nuclear weapons. They are most effectively delivered in aerosol form. They can also be used to contaminate food and water supplies. With an incubation period of days to weeks from deployment of the agent until the onset of illness, the terrorist has adequate time to evade law enforcement. 821

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Table 1 Web-Based Bioterrorism Resources a Source U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland CDC Public Health Emergency Preparedness & Response

CDC National Center for Infectious Diseases Johns Hopkins Center for Civilian Bio-Defense Studies

Website www.usamriid.army.mil/

www.bt.cdc.gov

www.cdc.gov/ncidod/dbmd/diseaseinfo www.hopkins-biodefense.org

Infectious Diseases Society of America

www.idsociety.org

Journal of American Medical Association

jama.ama-assn.org

American College of Physicians

www.acponline.org/bioterro

Association for Professionals in Infection Control and Epidemiology

www.apic.org/bioterror/

World Health Organization

www.who.int/

Food and Drug Administration National Institute for Allergy and Infectious Diseases Biodefense Research Federal Bureau of Investigation

www.fda.gov/

a

niaid.nih.gov/dmid/bioterrorism/

www.fbi.gov/

Comment Search of education, then reference material for Medical Management of Biological Casualties Handbook, ‘‘Blue Book’’ Biological agents Latest bioterrorism news Fact sheets Frequently asked questions Links to MMWR Preparation and planning Emergency response Laboratory information Information about specific pathogens BT agents medical summary Fact sheets Review of Dark Winter (smallpox) Links to BT-related journal articles BT agents Treatment algorithms Slide sets Key review articles Smallpox 1999;281:1735–45 Anthrax 1999;28:2127–37 Anthrax 2002;287:2236–52 Plague 2000;283;2281–90 Botulism 2001;285:1059–70 Tularemia 2001;285:2763–73 VHF 2002;287:2391–2405 Overview of BT agents Links to news services ACP testimony Links to federal BT-related websites BT agents, diagnosis, and therapy Isolation precautions Patient fact sheets Hospital readiness plans Search of health topics for smallpox, then ‘‘more information’’ for Power Point smallpox slide set Search of bioterrorism: health aspects of biological and chemical weapons Links to many good BT-related sites Research efforts for BT-related immunological vaccines, and antibiotics Search of bioterrorism: summary statements of anthrax investigation

BT, bioterrorism; MMWR, Morbidity and Mortality Weekly Report; VHF, viral hemorrhagic fever; CDC, Centers for Disease Control; ACP, American College of Physicians; APIC, Association for Professionals in Infection Control and Epidemiology; NIAID, National Institute for Allergy and Infectious Diseases.

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The use of biological weapons is not new. During the siege of Kaffa in the Crimea (1346–47), the attacking Tartars catapulted plague-infested corpses over the walls, forcing the capitulation of the defenders. During the French and Indian War (1754–63) the British sent smallpox-contaminated blankets to the Native Americans who were fighting in the Fort Pitt area. The German army used anthrax to infect the Allied Forces’ livestock during World War (WW) I. During WW II Japanese forces contaminated Soviet Union water supplies along the Mongolian border with typhoid bacillus and dropped plague-containing fleas over Manchuria to produce an epidemic. The United States began its offensive biological weapons program in 1943 at Camp Detrick, Maryland. Agents developed to fill munitions included anthrax, botulinum toxin, tularemia, brucellosis, Q fever, Venezuelan encephalitis virus, and staphylococcal enterotoxin B. Production increased to allow manufacture of tons of these agents. President Richard Nixon unilaterally dismantled the program in 1969. In 1971–72, all stockpiles were destroyed. In 1972 the United States, and many other countries, including the Soviet Union and Iraq, ratified the Biological Weapons Convention. In the early 1970s, the Soviet Union developed Biopreparat for the research, development, and implementation of offensive biological weapons. It eventually grew to a massive program involving 52 sites and employing more than 50,000 persons. Production capacity increased to hundreds of tons of biological agents that could be placed in intercontinental ballistic missiles. Agents mass-produced included those capable of causing plague, tularemia, anthrax, smallpox, and hemorrhagic fevers. An outbreak of inhalational anthrax occurred in 1979 in Sverdlovsk, Soviet Union, downwind from an anthrax military microbiological facility. Reportedly 68 people died, although U.S. intelligence sources suggest the accident may have caused 250 illnesses and 100 deaths. Now, more than 10 years after the breakup of the Soviet Union, the plans, personnel, and stockpiles for these weapons remain unaccounted for. 1.2

Who Are the Terrorists?

A bioterrorist is any person or organization who conspires to use a biological weapon for political, ideological, or religious gains. Terrorist organizations may be large, well-funded state-sponsored groups; nationalist and separatist groups; apocalyptic religious cults; or single-issue groups. The ‘‘lone wolf,’’ a person acting individually for personal psychopathic goals, continues to pose a serious threat in addition to larger groups. At least 13 countries may have offensive biological weapons programs, including Iraq, Iran, Libya, and Syria. It is feared that the Al Quaeda forces, which previously occupied Afghanistan, may also have acquired biological weapons. Between 1985 and 1991, Iraq developed an offensive weapons program including capacity for mass producing anthrax, botulinum toxin, and aflatoxin. By the end of the 1990s, it had 25 SCUD/Al-Hussein warheads readied with biological weapons including anthrax, botulinum toxin, and aflatoxin. The United Nations Special Commission (UNSCOM) believes that from 1991 to 1995 Iraq was actively involved in biological weapons research and development. In 1994, the Aum Shinrinkyo religious cult released sarin gas into a residential neighborhood in Japan. In 1995, they released the same agent into the subway system of Tokyo. The cult unsuccessfully attempted to release botulinum toxin around the Japanese Diet in 1990, at a wedding of the Japanese crown prince in 1993, and in the subway system in 1995. In 1993, they attempted to transport samples of Ebola virus from Africa for future use as a biological weapon. Aum has also experimented with anthrax, cholera, and Q fever as biological weapons.

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The United States has also experienced bioterrorism. In 1984, the Rajneeshee religious cult contaminated restaurant salad bars with Salmonella typhimurium in order to affect the outcomes of local elections in Dalles, Oregon. The attack caused 751 cases of food poisoning but no deaths. In 1998, Larry Wayne Harris, linked to white supremacist (Aryan Nation) and Christian identity groups, obtained and threatened to release Yersinia pestis and Bacillus anthracis. The more recent anthrax attacks in the fall of 2001 are summarized in the following discussion. 1.3

Laboratory Response Network

Laboratory identification of some of these agents must be carried out in specially equipped facilities because of their infectious risk. The Centers for Disease Control and Prevention (CDC) has established a Laboratory Response Network (LRN) throughout the United States. This is a multilevel system designed to link clinical (hospital-based) laboratories with public health laboratories. Laboratories in this network are categorized as LRN A–D on the basis of biosafety level (BSL) laboratory practices and techniques, safety equipment, and facilities. Routine hospital microbiology laboratories are considered level A. They should be used to ‘‘rule out’’ category A pathogens and forward specimens with suspected bioterrorist pathogens to higher-level laboratories for confirmatory testing. There are higher-level laboratories (LRN B, C) in each state, which have BSL 2 and 3 facilities and are equipped to identify contagious agents. There are two LRN D laboratories in the United States: the CDC in Atlanta, Georgia, and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland. Both are equipped with BSL 4 facilities to identify highly contagious pathogens (smallpox and viral hemorrhagic fever). The following website can be accessed for further explanation: www.cdc.gov/od/ohs/ biosfty/bmbl4/bmbl4s3.htm. If a LRN level A laboratory isolates a possible bioterrorist pathogen, it should immediately notify the regional or state health department. 1.4

Summary of Bioterrorist Agents

Pathogens that could be used as biological weapons were prioritized by the CDC in 1999, on the basis of the potential for morbidity and mortality, delivery to large populations, public perception and fear, and public health preparedness. Agents were assigned to priority categories A, B, and C (see Table 2). Agents in category A have the greatest potential for mass casualty, large-scale dissemination, and public panic. Category B agents would be expected to cause less morbidity and mortality. Category C agents do not currently represent a high risk to the public health but may in the future. Smallpox is ranked first because of its high mortality rate and contagiousness. Inhalational anthrax and plague are also ranked high because of their morbidity and mortality rates, although they are less contagious (plague) or not contagious (anthrax) when compared to smallpox. Preparedness planning for category A agents is being given the highest priority by the CDC. They are discussed in the following. 2 2.1

ANTHRAX Microbiological Characteristics and Use as a Biological Weapon

Anthrax is caused by Bacillus anthracis, an aerobic gram-positive spore forming rod. It is nonmotile, encapsulated, and lysed by ␥ -bacteriophage, all characteristics important for

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ANTHRAX Caused by Bacillus anthracis Biological weapon most likely used as aerosol or powder Cutaneous Incubation period 2–5 days Pruritic papule → painless ulcer/vesicles → necrotic blackened eschar (see Figure 1) Associated edema and regional lymphadenopahy Differential diagnosis (see Table 3) Inhalational No person-to-person transmission Incubation 1–6 days First stage: fever, cough, dyspnea, chest pain, nausea, vomiting Minimal rhinorrhea Differentiation from influenza (see Table 5) Second stage Progressive dyspnea → respiratory failure Chest radiograph finding of widened mediastinum, pleural effusions and infiltrates (see Figure 2) Septic shock and meningitis Algorithmic approach to diagnosis (see Figure 3) Signs and symptoms of 10 patients with inhalational anthrax from fall 2001 (see Table 6) Diagnostic approach to suspected anthrax (see Figure 3) Diagnosis (see Table 8) Gram stain and culture of blood, sputum, cerebrospinal fluid (CSF), or wound Management (see Table 4) Anthrax vaccine is available Standard infection control precautions (see Table 11) Suspicious powder threat assessment and handling (see Table 7)

its identification. It is a natural inhabitant of soil, where the spore may survive for decades. It has a worldwide distribution. Anthrax is most often a disease of cattle, goats, horses, and sheep. Humans naturally acquire the disease from contact with these animals or their products such as hair or skins. Transmission of the spores has occurred percutaneously, by inhalation, and by ingestion. The most common form of human disease is cutaneous anthrax; more than 2000 cases occur worldwide yearly. From 1944 to 1994, there were 224 reported cutaneous cases in the United States. Inhalational anthrax, or woolsorter’s disease, although uncommon, was seen most often in workers in wool processing mills. Between 1900 and 1976 there were 18 cases of inhalational anthrax in the United States. No naturally occurring cases have been diagnosed since then. Ingestion of contaminated meat may cause gastrointestinal disease. Person-to-person transmission of anthrax has not been reported. Once anthrax spores (⬃1 ␮m in size) enter the human body, they are phagocytized by macrophages, where they germinate into the vegetative or replicating bacillus form. Virulence of the pathogen depends on the presence of an antiphagocytic capsule and the presence of three toxins: protective antigen (PA), edema factor (EF), and lethal factor (LF).

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Table 2 Biological Agents That May Be Used as Weapons Agents Category A Variola major Bacillus anthracis Yersinia pestis Francisella tularensis Clostridium botulinum toxin Filovirus (Ebola, Marburg virus) and arenaviruses (Lassa, Machupo virus) Category B Coxiella burnetii Brucella spp. Burkholderia mallei Burkholderia pseudomallei Alphavirus (EEE, VEE, WEE)a Rickettsia prowazeki Chlamydia psittaci Ricin toxin b Clostridium perfringens toxin Staphylococcus enterotoxin B Salmonella spp., Escherichia coli 0157:H7, Shigella spp. Cryptosporidium parvum Vibrio cholerae Category C Nipah virus Hanta viruses Tick-borne hemorrhagic fever viruses Tick-borne encephalitis viruses Yellow fever virus

Disease Smallpox Anthrax Plague Tularemia Botulism Viral hemorrhagic fever

Q fever Brucellosis Glanders Melioidosis Encephalitis Typhus Psittacosis Initial gastroenteritis-like symptoms that may progress to death Gastroenteritis Gastroenteritis Gastroenteritis Gastroenteritis Cholera Encephalitis Hanta pulmonary syndrome, hemorrhagic fever with renal syndrome Hemorrhagic fever Encephalitis Yellow fever

a

EEE, eastern equine encephalitis; WEE, western equine encephalitis; VEE, Venezuelan equine encephalitis. b Made from Ricinus communis (castor bean). Source: Adapted from Rotz et al., 2002.

The capsule prevents phagocytosis by macrophages and neutrophils, thus allowing ongoing replication and dissemination. PA produces pores in the cell membrane, allowing binding and entry of EF and LF. EF then binds to PA to form edema toxin (ET), which interferes with neutrophil function and contributes to edema formation. PA also binds to LF, forming lethal toxin (LT) that causes release of inflammatory cytokines and cellular apoptosis. The vegetative form replicates rapidly, spreading both regionally and systemically with resultant bacteremia, sepsis, and death. Anthrax has been developed as a biological weapon by the United States, the United Kingdom, Japan, Iraq, and the Soviet Union. Its most feared use would be as an odorless, invisible aerosol. A U.S. Congressional Office of Technology Assessment in 1993 esti-

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mated that an airplane release of 100 kg of aerosolized anthrax spores upwind from Washington, D.C., would potentially cause between 130,000 and 3 million deaths. Manufacture of this type of finely milled (< 5-␮m particles) and coated (to prevent static clumping) anthrax as an inhalational weapon requires a high level of microbiological sophistication and is beyond the capacity of most small bioterrorist groups. It can also be disseminated in powder form, as in the attacks in the fall of 2001 (discussed later), causing both cutaneous and inhalational disease. 2.2

Cutaneous

The spores cause illness after contact with exposed abraded skin (most often the arms, face, and neck). After an incubation of 2–5 days, a pruritic papule emerges to progress over several days to a painless ulcer. There may be associated vesicles around the ulcer. The lesions develop a necrotic, depressed blackened center (the word anthrax is from the Greek for coal) surrounded by edema. The edema is nonpitting and can be quite extensive. There may be painful regional lymphadenopathy (see Figure 1). Most often the blackened eschar dries and falls off and the patient recovers. If it is left untreated, the mortality rate can approach 20%. The differential diagnosis of cutaneous anthrax is summarized in Table 3. Treatment recommendations are summarized in Table 4. Patients who have cutaneous disease can be treated with oral doxycycline, ciprofloxacin, or amoxicillin, depending on strain susceptibility. In contrast to those who have naturally occurring cutaneous anthrax, those infected as part of a biological attack should be treated for 60 days since natural immunity may be blunted by the antibiotics and the patient may potentially relapse as a result of inhaled dormant spores. If the patient has systemic symptoms, extensive edema, or lesions on the head and neck, a multidrug intravenous regimen similar to that for inhalational infection should be initiated. Immune-compromised patients can be treated similarly to immunologically normal hosts. 2.3

Inhalational

It is suggested that as few as several thousand spores can produce inhalational disease in humans (and as few as 100 spores in monkey studies), although the true lethal dose is not known. On the basis of the experience of several of the victims with inhalational anthrax the infectious dose may be as low as a few spores. Inhaled spores are rapidly phagocytized in the alveoli and transported to mediastinal lymph nodes. Rapid replication of the vegetative form causes the characteristic hemorrhagic mediastinitis and lymphadenitis with subsequent bacteremia. After an incubation period of 1–6 days, patients experience a nonspecific illness with fever, malaise, nausea, vomiting, nonproductive cough, and chest pain. Differentiation from influenza and other causes of community-acquired pneumonia (CAP) may be challenging during this early phase, especially during the winter months. Table 5 contrasts the symptoms of inhalational anthrax with those of influenza and other influenza-like illnesses (ILIs). Influenza and ILI have prominent rhinorrhea and sore throat with minimal shortness of breath, whereas inhalational anthrax produces shortness of breath but little rhinorrhea and sore throat. If a patient has rhinorrhea, is not toxic appearing after 2 days of symptoms, or has a normal chest radiography result, inhalational anthrax is unlikely. Some patients initially appear to improve from the ILI illness (first stage) for a short period, only to become toxic rapidly. Fever and worsening dyspnea progress over the next several days to respiratory failure and hemodynamic collapse (second stage). Stridor may

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Figure 1 Cutaneous anthrax. (A) Initial vesicle on a forearm at 7 days. (B) Finger papule at day 4. (C) Large ulceration on the upper arm with associated vesicles, eschar formation, and edema. (D) Eschar with surrounding erythema on the chest. (Photos courtesy of the Centers for Disease Control and Prevention Public Health Images Library. See the CDC bioterrorism website at www.bt.cdc.gov.)

be caused by enlarged lymph nodes’ impinging on the airways. Meningitis with headache and confusion leading to coma can occur. In the Sverdlovsk outbreak in the former Soviet Union, the average time from the onset of symptoms until death was 3 days with a range of 1–10 days. The chest radiograph has classically shown a widened mediastinum without infiltrates. In several of the victims of the anthrax letter attacks in the fall of 2001, though, pulmonary infiltrates and pleural effusions did develop on the chest radiographs. Computed tomography (CT) is more sensitive than routine radiographs for detecting mediastinal widening and lymphadenopathy and should be considered when patients are suspected to have inhalational anthrax (see Figure 2). Progressive hypoxemia, hemodynamic instability, meningitis, bloody diarrhea, mediastinal widening, and identification of a gram-positive rod in sputum, cerebrospinal fluid, or blood should raise concern of anthrax.

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Table 3 Differential Diagnosis of Cutaneous Anthrax Infection Spider bite

Staphylococcal furuncle Ecthyma gangrenosum

Orf

Cellulitis Rat bite fever

Ulceroglandular tularemia

Mycobacterial infection Rickettsial pox

Glanders and melioidosis

Comments Loxosceles sp. spiders (brown recluse) Midwest, South, Southwest, California Painful 2–8 hours after bite: bullae with edema progressing to necrotic ulceration Potential fever, myalgia, hemolysis Painful raised indurated lesion associated with hair follicle Potentially purulent or necrotic Gram-negative rod (most often Pseudomonas aeruginosa) bacteremia in neutropenic host Necrotic skin nodules Parapoxvirus infection of sheep and goats Human contact with animal lesion Vesicles progressing to pustular nodule Painful erythema, swelling due to staphylococcal or streptococcal infection Streptobacillus minus Ulceration at rat bite site Systemic illness with relapsing fever, rash Francisella tularensis transmitted by tick or flea bite or contact with infected rabbit or rodent Red painful papule progressing to necrotic ulcer Regional lymphadenopathy that may become fluctuant Mycobacterium tuberculosis or M. ulcerans Nodule or ulceration Rickettsia akari, transmitted by mouse mite bite Painless papule that ulcerates, forming an eschar Fever, chills, headache Generalized rash after 2–3 days Burkholderia mallei (glanders) in horses, mules, donkeys in Southeast Asia, Mideast, South America, Africa B. pseudomallei (melioidosis) in soil in Southeast Asia, Australia Localized papule or pustule that may ulcerate with regional lymphadenopathy

Patients with suspected inhalational anthrax should have blood cultures drawn and a lumbar puncture performed if there is suspicion of meningitis. An algorithmic approach, developed by the CDC, for suspected inhalation anthrax is shown in Figure 3. The risk assessment is based on the anthrax-laden letters mailed during the fall of 2001, which predominantly affected mail handlers and news media workers. It must be kept in mind that future attacks may not involve these groups and all persons must be considered at risk. The clinical illness of the first 10 cases of inhalational anthrax is summarized in Table 6. All 10 patients had fever and malaise. Most also had nausea, vomiting, cough, chest pain, and progressive dyspnea. All had abnormal chest radiographic findings: seven had mediastinal widening, seven had infiltrates, and eight had pleural effusions. Therapy should include either intravenous ciprofloxacin or doxycycline and one to two other agents with activity against B. anthracis (see Table 4). B. anthracis has a

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Table 4 Treatment of Anthrax Drug a,b

Dosage

Cutaneous c Ciprofloxacin d Doxycycline Amoxicillin Inhalational, gastrointestinal, and severe cutaneous c Ciprofloxacin or Doxycycline and One or two additional agents a,b Vancomycin Rifampin Imipenem-cilastatin Prophylaxis f Ciprofloxacin Doxycycline Amoxicillin

Comments

500 mg PO bid 100 mg PO bid 500 mg PO tid

Pregnant women initially treated with ciprofloxacin or doxycycline until sensitivities determined Treatment for 60 days e

400 mg IV q12h

Pregnant women initially treated with ciprofloxacin or doxycycline until sensitivities determined Treatment for 60 days e Can use PO route when clinically stable Doxycycline not used for suspected or confirmed meningitis

100 mg IV q12h

15 mg/kg IV q12h 300 mg IV q12h 500 mg IV q6h 500 mg PO bid 100 mg PO bid 500 mg PO tid

For suspected cutaneous, inhalation, or gastrointestinal exposure Complete 60-day course if confirmed exposure e Pregnant women initially treated with ciprofloxacin or doxycycline until sensitivities determined

a

Other drugs with potential activity include chloramphenicol, erythromycin, and other macrolides; clindamycin; aminoglycosides; vancomycin; first-generation cephalosporins. b Co-trimoxazole, sulfonamides, trimethoprim, aztreonam, second- and third-generation cephalosporins should not be used because of natural resistance. c Recommendations from MMWR October 26, 50(42):909–919, 2001. d Other fluoroquinolones may be equally effective. e Longer courses or adjuvant vaccine may be needed. f Recommendations from MMWR October 19, 50(41):889–893, 2001.

Table 5 Differentiating Inhalational Anthrax from Influenza Symptoms and signs

Inhalational anthrax

Influenza

Influenza-like illness a

Fever Cough Shortness of breath Chest pain Sore throat Rhinorrhea Nausea and vomiting Communicable

70% 90% 80% 60% 20% 10% 80% No

68%–77% 84%–93% 6% 35% 64%–84% 79% 12% Yes

40%–73% 72%–80% 6% 23% 64%–84% 68% 12% Yes

a

Rhinoviruses, respiratory syncytial virus, adenoviruses, parainfluenza viruses. Source: Adapted from MMWR 50(44):984–986.

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Figure 2 Inhalational anthrax. (A) Portable chest radiograph depicts a widened mediastinum (arrowheads), bilateral hilar fullness, a right pleural effusion, and bilateral perihilar airspace disease. (B) Noncontrast spiral computed axial tomography (CT) depicts an enlarged and hyperdense right hilar lymph node (arrowhead), bilateral pleural effusions, and edema of the mediastinal fat. (Reprinted with permission: JAMA 2001; 286:2552. Copyrighted (2001), American Medical Association.)

cephalosporinase that renders resistance to cephalosporins. It also possesses an inducible ␤ -lactamase, raising concern about the efficacy of penicillins, although the isolates from the anthrax attack were all sensitive to penicillin. Doxycycline and ciprofloxacin may not attain adequate cerebrospinal fluid levels, and other agents such as penicillin, a carbapenem, and rifampin should be used if meningitis is suspected. Antibiotic therapy may blunt an immune response and protective immunity may not be established. Therefore, relapse may result from dormant in vivo spores after recovery from the acute illness. Antibiotics can be switched to oral agents once the patient’s condition is stable and should be continued for 60 days. Current research efforts are investigating the need for more prolonged antibiotic treatment (100 days) or adjuvant vaccine (three doses over 4 weeks) along with the current 60 days of antibiotics for all forms of anthrax caused by a biological attack. 2.4

Gastrointestinal

Gastrointestinal (GI) anthrax follows the ingestion of undercooked contaminated meat. This may result in either oropharyngeal or abdominal symptoms. After 2–5 days, ulceration develops in the oropharynx with associated dysphagia, cervical swelling, and regional lymphadenopathy. Intestinal involvement most often occurs in the terminal ileum and cecum. Patients experience nausea, vomiting, and abdominal pain, which may progress to an acute abdominal crisis–like condition with bloody diarrhea, hematemesis, and ascites. Before the anthrax attacks in the fall of 2001, GI anthrax had not been reported in the United States. Nine of the initially reported inhalational anthrax patients had nausea

Figure 3 Approach to the patient with suspected inhalational anthrax. (1) See Table 4 for prophylaxis. (2) See Table 4 for therapy. (Source: MMWR, November 2, 2001/Vol. 50/No.3: page 945.) †Serologic testing at CDC may be additional diagnostic technique.

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Table 6 Inhalational Anthrax: Summary of the First 10 Cases Mean age (range) Male/female Median incubation period (range) Survival

56 (43–73) Years 7:3 4 (4–6) days 60%

Symptoms Fever Nonproductive cough Nausea and vomiting Dyspnea Chest pain Confusion Sore throat Rhinorrhea Clinical findings Temperature >37.8⬚C Pulse >100 beats/min Systolic BP <110 mm Hg White blood cell count (mean) Elevated transaminase level Metabolic acidosis Creatinine >1.5 mg% Hypoxemia Abnormal chest radiography result Mediastinal widening Infiltrates Pleural effusion Abnormal CTa scan finding Mediastinal widening Infiltrates Pleural effusion

Number 10 10 9 8 7 4 2 1 Number or laboratory 7 8 1 9800 cells/mm3 9 2 1 6 10/10 7 7 8 8/8 7/8 6/8 8/8

a

BP, blood pressure; CT, computed axial tomography. Source: Adapted from Jernigan et al., 2001.

or vomiting, three had abdominal pain, and one had evidence of GI anthrax on autopsy. Therapy is similar to that for inhalational anthrax. 2.5

Anthrax Bioterrorism in the United States: Fall 2001

On October 2, 2001, a photo editor of a tabloid newspaper in Palm Beach, Florida, died of inhalational anthrax complicated by septicemia and meningitis. On October 12, 2001, the CDC was informed that a TV news employee in New York City had cutaneous anthrax after handling a suspicious letter. Additional cases were found in Trenton, New Jersey; Washington, D.C.; and Oxford, Connecticut. By December 5, 2001, 22 persons had been identified: 11 with inhalational anthrax (5 of whom died) and 11 with cutaneous anthrax (7 confirmed) disease. The infections were the result of terrorist attacks with five letters mailed from Trenton, New Jersey, containing anthrax spore–laden powder. The letters

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were sent to news media companies or U.S. senators’ offices. Most of the victims were either mail handlers or employees of media companies. Seven of the initial 10 patients with inhalation anthrax were postal employees in New Jersey and the District of Columbia. One of the patients who worked in a New York City hospital, who died of inhalational anthrax, had no obvious source of infection. An elderly Connecticut woman also died of inhalational anthrax. No source for her infection was found, although cross-contamination of the mail from postal facilities in New York or New Jersey is suspected. The perpetrator has not been apprehended. The anthrax was ‘‘weapons grade’’ (high spore concentration, uniform particle size, low electrostatic charge, and treated to reduce clumping), suggesting a high level of sophistication involved in its production. The anthrax letters set off a blizzard of suspicious powder scares along with white powder hoaxes and fear of the mail throughout the United States and other countries. The LRN performed anthrax testing on more than 121,000 samples of suspicious powder. In response, the CDC developed guidelines for handling suspicious packages and envelopes (see Table 7). The vast majority of suspicious powder scares were innocent accidents involving sugar, foot powder, and artificial creamers. 2.6

Diagnosis

The diagnosis begins with a high degree of suspicion based on risk factors and clinical illness. Nasal swabs should not be used for clinical testing since the sensitivity is very poor. They have been used by the CDC for epidemiological investigation. Samples of blood, sputum, and cutaneous ulcerations should be sent for Gram stain and culture. Standard blood cultures should grow within 6–24 hours. Gram stain of the blood may yield a positive finding for gram-positive bacilli that form ‘‘bamboo-like’’ chains. The diagnosis of cutaneous anthrax can be established by Gram stain and culture of the lesion though the sensitivity is only 60%. The lesion can be biopsied and immuno-

Table 7 Suspicious Letters and Powder Threat assessment Obvious intentional act Powder deliberately spread in a wide area Written threat Suspicious letter Excessive postage Handwritten or poorly typed No return address Incorrect title or title with no name Misspelling of common words Oily stains or discoloration Excessive weight Lopsided or uneven envelope Protruding wires or aluminum foil Excessive security material such as tape, string Postmark that does not match return address

Handling Remain calm. Do not shake or empty contents. Carefully close the envelope or package so as not to create a dust cloud or disturb the contents. Do not carry the material or show it to others. Do not touch, sniff, taste, or look carefully at the envelope or spilled powder. If you are able, place the envelope or package in a plastic bag or cover the powder with something (newspaper, trash can) and leave it covered. Alert others in the area. All persons should leave the room. The door should be closed to prevent others from entering. Wash hands with soap and water. Call work supervisor or 911. Create a list of others in the room.

Source: Adapted from MMWR October 26, 2001, 50(42):909–919.

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histochemical staining performed. The confirmatory testing for B. anthracis should be performed at a level B or C laboratory of the LRN and not at a hospital clinical laboratory. Serological testing may be helpful retrospectively but should not be used for the diagnosis of acute illness. Serum may be collected for toxin assay analysis and blood for polymerase chain reaction (PCR) testing for bacterial deoxyribonucleic acid (DNA) (see Table 8).

Table 8 Diagnosis of Bioweapon Pathogens a Clinical syndrome Anthrax Cutaneous Inhalational

Gastrointestinal Smallpox

Plague

Botulism

Tularemia

Viral hemorrhagic fever

a

Clinical

Necrotic painless ulcer Widened mediastinum Pleural effusions Rapid progression to respiratory failure Abdominal pain Bloody diarrhea Rash and fever

Pneumonia Rapid progression to respiratory failure Hemoptysis Symmetrical descending paralysis Cranial palsies Abnormal nerve stimulation study results Initial flulike illness Pharyngitis, bronchitis Pneumonia that may progress to respiratory failure e Conjunctivitis Cutaneous ulceration and regional lymphadenopathy Initial flulike illness Conjunctivitis Maculopapular rash Mucocutaneous bleeding Shock

Routine microbiological tests b

Serological and molecular tests

GS, C/S of ulcer Blood culture for GS, C/S CSF for GS, C/S

Pathological testing for immunohistochemical or PCR findings Serum for toxin assay c Blood and sputum for PCRc Antibody to protective antigen d Skin scraping for viral culture, EM, and pathological testing IF for F1 capsular antigen Serum for IgM enzyme immunoassay

Blood culture for GS, C/S None

Blood, sputum for GS, C/S

None

Toxin identification in stool or serum by mouse neutralization bioassay c

Sputum and pharyngeal washings for GS, C/S f Blood culture

Direct FA, PCR, ELISA, on sputum c Serum antibody for epidemiological investigation

None

IgM antibody or fourfold rise in IgG level Viral isolation g

GS, Gram stain; C/S, culture and sensitivity; BC, blood culture; EM, electron microscopy; PCR, polymerase chain reaction; IF, immunofluorescent antibody; FA, fluorescent antibody; BSL, biosafety level. b For preliminary identification. Suspect isolates should be forwarded to a level B, C Laboratory Response Network (LRN) facility. c Performed at LRN facility level B, C, D. see text. d Not for the diagnosis of acute anthrax. e Less rapid progression to respiratory failure than anthrax and plague. f Isolation and identification may take weeks. Growth in the laboratory may be slow, and plates should be held for 10 days. Growth is improved with cysteine-enriched broth, thioglycolate broth, cysteine heart blood agar, chocolate agar, or buffered chocolate yeast agar. g Level D LRN laboratory. Source: Adapted from field manual: Treatment of Biological Warfare Agent Casualties.

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Newer technologies such as rapid-cycle real-time PCR and LightCycler PCR (Roche Applied Science, Indianapolis, Ind.) for rapid identification are being explored. 2.7

Postexposure Prophylaxis and Prevention

Approximately 10,000 persons potentially exposed to anthrax in Connecticut, Florida, New Jersey, New York City, and Washington, D.C., were advised to take at least 60 days of postexposure antibiotic prophylaxis, most often ciprofloxacin. Severe nausea, vomiting, diarrhea, or abdominal pain was reported in 19%. It has been estimated that this prophylaxis prevented an additional 10–20 cases of inhalational disease. Table 4 summarizes the CDC recommendations for prophylaxis. Louis Pasteur made the first anthrax vaccine in 1881. The current vaccine is an adsorbed cell free suspension of cellular products, including toxin antigens, made from an attenuated nonencapsulated strain of B. anthracis. The vaccine, anthrax vaccine adsorbed (AVA), is made by the Bioport Corporation in Lansing, Michigan, and has been licensed since 1970. Antibody developed to the PA in the vaccine blocks subsequent infection. It is administered subcutaneously at 0, 2, and 4 weeks and 6, 12, and 18 months along with yearly boosters. Studies of vaccine efficacy demonstrated response rates of 95% in those who received three or more doses. It is currently recommended for military personnel, laboratory workers researching anthrax, veterinarians, livestock handlers, and workers in wool or goat hair factories. The vaccine may be provided as part of postexposure prophylaxis at 1, 2, and 4 weeks with the hope of discontinuing antibiotic prophylaxis at 4 weeks instead of the suggested 60 days. The vaccine is considered safe; most reported adverse events are localized self-limited reactions. AVA caused no adverse effects on pregnancy or increase in the rate of birth defects. Recombinant vaccines that would require fewer doses are in development. 3

SMALLPOX

Smallpox is the most feared biological weapon because of its high mortality rate, severe morbidity rate, and highly contagious nature and the lack of natural immunity in most persons worldwide. Mortality rate during past smallpox epidemics averaged 30%. In nonimmune populations, such as the Native Americans of the 18th century, the mortality rate exceeded 50%. Those who survive are often badly scarred and 1% are left blind. 3.1

Virological and Epidemiological Characteristics and Use as a Biological Weapon

Smallpox is caused by a member of the Orthopoxvirus genus, the variola virus, a doublestranded DNA virus that replicates in the host cell cytoplasm. Humans are the only known host. There are two strains: variola major, the more virulent variety, responsible for untold deaths throughout history, and variola minor or alastrim, which has a mortality rate of <1%. Smallpox is spread from person to person by aerosols. This most often happens with close (ⱕ6 ft) contact. It can also be transmitted by direct contact with infectious lesions or fomites in contaminated clothing or bedding. Transmission rates to nonimmune persons, most often family members or those with close contact such as health care workers, range from 37% to 88%. Epidemics had been more frequent in winter months. Vaccinia virus is structurally similar to variola virus. It is the basis of the current smallpox vaccine. It most likely evolved from the cowpox virus. Edward Jenner, in the

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SMALLPOX Caused by variola virus 30% Average mortality rate Biological weapon most likely aerosol Incubation 7–17 days Prodrome Fever, headache, backache No rash Not contagious Rash syndrome (see Figure 4) Very contagious, especially with close contact (within 6 ft) Enanthem with oropharyngeal ulcers Maculopapular rash → papules → vesicles → pustules → scabs Face and extremities > trunk Pocks firm and deeply embedded in skin Synchronous rash developemnt Palms and soles involved Differentiation from chickenpox (see Table 9) Diagnosis (see Table 8) Biosafety level 4 (BSL 4) laboratory Electron microscopy Viral culture Management Respiratory and contact precautions (see Table 11) N-95 mask Negative-pressure rooms Supportive Cidofovir(?) Vaccinia vaccine Before exposure Within 4 days of exposure Vaccinia immune globulin Treatment of vaccine complication Late postexposure prophylaxis

late 1790s, recognized that milkmaids did not contract smallpox. He used material from bovine cowpox lesions to inoculate humans intradermally. This first vaccine successfully prevented smallpox. The World Health Organization (WHO) campaign, begun in 1967, successfully eradicated smallpox worldwide with the use of vaccinia vaccine. The last case of smallpox in the United States was in 1949. The last reported endemic case of smallpox was reported in Somalia in 1977. The last person to have contracted smallpox was a laboratory worker in England in 1978. The WHO declared that smallpox was eradicated worldwide in 1980. Vaccination against smallpox was halted in the United States in 1972 and worldwide in 1982.

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The only known reservoirs of smallpox virus are in laboratories of the CDC in the United States and the State Research Center of Virology and Biotechnology (Vektor Institute) in Novosibirsk, Russia. All other stocks should have been voluntarily destroyed. It is feared, though not proved, that repositories of smallpox virus exist in countries that did not destroy their stock. At the height of the former Soviet Union bioweapons development program in the 1980s, large quantities of smallpox virus were produced and readied for use in intercontinental ballistic missiles. With the collapse of the Soviet Union and its bioweapons program, it is feared that caches of virus could have been smuggled out and fallen into the hands of bioterrorists. Variola virus used as a biological weapon would most likely be in an aerosolized form. It is quite stable in this form, and the infectious dose very small. One gram of aerosolized smallpox has the potential to infect 100 persons. During the 1970s, the former Soviet Union stockpiled 20 tons of smallpox virus, and by 1990 they had factories that could produce up to 100 tons yearly. During past epidemics, each infected person transmitted the illness, on average, to 10 others before the epidemic was controlled. Intentional release of variola virus has the potential to cause worldwide pandemic with thousands to millions of deaths. During June 2001, the Johns Hopkins Center for Biodefense Strategies conducted a theoretical tabletop exercise named ‘‘Dark Winter’’ simulating a smallpox attack on three cities in the United States. Initially there are 20 confirmed cases. Thirteen days into the exercise there are 16,000 cases in 25 states with 1000 deaths. By day 25 of the theoretical attack, there are 30,000 cases with 10,000 deaths. The exercise was terminated without control of the theoretical epidemic. After inhalation, variola virus enters the oral and respiratory mucosa, spreads to regional lymph nodes, and disseminates asymptomatically. A secondary viremia results in invasion of dermal and oropharyngeal capillaries, causing the formation of cutaneous and mucosal poxlike lesions. During the early phases of the rash-related clinical illness, the patient is highly contagious. The immune response is mediated by cytotoxic T cells and neutralizing antibody. Natural immunity is lifelong. 3.2

Clinical Illness

After an incubation period ranging from 7 to 17 days (mean 10–12 days), a prodromal phase begins with the onset of severe headache, backache, and high fever. Less often there may be abdominal pain, nausea, and delirium. As the patient defervescences over several days the characteristic rash begins. An enanthem of the mouth, tongue, pharynx, and nose begins and progresses to painful ulcerations. The exanthema begins as a macular erythematous eruption initially concentrated more on the face and extremities. The lesions then progress characteristically to papules, vesicles, pustules, and then scabs, all of which are in the same stage of development. By day 4 of the rash, vesicles are evident; they quickly become pus filled. During days 7–9, the pustules continue to enlarge. They are firm to touch and deeply embedded in the skin. By days 10–14, the pustules begin to form scabs, which eventually fall off, leaving depigmented depressed scars. The face is most often left pockmarked and disfigured. The rash is centrifugal with lesions concentrated on the face and extremities more than the abdomen, chest, or back. Lesions are usually present on the palms and soles (see Figure 4). Lesions can also be seen in the mouth, pharynx, rectum, vagina, and conjunctiva. Panophthalmitis can result in blindness. Secondary bacterial infections of the skin, pneumonia, and bacteremia contribute to the mortality rate. Hemorrhagic (3% of cases) and malignant (7%) smallpox are uncommon but highly lethal forms. Pregnant women are more prone to development of the hemorrhagic form,

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Figure 4 Smallpox. (A) Pustules on the chest and abdomen. The lesions are firm to the touch and deeply embedded in the skin. (B) With smallpox, pocks are usually present on the palms of the hands and on the soles of the feet, in contrast to those of chickenpox. (From http://www.who.int/ emc/diseases/smallpox/slideset/pages/spox.)

which produces severe prostration and diffuse erythema followed by cutaneous and mucosal bleeding. Death usually follows within 5–7 days. Malignant smallpox is characterized by slowly forming, confluent, velvety flat lesions that do not progress to pustules. Variola minor accounted for about 2% of smallpox epidemics in the past. It is less severe than variola major with fewer and more superficial lesions and fewer constitutional symptoms. Death is uncommon. Smallpox has been confused with chickenpox, severe drug reactions, eczema herpeticum, molluscum contagiosum, acne, and insect bites. Measles can be confused with the early stages of smallpox. Hemorrhagic smallpox can be confused with meningococcemia. Chickenpox is the illness most often confused with smallpox. Table 9 summarizes the differences between the two viral illnesses. Patients with chickenpox do not have a history of previous infection or vaccination and have been exposed to someone with chickenpox during the preceding 2–3 weeks. The diagnosis of smallpox must be confirmed since even a single case would represent a bioterrorist attack and an international emergency. The diagnosis is based on clinical suspicion and confirmed by laboratory testing (see Table 8). Fluid from an opened vesicle or material from a scab should be placed in a tightly sealed container. The state or regional health department should be immediately notified. Only BSL 4 laboratories should process the samples. The diagnosis can be confirmed with electron microscopy,

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Table 9 Comparison of Smallpox and Chickenpox Characteristic

Smallpox

Chickenpox

Prodrome a Distribution Character of lesions Size of lesions Palms and soles Maturation of lesions Lesion development Erythema around lesion

Precedes rash onset Face, extremities > trunk Deep, firm Large (5–10 mm) Often In same stage Slow Not present Lesions isolated from one another

Scabs

Form later than day 10

At time of rash onset Trunk > face, extremities Superficial Small (1–5 mm) Infrequent In different stages at same time Rapid Present b Lesions often clustered or coalescent Begin to form by day 7

a b

Fever, headache, backache. ‘‘Dew drop on a rose petal’’ appearance.

characteristic growth in cell culture or chorioallantoic egg membrane, and biological assays such as PCR or restriction fragment-length polymorphism analysis. 3.3

Management

Smallpox is very contagious. Patients with suspected smallpox who require hospitalization should be cared for in negative-pressure isolation rooms that have at least 12 air exchanges per hour. They should remain in isolation until the lesions scab over. Care is supportive, concentrating on pain control, eye care, hydration, nutrition, and treatment of secondary bacterial infections. There are currently no U.S. Food and Drug Administration– (FDA)approved therapies. Topical idoxuridine may be used for corneal ulcers. Systemically administered cidofovir, used to treat cytomegalovirus, has shown efficacy in animal models of cowpox and vaccinia infection. Hexadecyclopropylcidofovir (HDP-CDV) has been shown to be more potent than cidofovir in vitro; it is not available at the time of publication of this chapter. Persons at risk for exposure during an epidemic should be vaccinated with vaccinia vaccine (VACV). All persons with direct contact with a patient with smallpox should be vaccinated and closely observed for 17 days for symptoms of fever and rash. Vaccination within 4 days of exposure may help prevent or lessen the clinical illness. Vaccinia immune globulin may be used as postexposure prophylaxis for those exposed more than a week previously. The current vaccine (Dryvax, Wyeth Corporation) is a lyophilized preparation of live vaccine made decades ago from lymph extracted from calves cutaneously infected with vaccinia virus. Release and use of VACV are under the control of the CDC, which has approximately 15.4 million freeze-dried doses of VACV. The current vaccine can be diluted at least 5-fold and perhaps 10-fold, and still stimulate immunity, thus potentially providing the United States with 75–150 million doses. Additionally, 70–90 million doses were donated in 2002 to the CDC by Aventis Pasteur of Lyon, France, after they were found in storage freezers in their Swiftwater, Pennsylvania, facility. Newer vaccines are being produced in cell culture (Acambis PLC). It is hoped that 280 million doses will be available by the end of 2002.

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The vaccine is given with a bifurcated needle that has been dipped in reconstituted vaccine. It is then used to inoculate the skin with 15 strokes applied intradermally within a 5-mm area. A successful vaccination ‘‘take’’ is characterized by erythema and pruritus at the vaccination site, which is then followed by vesicle formation that progresses to a pustule (jennerian pustule). The lesion then dries, crusts, and falls off, leaving a scar. A successful vaccination, occurring in >95% of those vaccinated, confers immunity for approximately 5–10 years. In 1968, 14.2 million persons in the United States were vaccinated. There were nine deaths. Other complications, which occurred at a rate of 1254 complications/million vaccinations, included accidental infection, progressive vaccinia, generalized vaccinia, erythema multiforme, eczema vaccinatum, and encephalitis. Complications were highest in children below 5 years of age. Vaccinia immune globulin may be used to prevent or treat vaccine complications. Because of the severity of these complications and the unknown risk of a smallpox attack, the CDC currently does not recommend preventative mass vaccination in the United States. Instead they plan to use the ‘‘ring-vaccination’’ strategy that was successful in eradicating smallpox. This approach involves active surveillance of cases followed by vaccination of all contacts, thereby blocking further person-to-person spread. The ring vaccination strategy is being actively debated, as some are calling for selected vaccination of ‘‘first providers’’ and medical personnel and others advocate voluntary mass vaccination. 4

PLAGUE

Like smallpox, plague has been a scourge to humankind throughout history. Three major pandemics of bubonic plague have been recorded. The first, in A.D. 541, caused mortality rates approaching 50%–60% of the populations of northern Africa, Europe, and parts of central Asia. The second pandemic, known as the ‘‘Black Death,’’ began in 1346, lasted more than 130 years; and killed one-third of the European population. The third pandemic started in China in 1855 and spread widely throughout Asia to cause at least 12 million deaths. Two large epidemics of pneumonic plague occurred in Manchuria in the early 20th century. In 1994, a small epidemic in Surat, India, caused widespread panic; an estimated 500,000 persons attempted to evacuate the city. 4.1

Microbiological and Epidemiological Characteristics and Use as a Biological Weapon

Plague is caused by Yersinia pestis, a bipolar staining gram-negative rod (GNR). It is a zoonotic infection spread to humans by infected fleas living on rats, squirrels, prairie dogs, and other rodents. Natural cases still occur worldwide; 390 cases were reported in the United States from 1947 to 1996, mostly in New Mexico, Arizona, Colorado, Utah, and California. Fifteen of those cases were transmitted from infected domestic cats. If Y. pestis were to be used as a biological weapon, it would most likely be used as an aerosol. Both the United States and the former Soviet Union developed technology to weaponize plague. The WHO estimated a 50-kg aerosolized release of Y. pestis over a city of 5 million would cause pneumonic plague in 130,000 persons, require 80,000 hospitalizations, and result in 36,000 deaths. Pneumonic plague is transmissible from person to person and could cause secondary spread after the initial aerosol attack had dissipated. 4.2

Clinical Manifestations

Y. pestis can cause three clinical syndromes: bubonic, septicemic, and pneumonic plague. The vast majority of naturally occurring plague is the bubonic type, which causes an acute

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PLAGUE Caused by Yersinia pestis Biological weapon most likely aerosol Bubonic Transmitted from rodents or mammals by infected flea bite Incubation period 2–8 days Mostly southwest United States Fever, headache, nausea, vomiting Tender, erythematous nonfluctuant lymphadenopahy May have septicemic type without bubo formation Pneumonic Incubation period 1–6 days Fever, dyspnea, productive cough Multifocal, bilateral pneumonia Person-to-person transmission with close contact Diagnosis (see Table 8) Sputum, blood, bubo Gram stain with bipolar staining of gram-negative rods (GNRs) Sputum, blood, bubo culture Management Respiratory droplet isolation (see Table 11) No longer infectious after 72 hours of antibiotic therapy Streptomycin, gentamicin Ciprofloxacin, doxycycline, co-trimoxazole Prophylaxis For close (<6 ft) contacts of case Ciprofloxacin or doxycycline for 7 days

bacterial lymphadenitis. After a bite from an infected flea, Y. pestis spreads via the lymphatics to regional lymph nodes. The incubation period varies from 2 to 8 days. Clinical illness then begins with fever, headache, nausea, diarrhea, and lymph node swelling (bubo formation). The buboes are very tender and erythematous and typically nonfluctuant. They can grow up to 10 cm in size. They most often occur in the groin, axilla, or neck, downstream from the initial flea bite. There may be associated hepatosplenomegaly. Patients occasionally become bacteremic from the infected lymph node. Differential diagnosis includes tularemia, cat scratch disease, tuberculosis, chancroid, lymphogranuloma venereum, and lymphoma. The septicemic form is a bacteremia from the initial flea bite characterized by progressive shock, disseminated intravascular coagulopathy (DIC), purpura, and distal gangrene of the fingers and nose. The pneumonic type is the least common natural occurring form of plague. It can develop from hematogenous spread from the bubo or inhalation of infectious droplets from other infected persons or animals. The use of aerosolized Y. pestis as a biological weapon would most likely result in primary pneumonic plague in a large number of patients. After an incubation period of 1–6 days, the patient would experience fever, cough, and progressive shortness of breath. There may be chest pain, and the sputum may be purulent and bloody. Associated nausea,

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vomiting, abdominal pain, and diarrhea are common. Patients progress rapidly to respiratory failure and death if therapy is not instituted. The chest radiograph shows a consolidative process that is often multifocal and bilateral and may demonstrate cavitation. There is usually a marked leukocytosis, evidence of DIC, renal insufficiency, and elevation of hepatic enzyme levels. An early clue to the diagnosis of plague would be the demonstration of the bipolar staining GNR in blood, sputum, or bubo aspiration. The diagnosis is based on identification of the plague bacillus in culture. It grows on routine agars used in the clinical laboratory within 24–48 hours. If plague is suspected, confirmation of the bacteriological feature should take place in a BSL 2 facility. Additional confirmatory testing can include immunofluorescent staining of the F1 envelope glycoprotein. Serological testing may be helpful retrospectively in suspected cases with negative culture and stain findings. 4.3

Management

All patients with suspected plague should be placed in respiratory isolation with droplet precautions because person-to-person transmission can occur. Health care workers in close contact with patients should use standard precautions and wear surgical masks. Negativepressure rooms and N-95 respirators are not needed. The patient is no longer infectious after 72 hours of antibiotic therapy. The drug of choice remains parenteral streptomycin, although other aminoglycosides such as gentamicin can be used. Tetracycline, doxycycline, chloramphenicol, co-trimoxazole, ciprofloxacin, and levofloxacin also have good activity. Those with close contact (⬃6 ft or less) to a person with untreated pneumonic plague should receive prophylaxis with 7 days of doxycycline or ciprofloxacin. The same drugs can be used for children and pregnant women. There are no licensed vaccines available in the United States. A vaccine against pneumonic plague is under investigation.

5 5.1

BOTULISM Microbiological and Epidemiological Characteristics and Use as a Biological Weapon

Botulism is a descending paralytic illness caused by the toxin of Clostridium botulinum, a spore-forming, anaerobic gram-positive bacillus. The organism is a natural inhabitant of soil. The botulism neurotoxins, designated A–G, are the most potent poisonous agents known. The toxin irreversibly binds to the presynaptic neuronal cell membrane, inhibiting acetylcholine release, thereby blocking skeletal and bulbar muscular contraction. Naturally occurring botulism in the United States is uncommon: approximately 200 cases are reported annually. Of these, the majority are food-borne with toxin absorbed from improperly home-canned foods such as vegetables, fruits, and fish. Nonpreserved foods such as foil-wrapped potatoes and saute´ed onions can also transmit botulism and restaurant outbreaks have occurred. Botulism can also develop from wounds contaminated with C. botulinum and in infants who have gastrointestinal colonization with the pathogen. If C. botulinum were to be used as a biological weapon, it would most likely be in the form of an aerosol or intentional contamination of food. The paralysis caused by an aerosolized form of C. botulinum would be similar to that of the food-borne illness. The former Soviet Union developed botulism as a biological weapon and field-tested it on islands in the Aral Sea. Iraq produced 19,000 L of concentrated botulinum toxin, much of

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BOTULISM Caused by toxins of Clostridium botulinum Biological weapon most likely aerosol Descending symmetrical paralysis Clinical manifestation Diplopia, blurred vision, dry mouth, dysarthria, dysphagia Progressive cranial nerve palsy Respiratory failure Sensory intact Afebrile Cerebrospinal fluid normal Diagnosis (see Table 8) Repetitive nerve stimulation Neurotoxin detection by mouse neutralization assay Management Standard infection control precautions (see Table 11) No person-to-person transmission Equine trivalent antitoxin Supportive care

which was deployed on military weapons. Iran, North Korea, and Syria are believed to be developing botulism weapons. 5.2

Clinical Manifestations

After an incubation period ranging from 12 hours to 3 days, patients have a progressive descending symmetrical paralysis. Initial symptoms include diplopia, blurred vision, and dry mouth. Gastrointestinal symptoms of nausea, vomiting, and abdominal cramps seen with food-borne botulism may not be present with the inhalational type. As the illness progresses, dysphagia, dysphonia, and dysarthria develop. Weakness progresses from the upper extremities to the trunk and lower extremities. Respiratory failure can ensue. Patients are afebrile and have normal mental status. Examination reveals ptosis, dilated pupils, nystagmus, multiple cranial nerve palsies, and symmetrical weakness that can progress to flaccid paralysis. Sensory examination findings are normal. The deep tendon reflexes may be depressed. Paralysis can last for weeks to months. The diagnosis should be suspected on the basis of compatible clinical presentation. Routine laboratory testing results are normal with negative cerebrospinal fluid (CSF) examination findings and sterile cultures of both blood and CSF. The Tensilon and nerve conduction velocity test results are normal. Repetitive nerve stimulation (at high frequency) may show a small incremental motor response. The diagnosis is confirmed by detecting the neurotoxin from the patient’s serum or stool with the mouse neutralization bioassay, which has a reported sensitivity of 75%. This assay is performed at BSL 2 or higher facilities. The differential diagnosis includes myasthenia gravis, tick paralysis, the Miller-Fischer variant of Guillain-Barre´ syndrome, Lambert-Eaton syndrome, poliomyelitis, magnesium intoxication, and brainstem infarction.

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Management

The mainstay of therapy is the administration of equine antitoxin. Early administration of a single dose has been associated with a shorter duration of illness and an improved mortality rate. The licensed antitoxin is a trivalent preparation with activity against toxins A, B, and E. Antitoxin can be obtained from the CDC by local and state health departments. Skin testing should be performed before infusion to exclude hypersensitivity to horse antigens. Repeat dosage of the antitoxin or use of antibiotics is not beneficial. Months of supportive and ventilatory care may be required. Botulism is not transmissible. Therefore, only standard infection control precautions are needed. Postexposure prophylaxis with antibiotics or antitoxin for exposed but asymptomatic persons is not indicated. A pentavalent vaccine is under current research. 6 6.1

TULAREMIA Microbiological and Epidemiological Characteristics and Use as a Biological Weapon

Tularemia is a naturally occurring zoonosis caused by Francisella tularensis, a pleomorphic, aerobic, non-spore-forming, intracellular GNR. F. tularensis biovar tularensis (type A) is found more commonly in North America and causes a more virulent infection. F. tularensis biovar palaearctica (type B), found more often in Europe and Asia, is less virulent. Tularemia is endemic in rabbits and rodents. Infection is transmitted to humans by tick, fly, or mosquito bite; direct contact with infected animal tissue or contaminated water; animal bites; ingestion of contaminated water or food; and, least commonly, aerosol.

TULAREMIA Caused by Francisella tularensis Endemic in rodents and rabbits Most cases in southwest United States Transmitted by direct contact, insect bite, ingestion Biological weapon most likely aerosol Clinical manifestations Cutaneous ulceration with regional lymphadenopathy Aerosolized form Incubation 3–5 days Fever, headache, pharyngitis, nausea, abdominal pain Atypical pneumonia Bilateral pneumonia with effusions Diagnosis (see Table 8) Gram stain and culture of sputum Further testing and identification in biosafety level 2 or 3 (BSL 2 or 3) laboratory Management Streptomycin or gentamicin for 10 days Ciprofloxacin, doxycycline, or chloramphenicol also useful Postexposure prophylaxis if initiated within 24 hours of exposure No person-to-person transmission Standard infection control measures (see Table 11)

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F. tularensis can survive for prolonged periods in dead animals, contaminated mud, and hay. In the United States, infection is most often seen in rural areas of Arkansas, Missouri, Oklahoma, South Dakota, Montana, Tennessee, Kansas, and Colorado. It is more common in men and seen most often during the spring, summer, and fall. There are <200 cases yearly in the United States. An outbreak caused by accidental aerosolization of F. tularensis by lawn mowing equipment involving 15 persons living on Martha’s Vineyard, Massachusetts, was reported in 2001. Human-to-human transmission does not occur. F. tularensis has been developed as a biological weapon by the former Soviet Union, Japan during WW II, and the United States because of its high infectivity (<50 organisms can cause disease) when used as an aerosol. It has been suggested that the Soviet Union used F. tularensis against the Germans during the battle of Stalingrad in 1942–43. Scientists in the former Soviet Union engineered antibiotic-resistant strains. The WHO estimated that 50-kg release of F. tularensis aerosolized over a city of 5 million would cause 250,000 persons to become ill and 19,000 deaths (Dennis et al., 2001). 6.2

Clinical Manifestations

The clinical manifestations of naturally occurring tularemia depend on the means of transmission. Most persons contract tularemia from an arthropod bite or direct injury involving infected animal tissue. In 75% of cases, a local cutaneous or mucosal ulceration develops with associated regional lymphadenopathy (ulceroglandular disease). In 25% of cases, a nonspecific febrile illness develops without a skin lesion (typhoidal tularemia). There may be an associated atypical pneumonia. A bioterrorist attack would most likely involve an aerosol release of F. tularensis resulting in a typhoidal-like syndrome. After an incubation period of 3–5 days (range up to 14 days), patients would have a nonspecific febrile illness characterized by headache, myalgia, pharyngitis, nausea, vomiting, diarrhea, and abdominal pain. Many would have an atypical pneumonia with infiltrates and effusions seen on chest radiograph. The pulmonary disease would be expected to be less fulminant than that caused by anthrax or plague, although the mortality rate of untreated pneumonic tularemia could be as high as 30%–60%. Differentiation from other causes of community-acquired pneumonia and influenza may be challenging. Chest radiography findings may be initially normal or show small peribronchial infiltrates. The pneumonia may progress to bilateral multilobar disease with pleural effusions and hilar lymphadenopathy. Microbiological confirmation of the illness can be challenging. There are no rapid diagnostic tests. Gram stain of sputum or a cutaneous/mucosal ulcer may reveal small pleomorphic coccobacilli. Blood culture results are most often negative. Isolation of the organism in culture is facilitated with media enriched with cysteine, but this type of identification should only take place in BSL 3 laboratories. Other confirmatory tests include antigen detection by PCR or enzyme-linked immunoassay on clinical specimens. Serological diagnosis requires a fourfold rise in antibody titer over 4 weeks or a single titer >1: 160 by tube agglutination. 6.3

Management

The drug of choice is streptomycin, although other aminoglycosides such as gentamicin can also be used. Doxycycline, chloramphenicol, and ciprofloxacin also have activity. Switch to oral equivalents can be made when the patient’s condition stabilizes. Treatment should be continued for 10 days.

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Postexposure prophylaxis is recommended for those exposed to an aerosol attack if treatment can be initiated within 24 hours. Doxycycline or ciprofloxacin for 14 days is recommended. If the exposure occurred more than 24 hours before initiation of the antibiotic, prophylaxis would not be expected to be beneficial. Exposed persons should be observed and treatment begun only if fever begins. This observation period should last 14 days. Tularemia is not transmitted from person to person. A live attenuated vaccine has been developed but is recommended only for laboratory workers. Because of the short incubation period of tularemia, vaccination is not suggested for postexposure prophylaxis. 7 7.1

VIRAL HEMORRHAGIC FEVER Microbiological and Epidemiological Characteristics and Use as a Biological Weapon

Viral hemorrhagic fevers (VHFs) are a group of zoonotic illnesses caused by small ribonucleic acid (RNA) viruses. The name of the syndrome is taken from the clinical illness, which is often characterized by a bleeding diathesis. The viruses of most concern for use as biological weapons are summarized in Table 10. None of these viruses is indigenous to North America or Europe. Other VHF viruses that are not considered a significant threat for bioterrorism include dengue, yellow fever, and the agent of hantavirus pulmonary syndrome. VHF is most often spread to humans by contact with rodents, rodent excreta,

VIRAL HEMORRHAGIC FEVERS Zoonotic ribonucleic acid (RNA) viruses (see Table 10) Biological weapon most likely aerosol Clinical manifestations Incubation period 2–21 days Initial symptoms Nonspecific viral-like illness Fever, myalgia, nausea, abdominal pain Maculopapular rash, conjunctivitis Late symptoms Bleeding diathesis Ocular, oral, gastrointestinal (GI), genitourinary (GU) mucosal bleeding Cutaneous petechiae Disseminated intravascular coagulopathy (DIC) Renal failure Shock Diagnosis (see Table 8) Serological Viral isolation in biosafety level 4 (BSL 4) laboratory Management Supportive Ribavirin for Lassa, Rift Valley fever, New World arenaviruses Respiratory isolation (see Table 11) Negative-pressure room N-95 mask

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Table 10 Viral Hemorrhagic Fevers Virus Ebola Marburg Lassa New World arenavirus c Rift Valley fever

Vector

Distribution

Unknown Unknown Rodent Rodent Mosquito

Africa Africa West Africa South America Africa Saudi Arabia Yemen

Mortality rate, %

Human-to-human transmission a

50–90 23–70 15–20 15–30 <1

Yes b Yes Yes Yes No

a

By direct contact of mucosa or abraded skin with infectious tissues or body fluids or contaminated needles. Potential for person-to-person spread by aerosol. c New World arenaviruses include Machupo, Junin, Guanarito, and Sabia. Source: Adapted from Borio et al., 2002. b

or arthropod vectors. Human-to-human transmission has occurred via mucosal or abraded skin contact with infected tissue or body fluid and by percutaneous needle injury. There are rare instances when Ebola virus may have been transmitted by respiratory aerosol. The United States and the former Soviet Union developed VHF viruses as biological weapons. The Japanese religious cult Aum Shinrikyo attempted to procure VHF viruses but fortunately was unsuccessful. If used as a biological weapon VHF viruses would most likely be aerosolized. This approach has been successfully demonstrated in experimental nonhuman primate models using Marburg, Ebola, Lassa, and New World arenaviruses. 7.2

Clinical Manifestations

The characteristics of the clinic illness vary by the type of VHF virus causing the infection. In general, after an incubation period of 2–21 days patients have a nonspecific illness with fever, myalgia, arthralgia, headache, abdominal pain, and diarrhea. The onset may be abrupt or more indolent, depending on the virus. Physical examination may reveal elevated temperature, hypotension, relative bradycardia, conjunctivitis, and a maculopapular rash. As the illness progresses, petechiae; ocular, oral, and gastrointestinal mucosa hemorrhage; and hematuria may begin. DIC and shock may progress to death. Laboratory analysis may show a leukopenia or leukocytosis, thrombocytopenia, coagulopathy, proteinuria, hematuria, and renal insufficiency. Diagnosis depends on high suspicion in the setting of a severe febrile illness associated with hemorrhagic diathesis. The diagnosis can be confirmed by detecting immunoglobulin M (IgM) antibody or demonstrating a fourfold rise in IgG antibody to the virus. Biosafety level 4 laboratories are required for virus isolation. 7.3

Management

Therapy is predominantly supportive. Ribavirin can be used intravenously for Lassa, New World arenaviruses, and Rift Valley fever. Postexposure prophylaxis with ribavirin is not recommended. There are no licensed vaccines for any of the VHF viruses that may be used as biological weapons. Because of the difficulty differentiating the various VHF and the concern of aerosol transmission with Ebola virus all patients with suspected VHF should be cared for in

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HOOFBEATS, ZEBRAS, AND SAFETY Need to include biological weapons in differential diagnosis of common clinical symptoms Biological agents of most concern (see Table 2) Clues to diagnosis of biological weapons (see Table 12) Current information and websites of interest (see Table 1) Centers for Disease Control (CDC) nationwide laboratory response network (LRN) to aid early identification of a biological attack Understanding of transmission modes, incubation periods, and risk of person-to-person transmission to lessen fear and panic (see Figure 5) Risk of person-to-person transmission and infection control measures (see Table 11) Reporting of any suspicion or concern of biological attack local or state health departments

negative-pressure rooms with 6–12 air changes per hour. Health care workers should use N-95 masks and eye protection in addition to standard precautions.

8

SAFETY AND INFECTION CONTROL

The threat of attack with a biological weapon can quickly paralyze a hospital or clinic with fear. It is imperative that health care workers (HCWs) have an understanding of transmission risk, incubation period, and measures that can be taken to prevent transmission and illness. Some agents such as anthrax, tularemia, and botulism are not transmissible from person to person. Several infections such as anthrax, plague, tularemia, and smallpox can be prevented if antibiotics or vaccines are initiated during the incubation period. Anthrax, plague, tularemia, botulism, and several VHF viruses can be effectively treated if diagnosed early. Strict adherence to infection control practices can prevent person-toperson transmission (See Figure 5). Table 11 reviews the six major category A pathogens, including incubation period, potential for person-to-person spread, and infection control measures needed for HCW safety. Standard precautions including wearing of gloves and gowns should be used if contact with any body fluids or secretions (except sweat), nonintact skin, or mucous membranes is expected. Eye guards or face shields should be used if facial splashing may occur. Hand washing is essential before and after all contact with patients. Contact precautions prevent transmission of microorganisms by direct skin-to-skin contact or indirect contact with environmental surfaces or patient care equipment. Contact precautions prevent transmission to the HCW as well as to other patients. Gowns and gloves should be used during the care of these patients. Droplet precautions are used to prevent transmission of large (>5 ␮m in size) infectious particles that may be generated by coughing, sneezing, or talking. Transmission of infection usually requires close contact (<3 ft) with the patient. Special air handling equipment and negative-pressure rooms are not needed. Patients with pneumonic plague should be cared for under these precautions. Airborne precautions are intended to prevent transmission by airborne droplet nuclei (<5 ␮m in size) that may remain suspended in air for long periods. Airborne precautions should be used for patients with smallpox and VHF. Patients with these infections should be placed in negative-pressure rooms that have 6–12 air exchanges per hour. HCWs should

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Figure 5 Prevention of bioweapon-related illnesses. (A) Infection risks and exposure may lead to a bioweapon-related illness. Fear and uncertainty interfere with any efforts to prevent infection and illness. (B) The public’s and health care worker’s fear of contagion and illness from a biological weapon can be lessened by understanding of the mechanism of transmission (or lack thereof) and potential for infectivity. Some agents are not transmissible from person to person. Infection control precautions can be instituted to prevent exposure. Therapeutic interventions (antibiotics, vaccines, antitoxins) can prevent or lessen infection in those already exposed. These measures can block progression to illness and help contain fear and uncertainty. VHF, viral hemorrhagic fever.

use standard precautions and a fit-tested N-95 mask. If the HCW cannot be properly fitted for a N-95 mask, then a powered air-purifying respirator (PAPR) should be used. 9

HOOFBEATS AND ZEBRAS

The pathogens most feared as biological weapons are unusual. Most practicing clinicians have not seen any of them, and thus recognition, diagnosis, and management of these infections are challenging. The early identification is vital for instituting appropriate infection control measures and treatments and controlling mass panic. This requires a change in our thinking about the old adage concerning hoofbeats and zebras. We now need to think about these zebras in addition to the horses. The differential diagnosis of communityacquired pulmonary infection now needs to include inhalation anthrax, plague, and tularemia. The differential diagnosis of a diffuse vesicular/pustular skin rash must consider smallpox in addition to chickenpox. A tender lymph node may represent tularemia or plague. A paralytic illness may be botulism. Shock and DIC may represent VHF.

2–3 days 7–17 days

1–14 days

Plague (pneumonic)

Smallpox

Tularemia

a

Animal or arthropod Inhalation Contact with infected material Animal or arthropod Contact with infected blood or secretions Possibly airborne (Ebola)

Inhalation Contact with lesions Contact with clothing/linens

Ingestion of contaminated food Ingestion of contaminated food Inhalation of toxin if aerosolized Inhalation

Contact with spores of nonintact skin

Inhalation

See text and www.cdc.gov/ncidod/hip/isolat/isopart2.htm for definitions.

Viral hemorrhagic fevers 2–21 days

1–7 days 1–5 days

1–7 days (up to 60 days) 1–7 days

Incubation period Mode of transmission

Gastrointestinal Botulism

Cutaneous

Anthrax Pulmonary

Disease

Airborne and contact precautions with mask and eye protection Use of appropriate airborne isolation room N-95 respirator worn by all staff who enter room Yes Direct contact with body fluids Possibly airborne aerosol (Ebola)

No

Droplet until 72 hours of antibiotic therapy Airborne and contact Use of appropriate airborne isolation room N-95 respirator worn by all staff who enter room Exposed individuals quarantined during incubation period Standard

Standard Standard

Standard and contact

Standard

Precautions a

Yes Droplet aerosol Yes Airborne aerosol Direct contact with lesion Contact with clothing/linens

Possible Direct contact of nonintact skin with draining lesion No No

No

Person-to-person transmission

Table 11 Transmission and Infection Control Measures for Category A Bioweapon Agents

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A covert biological attack may also be recognized by disease surveillance in the office, emergency department, hospital, or regional health department. Increases in acute severe respiratory illnesses, clusters of persons with similar symptoms, influenza-like illness out of season, or isolation of unusual pathogens may herald the attack. Table 12 summarizes some of the zebras that should be considered when hearing hoofbeats. Sir William Osler, in his speech to the British soldiers in the camps at Churn at the start of World War I, referred to the devastation of poor sanitation and infectious disease that haunts any army. The following quotation, from that speech, was frighteningly prophetic of the devastation a biological weapon could cause. It is incumbent upon us to heed his warning. What I wish to urge is a true knowledge of your foes, not simply the bullets, but of the much more important enemy—the bacilli. In the wars of the world they have been as Saul and David—the one slaying thousands, the other tens of thousands.

Table 12 Clues to Recognizing a Biological Attack Clues a Flulike illness followed by rapid progression to respiratory failure Widened mediastinum Meningitis GPR in CSF, sputum, or blood Gram stain or culture Painless ulceration with necrosis and edema GPR from wound culture Acute fulminant CAP Hemoptysis GNR on Gram stain or culture of sputum Fever preceding vesicular/pustular rash Suspected chickenpox in patient with history of varicella or immunization Vesicular rash on face, extremities > trunk Acute CAP Descending paralysis Bulbar palsies Normal mental and CSF findings Afebrile Shock with hemorrhagic diathesis Pneumonia deaths in otherwise healthy young adults Clusters of unusual, severe, or unexplained illnesses Unexplained critical illness in healthy young adults Seasonal illnesses at different time of year Outbreak of disease in nonendemic area a

Incubation period average (range)

Biological agent

2–6 days (2 days–8 weeks)

Inhalational anthrax

2–6 days

Cutaneous anthrax

1–3 days

Pneumonic plague

12–14 days (7–17 days)

1–3 days 12–72 Hours b (2 hours–8 days)

2–21 days c

Smallpox

Inhalational tularemia Botulism

Viral hemorrhagic fever Report to local department of health

CAP, community-acquired pneumonia; GPR, gram-positive rod (B. anthracis); GNR, gram-negative rod (Y. pestis); CSF, cerebrospinal fluid. b For ingestion of toxin; limited data are available on inhalational form; suggested to be within 72 hours of exposure. c Variable by type of virus.

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BIBLIOGRAPHY Arnon SS, Schecter R, Inglesby TV, Henderson DA, Bartlet JG, Ascher MS et al. Botulinum toxin as a biological weapon: Medical and public health management. JAMA 285:1059–2081, 2001. Breman JG, Henderson DA. Diagnosis and management of smallpox. N Engl J Med 346:1300– 1308, 2002. Borio L, Inglesby T, Peters CJ, Schmaljohn AL, Hughes J, Jahrling PB, Ksiazek T et al. Hemorrhagic fever viruses as biological weapons: Medical and public health management. JAMA 287: 2391–2405, 2002. Dennis D, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E et al. Tularemia as a biological weapon: Medical and public health management. JAMA 285:2763–2773, 2001. Dixon TC, Meselson M, Guillemin J, Hanna PV. Anthrax. N Engl J Med 341:815–826, 1999. Emerg Infect Dis 5(4), 1999. Feldman KA, Enscore RE, Lathrop SL, Matyas BT, McGuill M, Schriefer ME et al. An outbreak of primary pneumonic tularemia on Martha’s Vineyard. N Engl J Med 345:1601–1606, 2001. Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Jahrling PB, Hauer J et al. Smallpox as a biological weapons: Medical and public health management. JAMA 281:2127–2137, 1999. Inglesby TV, David DT, Henderson DA, Bartlett JG, Ascher MS, Eitzen E et al. Plague as a biological weapon. JAMA 283:2281–2290, 2000. Inglesby TV, O’Toole T, Henderson DA, Bartlett JG, Ascher MS, Friedlander AM et al. Anthrax as a biological weapon 2002: Updated recommendations for management. JAMA 287:2236– 2252, 2002. Jernigan JA, Stephens DS, Ashford DA, Omenaca C, Topiel MS, Gailbraith M. Bioterrorism-related inhalational anthrax: The first 10 cases reported in the United States. Emerg Infect Dis 7(6): 933–944, 2001. Notice to readers: Considerations for distinguishing influenza-like illness from inhalational anthrax. MMWR 50(44):984–986, November 9, 2001. Osterholm M, Schwartz J. Living Terrors. 2000. New York: Delta Trade Publishing. Rotz LD, Khan AS, Lillibridge SR, Ostenoff SM, Hughes JM. Public health assessment of potential biological terrorism agents. Emerg Infect Dis 8:225–229, 2002. 21st century bioterrorism and germ weapons. U.S. Army field manual for the treatment of biological warfare casualties. Departments of the Army, the Navy, the Air Force and Commandant, Marine Corps. Washington, D.C. July 17, 2000. Update: Investigation of bioterrorism-related anthrax and interior guidelines for exposure management and antimicrobial therapy. MMWR 50(42):909–919, October 26, 2001. Update: Investigation of bioterrorism-related anthrax and interior guidelines for clinical evaluation of persons with possible anthrax. MMWR 50(43):941–948, November 2, 2001. Varkey P, Poland GA, Cockerill FR, Smith TF, Hagen PT. Confronting bioterrorism: Physicians on the front line. Mayo Clin Proc 77:661–672, 2002.

Index

Abacavir, 511 dose, 794 postexposure prophylaxis, 794, 799 toxicities, 527, 794 Abdominal pain appendicitis, 481 approach to patient, 473–475, 476 cholangitis, 480 cholecystitis, 479 diverticulosis, 482 hepatitis abscess, 480 human immunodeficiency virus infection, 530 pancreatic abscess, 487 peritonitis, 478 rocky mountain spotted fever, 613 splenic abscess, 487 tularemia, 846 viral hemorrhagic fever, 848 Abiotrophia sp. diagnosis, 108 endocarditis, 354, 359 Abscess appendiceal, 481 brain, 201, 353 diverticular, 483 hepatic, 484–487 injection drug use, 679 myocardial, 351 renal, 282, 488 occult and FUO, 163, 165 pancreatic, 487 paravertebral, 560 pericholecystic, 480

[Abscess] perinephric, 282 skin, 679 splenic, 487, 682 Staphylococcus aureus, 375 submandibular, 224–225 tubo-ovarian, 308 Absolute neutrophil count, 666, 672 Acanthamoeba sp. keratitis, 424 Achlorhydria, 664 causes of, 602 infection due to, 602 Acid fast bacilli (see Myobacterium) Nocardia, 259 stain, 100, 259 tuberculosis, 251–264 Acinetobacter sp. bacteremia, 178, 181 Acquired Immune Deficiency Syndrome (see human immunodeficiency virus) Acrodermatitis chronica atrophica, 605 Actinobacillus actinomycetemcomitans diagnosis, 108 endocarditis, 360 Actinomyces sp. culture, 98 submandibular abscess, 225 Activated protein C (see Drotrecogin alfa) Acute phase reactant fever, 9

Acute retroviral syndrome, 500– 502 CD4 count, 515 differential diagnosis, 501 signs and symptoms, 501 Acute urethral syndrome, 316 Acyclovir cutaneous herpes simplex virus, 407 dosage in renal disease, 88 genital herpes simplex virus, 312, 332 herpes keratitis, 425 herpes zoster ophthalmicus, 426 herpes simplex virus 1 encephalitis, 24 outpatient parenteral antibiotic therapy, 122, 125 oral herpes, 222 pregnancy, 649 varicella zoster, 223, 408, 777 Adefovir dipivoxil hepatitis B virus, 464 Adenovirus common cold, 266 conjunctivitis, 413, 415 keratitis, 424 nucleic acid detection, 106 pharyngitis, 189 pneumonia, 780 Aeromonas sp. bacteremia, 178 diagnosis, 111 lacerations, 382 puncture wounds, 387 skin infections, 374, 380

855

856 Albendazole enterobiasis, 643 giardiasis, 638 hookworm, 643 microsporidiasis, 638 Microsporidium, 517, 521 strongyloidiasis, 643 Alcoholism skin infection, 374, 376 Alkaline phosphatase elevation fever of unknown origin, 167 Allergic bronchopulmonary aspergillosis, 628 Allopurinol fever, 154 Alopecia syphilis, 312 Alternaria sp. keratitis, 427 Amantadine, 240, 274, 275 elderly, 779 prophylaxis, 277 Amblyomma ticks ehrlichiosis, 32, 610 lyme disease, 601 rocky mountain spotted fever, 29 tularemia, 617 Amebiasis (also see Entamoeba histolytica) clinical syndromes, 640 diagnosis, 640 diarrhea, 445, 639–640 genital ulcer, 309 therapy, 638 Amikacin hemodialysis infection, 199 Mycobacterium avium, 520 neutropenic fever, 36 peritoneal dialysis infections, 702 Aminoglycosides dosing, 84, 90 hemodialysis, 699–700 intraabdominal infections, 476, 484, 485 once daily dosing, 90 outpatient parenteral therapy, 122 peritoneal dialysis, 702 pharmacodynamics, 82, 83 pharmacokinetics, 78, 80 pregnancy, 647 tissue penetration, 93 traditional dosing, 91 Amoxicillin, 46 anthrax cutaneous, 827, 830

Index [Amoxicillin] prophylaxis, 830 cervicitis, 307 costs, 42 dosage, 42 dose with renal disease, 45, 88 endocarditis prophylaxis, 370 Helicobacter pylori, 491 Lyme disease, 606 otitis media, 196, 197 pharmacokinetics, 44 pneumonia, 238 sinusitis, 47 spectrum, 47 urinary tract infection, 280, 650 Amoxicillin–clavulanate (Augmentin) animal bit infections, 76 costs, 42 decubitus ulcers, 776 diabetic foot infections, 596 dosage, 42 dose with renal disease, 45, 88 intraabdominal infections, 476, 484, 485 neutropenic fever, 36–37 otitis media, 197 pharmacokinetics, 44 pneumonia, 238, 782 pregnancy, 647 septic arthritis, 538 sinusitis, 197 skin infections, 378 urinary tract infections, 286, 287 Amphotericin B bladder irrigation, 297 blastomycosis, 626 coccidioidomycosis, 627 cryptococcal meningitis, 517, 519, 628 drug fever, 152 histoplasmosis, 624, 625 outpatient parenteral therapy, 122, 125 oral swish and swallow, 220 urinary tract infection, 297 Amphotericin B lipid complex (Abelcet), 125 Amphotericin B liposome (AmBisome) outpatient parenteral antibiotic therapy, 125 Ampicillin bacterial meningitis, 23 chorioamnionitis, 652 cost, 125 diabetic foot infection, 596

[Ampicillin] dosage in renal disease, 88 dose, 125 endocarditis, 363, 365, 370 half life, 125 hemodialysis infection, 699 intraabdominal infection, 476, 484, 485, 487 outpatient parenteral therapy, 125 oral, 46 pelvic inflammatory disease, 653 peritoneal dialysis infection, 702 pregnancy, 646–647 prostatitis, 341 pyelonephritis, 299, 651 urinary tract infections, 286 vertebral osteomyelitis, 568 Ampicillin–sulbactam (Unasyn) animal bites, 711 cost, 125 decubitus ulcer, 776 diabetic foot infection, 596 dose, 125 outpatient parenteral therapy, 125 pneumonia, 770 pregnancy, 647, 651 pyelonephritis, 651 septic arthritis, 538 skin infections, 378 Amprenavir, 511 toxicities, 527 Anaerobic infections animal bites, 711 antibiotics for, 484 antibiotic therapy, 184 bacteremia, 179 chorioamnionitis, 652 cultures, 105 decubitus ulcers, 776 diabetic foot infection, 589 endometritis, 652 hepatic abscess, 485 intraabdominal infection, 476, 483, 484, 485, 487 pancreatic abscess, 487 pharyngitis (Vincent’s angina), 189 primary peritonitis, 478, 483 secondary peritonitis, 478, 483 specimen collection, 98 splenic abscess, 487 Anatomic immunity, 661, 662 defects in, 663 Ancylostoma sp. (see hookworm)

Index Angiostrongylus sp., 634 clinical syndromes, 636 exposure risk, 636 Angular cheilitis, 219 Animal bites, 710–712 approach to management, 717 rabies prophylaxis, 716–719 treatment, 711 Anopheles sp. malaria, 33 Anthrax, 383–384, 824–836 cutaneous, 383, 715, 827, 828, 835, 852 differential diagnosis, 829 treatment, 830 diagnosis, 834, 835 differentiation of suspicious powder, 834 gastrointestinal, 831 infection control, 851 inhalational, 827–831, 835 approach to diagnosis, 832 clinical manifestations, 833, 852 differential from influenza, 830 prophylaxis, 830 therapy, 830 pathophysiology, 825–826 post-exposure prophylaxis, 830, 836 transmission, 851 United States attack, 833–834 vaccine, 836 Antibiotics bacteriocidal, 81–82 bacteriostatic, 81–82 concentration dependent, 82, 84 concentration independent, 82, 86 dosage in hepatic failure, 85 dosage in renal failure, 85 drug interactions, 87 half life, 125 outpatient parenteral ambulatory therapy, 122, 125 ophthalmic, 420–421 oral, 41–75 pharmacodynamics, 77, 80–85 pharmacokinetics, 77–80 pregnancy, 646–649 susceptibility testing, 112 E-test, 113 synergy, 81 topical, 385 Antibiotic associated diarrhea, 449–452

857 Anticholinergic agents common cold, 268, 269 Antigen detection tests, 105 Antigenic drift influenza, 272 Antigenic shift influenza, 272 Antihistamines common cold, 269 Antinuclear antibody (ANA) fever of unknown origin, 163 systemic lupus erythematosus, 156 Antineutrophil cytoplasmic antibodies (ANCA), 157, 158 Antipyretic therapy, 13–15 cyclooxygenase, 14 history, 13 pros and cons, 13, 14 Antiretroviral agents current agents, 511 recommendations for initiating, 510 toxicities, 527 Antistreptolysin-O (ASLO) rheumatic fever, 159 Aphthous ulcerations genital, 327 oral stomatitis, 223 Aplastic anemia parvovirus B19 infection, 143 Appendicitis 481–482 key points, 479 pelvic inflammatory disease, 308 Arcanobacterium haemolyticum erythema, diffuse, 140 pharyngitis, 189 Arenavirus new world, 848 Arthritis, reactive, 537 Arthritis, septic, 535–553 antimicrobial therapy, 538, 547–548 approach to the patient, 542 coccidioidomycosis, 626 diagnostic imaging, 545–547 differential diagnosis, 543 endocarditis, 353 epidemiology, 535, 538 fungal, 550–551 gonococcal, 321, 543 joints involved, 536 key points, 536, 548 Lyme, 551–552, 603–605 microbiology, 537, 538 monoarticular, 535, 541, 550 mycobacterial, 550, 551

[Arthritis, septic] nongonococcal, 541–543 outpatient parenteral antibiotic therapy, 121 pathogenesis, 537, 539 polyarticular, 535, 543 prosthetic joint, 548–550 key points, 548 risk factors, 539, 541 synovial fluid analysis, 544 syphilis, 312 viral, 535, 552–553 Ascariasis cat (see toxocara) classification, 635 dog (see toxocara) eosinophilia, 635 giant intestinal worm, 635, 642–643 risks, 643, 636 stool exam, 634, 642 syndromes, 643, 636, 642 therapy, 643, 644 Ascitic fluid peritonitis, 478 Asparaginase fever, 154 Aspergillus sp. allergic bronchopulmonary aspergillosis, 628 fungemia, 182 malignant otitis externa, 784 neutropenia, 666 pneumonia, 628 Aspiration pneumonia, 236 Asplenic patients, 136 pneumococcal meningitis, 21 Atovaquone babesiosis, 613 malaria prophylaxis, 755 Pneumocystis carinii, 518 Atrioventricular block Lyme disease, 605, 607, 603 Atypical cells of uncertain significance (ASCUS), 315 Auramine-rhodamine stain, 100 Azithromycin, 51 adverse reactions, 57–58 babesiosis, 613 cat scratch disease, 722 cervicitis, 306, 307 chancroid, 314 clinical indications, 55 costs, 56, 125 cryptosporidiosis, 638 dose, 56, 125 dose in renal disease, 54, 88 endocarditis prophylaxis, 370

858 [Azithromycin] Mycobacterium avium, 520 nephritis, 324 outpatient parenteral antibiotic therapy, 125 otitis media, 197 pharmacokinetic properties, 53 pharyngitis, 192 pneumonia, 238, 781 sinusitis, 197 spectrum of activity, 55 Aztreonam costs, 125 dose, 125 dose in renal disease, 88 outpatient parenteral antibiotic therapy, 125 osteomyelitis, 578 primary peritonitis, 478 vertebral osteomyelitis, 567, 568 Babesiosis, 612–613 diagnosis, 101, 612–613, 713 key points, 609 treatment, 613 splenectomy, 663, 713 zoonosis, 713 Bacillary angiomatosis, 149, 522, 720 Bacille Calmette-Gue´rin vaccine (BCG), 263 Bacillus sp. bacteremia, 180 diarrhea, 445, 446 Bacillus anthracis, 824 (also see anthrax) biological weapon, 824–836, 383–384 inducible beta-lactamase, 831 serological diagnosis, 107 toxins, 825–826 zoonosis, 715, 825 Back pain endocarditis, 353 Bacteremia, 174–185 (also see septicemia) Acinetobacter sp., 178, 181 Aeromonas sp., 178 anaerobes, 179 Bacillus sp., 180 Bacteroides sp., 178 cholangitis, 480 chorioamnionitis, 652 Clostridium sp., 180 Corynebacterium sp., 180 cutaneous manifestations, 389– 390

Index [Bacteremia] Escherichia coli, 178 endocarditis, 349, 690 Enterobacter sp., 178 Enterococcus, 176, 349 Fusobacterium sp., 178 gram-negative diplococci, 181 gram-negative rods, 177–179 gram-positive cocci, 174–177 gram-positive rods, 179–181 Gram stain, 101 group A Streptococcus, 176 Group B Streptococcus, 176 Haemophilus sp., 178 hemodialysis access, 697, 698 immune compromised host, 373 injection drug user, 680–682, 690 Klebsiella sp., 178 Lactobacillus sp., 180 Listeria monocytogenes, 180 Moraxella catarrhalis, 181 Morganella sp., 178 Mycotic aneurysm, 682 Neisseria gonorrhea, 181, 390 Neisseria meningitis, 181, 390 neutropenic fever therapy, 37 osteomyelitis, 557, 559 Pasteurella multocida, 178, 181 Peptostreptococcus, 176 petechiae, 135 polymicrobial, 182 Proteus sp., 178 Pseudomonas aeruginosa, 178 Salmonella sp., 178 Staphylococcus aureus, 176– 177 Streptococcus pneumoniae, 176 symptoms and signs, 172 Viridans streptococcus, 176 Bacterial vaginosis, 301–303 diagnosis, 302 postpartum, 303 pregnancy, 303 treatment, 303 urinary tract infections, 282 Bacteriuria asymptomatic, 298–299, 773 elderly, 773 pregnancy, 649–651 prostatitis, 338, 339 urinary tract infection, 279– 280, 283, 285, 294, 296 Bacteroides sp. animal bites, 711 bacteremia, 178 decubitus ulcers, 387

[Bacteroides sp.] diabetic foot infection, 589 endometritis, 652 human bites, 388 myonecrosis, 28, 30 necrotizing fasciitis, 30, 382 primary peritonitis, 478 secondary peritonitis, 483 submandibular abscess, 225 surgical site, 389 Balantidium sp. diarrhea, 642 Bartholinitis, 316 Bartonella, sp. endocarditis, 354, 360 lysis centrifugation, 108 skin nodules, 149 Bartonella henselae (also see cat scratch disease) cat scratch disease, 719 serological diagnosis, 107, 721 skin nodules, 149, 522 Bartonella quintana skin nodules, 149, 522 Becaplermin gel, 597 Bedsores (see decubitus ulcers) Behc¸et’s disease epididymitis, 342 genital ulcers, 310, 327 oral ulcers, 211 Bell’s palsy Lyme disease, 603 shingles, 408 Beta-lactam antibiotics, 41–51 adverse reactions, 49–51, 154 mechanism of action, 41 pharmacological properties, 43 post-antibiotic effect, 83–84 resistance, 43 skin testing, 50 synergy with aminoglycosides, 81 tissue penetration, 93 urinary tact infection, 287 Bichloracetic acid (BCA), 316, 335 Bioavailability, 93 antibiotics, 96 Bioterrorism, 821–853 anthrax, 824–836, 383–384 biological agents, 826, 824 botulism, 843–845 diagnosis clinical, 835, 852 laboratory, 835 infection control, 849–850 key points, 825, 837, 842, 844, 845, 847, 849

Index [Bioterrorism] laboratory response network, 824 plague, 841–843 recognition, 852 smallpox, 836–841 transmission, 851 tularemia, 845–847 viral hemorrhagic fever, 847– 849 web-based resources, 822, 824 Bites – animal, 388, 574, 575 Bites – human, 388, 574, 575 Bites – insect erythema migrans, 603 Blackwater fever, 34 Blastocystis hominis, 642 diarrhea, 445, 642 Blastomyces dermatitidis, 625 blastomycosis, 625–626 diagnosis, 623, 625 geographical distribution, 623 major syndromes, 623, 625 therapy, 623, 625 serology, 107 Blastomycosis (see Blastocystis dermatitidis) Bleomycin drug fever, 152 Blepharitis, 419, 423 differential diagnosis, 412, 419, 423 key points, 422 management, 423 Blood culture, 105–108, 169–185 antimicrobial therapy, 183–185 contamination, 98, 107 endocarditis, 353 gram-negative diplococci, 181 gram-negative rod, 177–179 gram-positive cocci, 174–177 gram-positive rod, 177–179 histoplasmosis, 624 indications, 171–172 immune compromised host, 673 inhalation anthrax, 829 interpretation of results, 174– 183 key points, 170 lysis centrifugation system, 107, 171 negative results, 182 number to obtain, 105–106, 173, 174 polymicrobial, 182 pyelonephritis, 650 routine technique, 169–171, 173

859 [Blood culture] septic arthritis, 544 site preparation, 98 timing, 106, 173 vertebral osteomyelitis, 563 yeast, 182 yield, 105 Bone scan, 563, 654, 565 diabetic osteomyelitis, 587, 588 Blood-brain barrier fever, 10 Booster effect tuberculosis testing, 257–258 Bordetella pertussis bronchitis, 243, 245 nucleic acid detection, 106 treatment, 244 Borrelia burgdorferi, 600 (also see Lyme disease) arthritis, 535, 538, 551–552 perinatal infection, 655 serological diagnosis, 107 Borrelia hermsii (see relapsing fever) Borrelia recurrentis (see relapsing fever) Botfly clinical syndromes, 637, 769 geographic local, 637 myiasis, 769 risk exposure, 637 Botulism bioterrorism, 843–845 clinical manifestations, 844, 835 diagnosis, 844, 835, 852 differential diagnosis, 844 infection control, 851, 845 management, 845 transmission, 851 food borne, 843 injection drug use, 691 wound, 843 Bradycardia babesiosis, 612 drug fever, 153 Branched chain DNA assay (bDNA) HIV testing, 502 Brain abscess, 690 Bronchiectasis, 242 Bronchitis, 242–249 acute, 242–245 antibiotics for, 230, 247 approach to patient, 228 ‘‘chest cold,’’ 245 chronic, 245–246 influenza, 273

[Bronchitis] key points, 242 pathogens, 243, 247, 245 risk stratification, 247 Bronchoalveolar lavage (BAL) HIV infection, 529 Brucella sp. diagnosis, 713 endocarditis, 354, 360 FUO, 166 lysis centrifugation, 108 septic arthritis, 538, 543 serological diagnosis, 107, 713 vertebral osteomyelitis, 566 zoonosis, 713 Brugia sp., 634 (see also filariasis) classification, 634 exposure risk, 637 geographic locale, 637 skin lesions, 637 Brudzinski sign, 18 Bullous disease impetigo, 377 Bubonic plaque (see Yersinia pestis) Burkholderia sp., 829 Burn infections, 389 Bursitis, 553–555 approach to patient, 542 key points, 554 Calymmatobacterium granulomatis (see donovanosis) genital (female), 309 genital (male), 326 Campylobacter sp., 440 acquired immune deficiency syndrome, 454 diagnosis, 111, 440, 445 diarrhea, 440, 446, 454 reactive arthritis, 541 stool culture, 446 treatment, 448 Campylobacter jejuni diagnosis, 712 diarrhea, 440, 712, 756 traveler’s diarrhea, 756 Campylobacter pylori (see Helicobacter pylori) Candida infections antifungal sensitivities, 297 cell mediated immune defect, 668 diarrhea, 449 endophthalmitis, 433 esophagitis, 509, 517, 519, 629 folliculitis, 385

860 [Candida infections] fungemia, 182, 390 hepatic abscess, 486 human immunodeficiency virus, 499, 508, 509 intraabdominal infection, 484 keratitis, 427 malignant otitis externa, 784 neutropenia, 666 oropharyngeal, 112, 211, 218– 219, 629 paronychia, 386 peritoneal catheter infections, 703 skin lesions, 390, 400–401 surgical site, 389 urinary tract infection, 281, 296–297 vaginitis, 101 vertebral osteomyelitis, 566 vulvovaginitis, 303–304, 629 Canker sores (see aphthous ulcerations) Capnocytophaga sp. animal bites, 388, 711 exposure risk, 132 petechiae, 136 rash, 132 splenectomy, 663 Capsaicin (Zostrix), 408, 777 Carbamazepine fever, 154 Carbenicillin, 48 costs, 42 dosage, 42 dose with renal disease, 45 pharmacokinetics, 44 spectrum, 47 Carbuncles, 385–386 key points, 384 Cardiobacterium hominis diagnosis, 108 endocarditis, 360 Carditis rheumatic fever, 159 Cat scratch disease, 719–722 atypical, 720 diagnosis, 720–721 management, 721 symptoms, 791 therapy, 721–722 Cavernous sinus thrombosis, 430 CD4 antiretroviral therapy, 510 human immunodeficiency virus, 496, 502, 503, 505 human immunodeficiency virus assessment, 513–515, 672

Index [CD4] opportunistic infections, 502, 515, 527 prophylaxis for human immunodeficiency virus, 508 Cefadroxil, 48 costs, 42 dose, 42 Cefaclor, 49 costs, 42 dose, 42 dose with renal disease, 45 pharmacokinetics, 44 spectrum, 47 Cefazolin cost, 125 dose, 125 dose in renal disease, 88 endocarditis, 364 endocarditis prophylaxis, 370 half life, 125 hemodialysis infection, 699 outpatient parenteral antibiotic therapy, 125 peritoneal infection, 702 pharmacokinetics, 80 skin infections, 378 surgical prophylaxis, 490 vertebral osteomyelitis, 567, 568 Cefdinir, 49 costs, 42 dose, 42 Cefepime costs, 125 dose, 125 neutropenic fever, 36–37 outpatient parenteral antibiotic therapy, 125 Cefixime, 49 cervicitis, 306, 307 costs, 42 decubitus ulcer, 776 dose, 42 dose with renal disease, 45 pharmacokinetics, 44 septic arthritis, 538 spectrum, 47 Cefotetan decubitus ulcers, 776 diabetic foot infection, 596 dose in renal disease, 88 intraabdominal infection, 476, 484, 485 pelvic inflammatory disease, 653 pregnancy, 646 surgical prophylaxis, 490

Cefoxitin decubitus ulcers, 776 pelvic inflammatory disease, 308 pregnancy, 646 Cefpodoxime proxetil, 49 costs, 42 dose, 42 dose in renal disease, 45, 88 intraabdominal infection, 476, 484, 485 pharmacokinetics, 44 pneumonia, 238 urinary tract infection, 286 Cefprozil, 49 costs, 42 dose, 42 pneumonia, 238 Ceftazidime cost, 125 diabetic foot infection, 596 dose, 125, 792 dose in renal disease, 88, 702 half life, 125 meningitis, 22 necrotizing fasciitis, 30 neutropenic fever, 36 outpatient parenteral antibiotic therapy, 125 orchitis, 345 osteomyelitis, 575, 578 peritoneal dialysis, 702 pneumonia, 242 septic arthritis, 538 septic shock, 39 vertebral osteomyelitis, 567, 568 Ceftibuten, 49 costs, 42 dose, 42 Ceftriaxone cervicitis, 307 chancroid, 314 cost, 125 diabetic foot infection, 596 dose in hepatic failure, 92 dose in renal disease, 88 endocarditis, 362, 365 epididymitis, 344 half life, 125 intraabdominal infection, 484, 485, 476 Lyme disease, 600 meningitis, 22–23 neutropenic fever, 37 outpatient parenteral antibiotic therapy, 122, 125 osteomyelitis, 575, 578

Index [Ceftriaxone] vertebral, 567, 568 otitis media, 197 pelvic inflammatory disease, 308 pneumonia, 781 pregnancy, 651 primary peritonitis, 478 resistance to Pneumococcus, 234 secondary peritonitis, 484 septic arthritis, 538 septic shock, 39 sinusitis, 197 skin infections, 378 splenic abscess, 487 urethritis, 324 urinary tract infection, 286, 651 Cefuroxime costs, 125 dose, 125 outpatient parenteral antibiotic therapy, 125 pneumococcal resistance, 234 pneumonia, 238, 781, 782 Cefuroxime axetil, 49 costs, 42 dose, 42 dose in renal disease, 45 Lyme disease, 606 otitis media, 197 pharmacokinetics, 44 pharyngitis, 192 pneumococcal resistance, 234 pneumonia, 238, 782 sinusitis, 197 spectrum, 47 Cell mediated immunity, 661, 662 causes, 662 defects, 667–670 pathogen, 662 Cellulitis, 379–382 bursitis, 553 cutaneous anthrax, 829 erythema migrans, 603 injection drug use, 678–679 key points, 379 outpatient parenteral antibiotic therapy, 121 prophylactic antibiotics, 382 recurrent, 382 risks, 380 Staphylococcus aureus, 375, 380 Streptococcus pyogenes, 376, 380 treatment, 378–382

861 Centers for Disease Control and Prevention (CDC) diarrhea, 438 sexually transmitted diseases guidelines, 319, 329 Central venous catheters blood cultures, 107, 173 complications, 118 hemodialysis access, 697 hepatic abscess, 485 infections, 126, 127 outpatient parenteral antibiotic therapy, 118–120 Staphylococcus aureus bacteremia, 177 vertebral osteomyelitis, 560 Cephalexin, 48 costs, 42 diabetic foot infection, 596 dose, 42 dose in renal disease, 45, 88 endocarditis prophylaxis, 370 otitis media, 197 pharmacokinetics, 44 pharyngitis, 192 sinusitis, 197 skin infections, 378 spectrum, 47 urinary tract infection, 286, 650 Cephalosporins (oral), 48–49 cephalosporin resistance, 234 cross reactions with penicillin, 50 Cephradine, 48 costs, 42 dose, 42 Cerebrospinal fluid (CSF) Acquired immune deficiency syndrome dementia, 522 anthrax, 828 bacterial antigen detection, 109 bacterial meningitis, 19 culture, 108–109 cryptococcal meningitis, 628 cryptococcus meningitis, 519 herpes simplex-1 encephalitis, 24 Lyme disease, 605 tuberculosis, 254 viral encephalitis, 630 Cerebrospinal fluid shunts meningitis, 20 Cervicitis, 306 treatment, 306, 307 Chalazion, 419 Chancre, 312, 329, 383

Chancriform lesions, 382–384 Bacillus anthracis, 383 Francisella tularensis, 383 key points, 383 Mycobacterium marinum, 383 Sporothrix schenckii, 383 Treponema pallidum, 382 Chancroid, 309, 314 counseling, 333 male, 325–333 partner notification, 333 treatment, 314, 331 Charcot joint, 582, 584, 585, 588 Charcot’s triad, 480 Chemosis, 410, 412, 434 Chest x-ray, 230 anthrax, 828, 831, 833 blastomycosis, 625 coccidioidomycosis, 626 cryptococcosis, 627 follow up after pneumonia, 240 histoplasmosis, 621–624 human immunodeficiency virus infection, 528 plague, 843 Pneumocystis carinii pneumonia, 516 pneumonia vs. bronchitis, 230 tuberculosis, 258, 260, 520 tularemia, 846 Cheyletiella sp. (see mites), 397 Chicken pox (also see Varicella zoster virus), 407 Chiggers, 397 Chlamydia pneumoniae bronchitis, 243, 245 pharyngitis, 189 pneumonia, 233, 234–235 serological diagnosis, 107 Chlamydia psittaci endocarditis, 354, 360 fever of unknown origin, 166 pneumonia, 712 rash, 145 serological diagnosis, 107 Chlamydia trachomatis arthritis, 543 cervicitis, 306 conjunctivitis, 413 diagnosis, 110 epididymitis, 342 Fitz-Hugh-Curtis syndrome, 317 lymphogranuloma venereum, 326 nucleic acid detection test, 106 pelvic inflammatory disease, 308, 653

862 [Chlamydia trachomatis] perinatal screening, 653, 654 proctitis, 446 prostatitis, 339 treatment, 307 urethritis (female), 304, 316 urethritis (male), 319–325 Chloramphenicol dosage in hepatic disease, 92 plague, 843 rocky mountain spotted fever, 32 Chloroquine phosphate malaria prophylaxis, 755 malaria treatment, 763 Cholangitis, 480–481 cryptosporidium, 640 cytomegalovirus, 522 key points, 475 Cholecystitis, 478–480 acalculous, 479 cryptosporidiosis, 520, 530, 640 key points, 479 microsporidiosis, 520, 530 Chronic granulomatous disease, 662, 667 Chorea, Sydenham, 159 Chorioamnionitis, 652 Chronic fatigue syndrome, 727– 734 case definition, 728 clinical illness, 727–730 management, 730–732 Chronic fatigue and immunodeficiency syndrome (CFIDS), 727 Cidofovir cytomegalovirus infection, 521 outpatient parenteral antibiotic therapy, 122, 125 smallpox, 840 Cimetidine cutaneous warts, 404 Cinoxacin, 64 costs, 56 dose, 56 Ciprofloxacin, 65–67 adverse reactions, 66 animal bites, 717 anthrax cutaneous, 827, 830 inhalation, 829, 830 prophylaxis, 830 cat scratch disease, 722 cervicitis, 307 chancroid, 314 costs, 56

Index [Ciprofloxacin] diabetic foot infections, 596 dose, 56 dose in renal disease, 54, 88 drug interactions, 94 epididymitis, 344 intraabdominal infection, 476, 484, 485 hemodialysis infections, 699 meningococcal prophylaxis, 21 Mycobacterium avium, 520 neutropenic fever, 36–37 outpatient parenteral antibiotic therapy, 125 orchitis, 345 osteomyelitis, 575, 578 peritoneal dialysis infection, 702 pharmacokinetic properties, 53 plague, 843 prostatitis, 341 secondary peritonitis, 484 septic shock, 39 spectrum, 65, 59 traveler’s diarrhea, 756, 757 tularemia, 846 urethritis, 324 urinary tract infections, 286, 291, 295 Ciprofloxacin HC Otic, 197 Clarithromycin, 52 adverse reactions, 57–58 clinical indications, 55 costs, 56 dose, 56 dose in renal failure, 54 drug interactions, 55, 94 Helicobacter pylori, 491 Mycobacterium avium, 517, 520 otitis media, 197 pharmacokinetic properties, 53 pharyngitis, 192 pneumonia, 238 sinusitis, 197 spectrum of activity, 55 Clearance drug, 78 CLIA (Clinical Laboratory Improvement Act), 97 CLIA waived rapid tests, 101 Clindamycin adverse reactions, 60 animal bites, 716, 717 babesiosis, 613 bacterial resistance, 58 bacterial vaginosis, 303

[Clindamycin] clinical indications, 58, 476, 490 costs, 56, 125 diabetic foot infection, 596 dosage in hepatic failure, 92 dosage in renal disease, 88 dose, 56, 125 dose in renal failure, 54 endocarditis, 370 endometritis, 652 intraabdominal infections, 476 mechanism of action, 58 necrotizing fasciitis, 29, 30 outpatient parenteral antibiotic therapy, 125 pharmacokinetics, 53 pharmacological properties, 58 Pneumocystis carinii, 518 pneumonia, 238 pregnancy, 647 resistance to pneumococcus, 234 skin infections, 378 spectrum of activity, 58, 60, 59 surgical prophylaxis, 490 toxic shock syndrome, 390 vertebral osteomyelitis, 567, 568 Clindamycin phosphate gel, 385 Clonorchis sinensis, 636 Clostridium sp. bacteremia, 179, 180 diabetic foot infections, 589 intraabdominal infection, 483 necrotizing fasciitis, 382 puncture wounds, 387 pyomyositis, 392 Clostridium botulinum, 843 Clostridium difficile, 450 acquired immune deficiency syndrome, 454, 531 diagnosis, 111, 443, 444, 445, 446, 450, 451 diarrhea, 449–452, 443, 454 key points, 449 key points, 449 nucleic acid detection test, 106 relapse, 452 stool culture, 451 toxins, 450, 451 treatment, 448, 451–452 Clostridium perfringens bacteremia, 181 cellulitis, 26 diarrhea, 439, 445 necrotizing fasciitis, 25, 30, 382

Index [Clostridium perfringens] myonecrosis, 25, 392 toxins, 439 wound infection, 376 Clostridium septicum bacteremia, 181 myonecrosis, 28 necrotizing fasciitis, 382 wound infection, 376 Clotrimazole candidal vaginitis, 305 candida skin infection, 400 dermatophyte infection, 400 oral candidiasis, 220 pityriasis versicolor, 400, 402 Clubbing endocarditis, 352 Clue cells bacterial vaginosis, 302 Coagulase test gram-positive cocci, 174 Coccidioides immitis, 626 coccidioidomycosis diagnosis, 623, 626 disseminated, 626 geographic distribution, 623 major syndromes, 623, 626 therapy, 623, 627 human immunodeficiency virus, 515 prostatitis, 341 serological diagnosis, 107, 626 Coccidioidomycosis (see Coccidioides immitis) Cold sores, 222 Colitis amebiasis, 639–640 bacterial, 437, 440, 441, 446 balantidium, 642 cytomegalovirus, 522 management, 447, 448, 449 Colonizing flora, 99 Colorado tick fever, 618, 713, 715 Combivir, 511 Common cold, 265–271 bronchitis, 244 causes, 266 clinical illness, 266 differential diagnosis, 267 key points, 265 management, 271 pharyngitis, 189 sinusitis, 201 symptomatic treatment, 244, 267–271

863 Common variable immunodeficiency (see hypogammaglobulinemia) Complement deficiency, 665 Computerized axial tomography (CAT) acquired immune deficiency syndrome, 526, 528 abdominal pain, 530 pneumonia, 529 anthrax, 828, 833 appendicitis, 481 bacterial meningitis, 18, 23 colitis, 456 dementia (acquired immune deficiency syndrome), 522 diverticulitis, 483 hepatic abscess, 486 Herpes simplex virus-1 encephalitis, 24 intraabdominal infection, 475, 477 mycotic aneurysm, 682 orbital cellulitis, 429 ovarian vein thrombophlebitis, 653 pancreatic abscess, 487 preseptal cellulitis, 428 primary peritonitis, 478 prostatitis, 339, 340 renal abscess, 488 secondary peritonitis, 478 septic arthritis, 545 septic bursitis, 554, 555 splenic abscess, 487, 682 submandibular abscess, 225 thrombophlebitis, 682 toxoplasmosis, 520 tuberculosis, 260 urinary tract infection, 285 vertebral osteomyelitis, 564, 565, 698 Condylomata acuminata, 314 Condylomata lata (also see syphilis), 329, 334 Confusion human immunodeficiency virus encephalitis, 24 Congenital infections, 646, 653– 656 screening for, 654, 655 Conjunctivitis, 410–419 bacterial, 417–419 common cold, 267 differential diagnosis, 412 leptospirosis, 713 management, 418–419, 420– 421

[Conjunctivitis] pharyngitis, 190 smallpox, 838 toxic shock syndrome, 139 urethritis, 321 viral, 413, 414–417 viral hemorrhagic fever, 848 Contact tracing tuberculosis, 263 Continuous ambulatory peritoneal dialysis, 700 infections, 700–703 Corona virus common cold, 266 Cortisporin Otic suspension, 197 Corynebacterium sp. bacteremia, 179, 180 Corynebacterium diphtheria conjunctivitis, 413 pharyngitis, 189 Corynebacterium pseudodiphtheriticum bronchitis, 245 Cough acute, 246, 248 anthrax (inhalation), 827, 829, 830, 833 approach to patient, 246 blastomycosis, 625 bronchitis, 242 chronic, 246, 248 coccidioidomycosis, 626 cryptococcosis, 627 differential diagnosis, 268 endocarditis, 352 histoplasmosis, 622 human immunodeficiency virus infection, 528, 529 influenza, 273 leptospirosis, 713 Lyme disease, 604 malaria, 761 plague, 842 pneumonia, 227 treatment, 244, 246, 267, 268 tuberculosis, 253 Co-trimoxazole (Bactrim, Septra), 68–71 adverse reactions, 69–70 clinical indications, 68–69 costs, 56 cyclosporiasis, 638 decubitus ulcer, 776 dose, 56 dose in renal disease, 54, 89 drug interactions, 94 intraabdominal infection, 476, 484

864 [Co-trimoxazole (Bactrim, Septra)] otitis media, 197 pediculosis, 394 pharmacokinetic properties, 53 plague, 843 Pneumocystis carinii, 517, 518 pneumonia, 238 pregnancy, 647 primary peritonitis, 478 prostatitis, 341 resistance to pneumococcus, 234 secondary peritonitis, 484, 485 serositis, 197 spectrum, 59, 68–69 urinary tract infections, 286, 287, 289, 295, 296, 650 Isosporiasis, 638 Coxiella burnetii (also see Q fever) endocarditis, 354, 360 pneumonia, 712 serological disease, 107 Coxsackie virus conjunctivitis, 415 mouth ulcers, 211 pharyngitis, 189 C-reactive protein diabetic foot infection, 587 fever, 9 osteomyelitis (vertebral), 562, 563, 565 Cranial nerve damage bacterial meningitis, 17 Creatinine clearance corrected formula, 87 formula, 85 Creatinine phosphokinase lactic acidemia, 532 myonecrosis, 28, 375, 382 rocky mountain spotted fever, 614 Cromolyn sodium common cold therapy, 269 Crohn’s disease (see inflammatory bowel disease) Cryptococcus neoformans, 627 cell-mediated immune defect, 662, 668, 669, 671–672 cryptococcosis fungemia, 182 meningitis, 517, 519, 628, 783 pneumonia, 627–628 prostatitis, 34 human immunodeficiency virus infection, 514, 515 immune reconstruction syndrome, 524 prophylaxis, 508

Index [Cryptococcus neoformans] nucleic acid detection, 106, 627 serological diagnosis, 107 Cryptococcosis (see Cryptococcus neoformans) Cryptosporidium sp., 640 acquired immune deficiency virus, 454, 515, 520–521 diagnosis, 517, 520–521 presentation, 517, 520, 531 therapy, 517 cell-mediated immune defect, 669 cholecystitis, 640 diagnosis, 445, 446, 712 diarrhea, 446, 454, 531, 691, 712 nucleic acid tests, 106 treatment, 448, 638, 641 zoonosis, 612 Cultures, 105–111 blood, 105, 169–185 cerebrospinal fluid, 108 diabetic foot infection, 590 fungal pathogens, 111–112 genital tract, 110 peritoneal dialysis fluid, 701 pressure sores, 776 prostatitis, 339 respiratory tract, 108 sample collection, 97–98 skin and soft tissue, 100 stool, 111, 444 transport, 97–98 viral pathogens, 111 urinary tract, 109, 284 Curvularia sp. keratitis, 427 Cyclooxygenase COX-1, 13 COX-2, 13–14 fever, 10 inhibition, 14 Cyclospora, 641 acquired immune deficiency virus, 454, 531 diagnosis, 446, 454, 641 diarrhea, 437, 446, 641 stool examination, 445 treatment, 448, 638, 641 Cysticercosis, 634, 635 serological diagnosis, 107 Cystic fibrosis, 242 Cysticercosis, 634, 635 Cystitis (see urinary tract infection) viral, 284

Cytokines fever, 8, 10–11 interleukin-1, 8 interleukin-6, 8 septic shock, 38 tumor necrosis factor, 8 Cytomegalovirus, 521 acute retinal necrosis, 432 cell-mediated immune defect, 668 diarrhea, 454 human immunodeficiency virus infection, 505, 514, 515, 517, 521–522 diagnosis, 517 gastrointestinal disease, 522 immune reconstitution syndrome, 524 presentation, 517 prophylaxis, 508 presentation, 517 retinitis, 521 therapy, 517, 521 infectious mononucleosis, 744– 745 maculopapular rash, 143 nucleic acid detection test, 106 outpatient parenteral antibiotic therapy, 123 perinatal infection, 655 pharyngitis, 189 primary infection, 670 retinitis, 432, 521 Dark field microscopy syphilis, 310, 313, 330, 391 Dark winter, 838 Decongestants common cold, 267, 268 Decubitus ulcers, 387, 574, 575 elderly, 774–776 prevention, 775 treatment, 776 Deep space infections (see head and neck infections) Delavirdine, 511 toxicities, 527 Dementia human immunodeficiency virus, 515, 522, 526 Dengue fever, 765 causes, 154 hemorrhagic fever, 765 rash, 145, 765 Dental caries, 210–213 key points, 210 Dermatobia hominis (see botfly)

Index Dermacentor sp., 29, 613, 616, 617, 618 Dermatophyte infection, 398–400 diagnosis, 399 treatment, 400 Desquamation toxic shock syndrome, 390 Diabetes mellitus cholecystitis, 480 foot care, 585, 597 foot infections bacteriology, 588–590 characteristics, 584 classification, 580, 591 culturing, 590 diagnosis, 584–588, 589, 590–595 ischemia, 582, 592, 593 key points, 582, 590 osteomyelitis, 586–587, 589 pathophysiology, 581–584 radiological evaluation, 587– 588 treatment, 595–598 vascular destruction, 592–595 malignant otitis externa, 195, 572, 784 mucormycosis, 430, 629 myonecrosis, 28 necrotizing fasciitis, 25 prosthetic joint osteomyelitis, 576 pyelonephritis, 651 sinusitis, 201 skin infections, 374, 376 staphylococcal skin infections, 674 surgery, 596–597 surgical site infection, 388 tuberculosis, 251 urinary tract infection, 297, 651 vaginitis, 303 vertebral osteomyelitis, 560, 561 Dialysis infections (see hemodialysis and peritoneal dialysis) Diarrhea, 437–454 acute, 443, 446 acquire immune deficiency syndrome, 452–454, 530–531 antiretroviral agents, 530 Clostridium difficile, 531 wasting, 523 amebiasis, 639 anthrax, 828, 831 approach to diagnosis, 443 Balantidium coli, 642 Blastocystis hominis, 642

865 [Diarrhea] Campylobacter jejuni, 440, 712 chronic, 442, 443, 444, 446 Clostridium difficile, 449–452 cryptosporidiosis, 517, 520, 640, 712 Cyclospora sp., 641 cytomegalovirus, 522 diagnostic tests, 446 empirical therapy, 449 epidemiology, 438 evaluation, 441–446 giardiasis, 639, 712 Isospora sp., 641 key points, 438, 442, 449, 452, 638 leptospirosis, 713 management, 447–449 microsporidiosis, 520, 641 Mycobacterium avium, 519 parasites, 637–642 pathogens, 439–441 pathophysiology, 438–439 plague, 842 risk factors, 438 Salmonella enteritides, 440, 712 syndromes, 446 toxins, 349 traveler’s, 449, 639, 756, 757 tularemia, 846 viral hemorrhagic fever, 848 zoonosis, 712 Dicloxacillin, 46 costs, 42 dosage, 42 dose with renal disease, 45 pharmacokinetics, 44 septic arthritis, 538 skin infections, 378 Didanosine, 511 dosage, 794 pancreatitis, 530 postexposure prophylaxis, 791, 798 toxicities, 527, 794 Diethyltoluamide (DEET) travel, 751 Dilantin, 140 fever, 154 rash, 133 Diphyllobothrium sp. classification, 635 worms in stool, 642 Diphtheria–tetanus vaccine HIV, 507 pregnancy, 658

Diphtheroids (see Corynebacterium) bacteremia, 179 Directly observed therapy tuberculosis, 261, 685 Disseminated intravascular coagulopathy myonecrosis, 28 Disulfiram-like reaction (Antabuse-like) cefamandole, 124 cefoperazone, 124 Diverticulitis, 482–483, 701 key points, 479 Diverticulosis, 482 Donovanosis genital ulcer (female), 309 genital ulcer (male), 326 Doxycycline, 60–63 anthrax cutaneous, 827, 830 inhalation, 829, 830 prophylaxis, 830 cat scratch disease, 720 cervicitis, 307 costs, 56 dose, 56 dose in renal disease, 54, 89 drug interactions, 94 ehrlichiosis, 32, 612 epididymitis, 344 Lyme disease, 606, 608 malaria, 34, 755, 763 Pasteurella multocida, 716 pelvic inflammatory disease, 308 pharmacokinetics, 53 plague, 843 pneumococcal resistance, 234, 237 pneumonia, 237, 238 prostatitis, 341 relapsing fever, 617 rocky mountain spotted fever, 32, 616 septic arthritis, 538 spectrum, 54 syphilis, 313, 331 surgical prophylaxis, 490 toxicities, 62, 237 tularemia, 618, 843 urethritis, 324 Drotrecogin alfa (activated protein C), 40 Drug fever, 151–153 causes, 154 fever of unknown origin, 165 smallpox, 839

866 Dry socket, 210, 213–214 Duke criteria endomyocarditis, 355–356 Dysentery, 437, 440–441, 446 management, 447, 448, 449 Dysgonic fermenter type 2 (see Capnocytophaga canimorsus) Dysphagia esophageal candida, 517, 519 human immunodeficiency virus infection, 530 lymphoma, 530 Kaposi’s sarcoma, 530 Dysuria acute urethral syndrome, 316 approach to diagnosis, 323 epididymitis, 342 male urethritis, 319 prostatitis, 336 pyelonephritis, 299 urinary tract infection, 282, 290, 650 vaginitis, 304 Ear anatomy, 192, 194 Eastern equine encephalitis, 630– 631 Ebola virus (also see viral hemorrhagic fever), 848 Echinacea common cold, 268, 270 Echinococcus sp. classification, 635 eosinophilia, 635 serological diagnosis, 107 Echocardiogram Duke criteria, 355 endocarditis, 355–358, 698 injection drug use, 698 Econazole, 400 Ecthyma gangrenosum cutaneous anthrax, 829 neutropenic fever, 35, 390 rash, 132 septic shock, 38 Eczema herpeticum, 406 Efavirenz, 511 dose, 794 postexposure prophylaxis, 794, 799 toxicities, 527, 657, 794 Ehrlichia chaffeensis, 32, 608 Ehrlichia equi, 608 Ehrlichia ewingi, 608 Ehrlichia phagocytophilia, 32, 608

Index Ehrlichiosis, 32–34, 608–612 diagnosis, 32, 101, 611–612, 713 epidemiological characteristics, 608 geographic distribution, 610 key points, 31, 609 manifestations, 32, 609 rash, 132, 715 risk exposure, 132 serological diagnosis, 107 treatment, 32, 612 zoonosis, 713 Eikenella corrodens diagnosis, 108 endocarditis, 360 human bites, 388 Elderly (also see nursing home) infections asymptomatic bacteruria, 773 atypical presentations, 772 encephalitis, 783–784 influenza, 778 malignant otitis externa, 784 meningitis, 783 mortality, 771–772 pneumonia, 779–781 predisposition, 772 pressure sores, 774–776 tuberculosis, 781–783 urinary tract infections, 773– 774 zoster, 777 Emboli endocarditis, 353, 683 fever, 160 injection drug use, 683 Emergencies, 17–40 Encephalitis California, 630 Eastern equine, 630–631 Epstein-Barr virus infection, 743 herpes simplex type 1, 23–25 clinical manifestations, 24 diagnosis, 24 key points, 24 therapy, 24 influenza, 273 injection drug user, 690 LaCrosse, 630–631 Lyme disease, 605 Powassan viral, 618 rocky mountain spotted fever, 614 St. Louis, 630–631 Western equine, 630–631 West Nile, 631

Endocarditis, 347–372 Abiotrophia sp., 354, 359 acute vs. subacute, 349 Bartonella sp., 354, 360 Brucella sp., 354, 360 Chlamydia psittaci, 354, 360 clinical presentation, 349–353, 389 Coxiella burnetii, 354, 360 culture negative, 354 diagnostic criteria, 354–458 echocardiogram, 354–358 Enterococcus sp., 359, 361 epidemiology, 347–348 heart murmur, 350–351 HACEK organisms, 360, 365 injection drug user, 348, 680– 682, 683 key points, 351, 358, 368 Legionella sp. 354 Listeria monocytogenes, 360 native valve, 358–366 pathogens, 358–360 treatment, 360–365 Neisseria gonorrhoeae, 321, 349, 360 neurological manifestations, 353 nonbacterial thrombosis, 349 outpatient parenteral antibiotic therapy, 116 pathophysiology, 348–349 petechiae, 136 prophylaxis, 368–371 prosthetic valve, 347 prosthetic valve endocarditis, 366–367 pathogens, 366 treatment, 366 Pseudomonas aeruginosa, 366 rash, 351–352 renal complications, 352 right sided, 353, 355, 683 Staphylococcus sp., 364–365 Staphylococcus aureus, 349, 353, 366 methicillin resistant Staphylococcus aureus, 367 Staphylococcus epidermidis, 360, 366 Streptococcus sp., 361 Streptococcus agalactiae, 359 Streptococcus bovis, 359 Streptococcus pneumoniae, 349, 359 Streptococcus pyogenes, 349, 359 surgery, 367–368

Index [Endocarditis] Tropheryma whippelii, 354 vasculitis, 157 Endometritis, 652–653 Endophthalmitis, 433–434, 410 bacterial, 434, 692 fungal, 433, 692 injection drug use, 691 key points, 434 Enoxacin, 65–67 adverse reactions, 66 costs, 56 dose, 56 drug interactions, 94 spectrum, 65 urinary tract infections, 286 Entamoeba coli diarrhea, 445 Entamoeba dispar, 640 Entamoeba histolytica (see also amebiasis) acquired immune deficiency virus, 454 diagnostic tests, 446, 640 diarrhea, 445, 454, 640 hepatic abscess, 484 nucleic acid antigen test, 106 ova and parasite examination, 101 serological diagnosis, 107 stool examination, 445 therapy, 638 Enterobacter sp. bacteremia, 178 diabetic foot infection, 589 primary peritonitis, 477 prostatitis, 338 secondary peritonitis, 483 urinary tract infection, 281 Enterobiasis sp. classification, 625 clinical syndrome, 637, 643 exposure risk, 637, 643 geographic local, 637 therapy, 643 Enterococcus sp. antibiotic synergy, 81 bacteremia, 176, 359 decubitus ulcers, 387 endocarditis, 359 treatment, 361, 363 endometritis, 652 hemodialysis access infection, 696 hepatic abscess, 485 peritoneal dialysis infection, 701 primary peritonitis, 478

867 [Enterococcus sp.] prostatitis, 338 secondary prostatitis, 483, 484 surgical site, 389 urinary tract infection, 287, 288, 650 vertebral osteomyelitis, 566 Enterocytozoon sp. (see Microsporidia) acquired immune deficiency syndrome, 515, 520–521 Enterovirus sp. common cold, 266 conjunctivitis, 415 hormonal defects, 664 nucleic acid antigen test, 106 otitis media, 193 petechiae, 136 Eosin-methylene blue (EMB), 105, 178 Eosinophilia, 633–634 allergic bronchopulmonary aspergillosis, 629 coccidioidomycosis, 626 cutaneous lesions, 637 differential diagnosis, 635 drug reaction, 50, 153, 633 fever of unknown origin, 167 hyperimmunoglobulin E syndrome, 665 international traveler, 766 key points, 634 parasite infections, 633, 636, 644 primary eosinophilic disorders, 633 Epidemic keratoconjunctivitis (EKC), 415 Epidermophyton sp. skin infections, 398–400 Epididymitis, 342–344 blastomycosis, 625 complications, 342 difficulty from testicular torsion, 343 key points, 342 treatment, 344 Epiglottitis, 203–206 key points, 203 therapy, 206 Epstein-Barr virus, 735–736 cell-mediated immune defect, 668 chronic fatigue syndrome, 738 epidemiology, 736 fever of unknown origin, 166 hairy leukoplakia, 219, 743 infectious mononucleosis, 738– 743

[Epstein-Barr virus] clinical manifestations, 738– 739 complications, 742–743 laboratory diagnosis, 740–742 treatment, 743 key points, 736 monospot, 102, 740 pharyngitis, 189, 738 petechiae, 136, 138 rapid testing, 102 rash, 144 serologic diagnosis, 112, 740– 742 vasculitis, 157 Erysipelas, 374, 379 key points, 377 Erysipelothrix rhusiopathiae cellulitis, 380 Erythema (diffuse), 138–140 Arcanobacterium haemolyticum, 140 Dilantin hypersensitivity, 140 drug hypersensitivity, 138 Kawasaki disease, 140 key points, 135 scarlet fever, 138 staphylococcal scalded skin syndrome, 140 staphylococcal toxic shock syndrome, 139 streptoccocal toxic shock syndrome, 139 toxic epidermal neurolysis, 140 Erythema infectiosum (see fifth’s disease and parvovirus B-19) Erythema marginatum, 145, 159 Erythema migrans, 145, 391, 602–604 differential diagnosis, 603 Erythema multiforme, 145 coccidioidomycosis, 625 differential diagnosis, 146, 391 mouth ulcers, 211 Erythema nodosum, 149 coccidioidomycosis, 626 sarcoidosis, 159 Erythrocyte sedimentation elevation diabetic foot infections, 587 fever of unknown origin, 167 relapsing fever, 617 sarcoidosis, 160 vertebral osteomyelitis, 562, 563, 565 Erythromycin adverse reactions, 57–58 cervicitis, 307

868 [Erythromycin] chancroid, 314 clinical indications, 55 costs, 56 dose, 56 dose in renal disease, 89 drug interactions, 55, 94 pelvic inflammatory disease, 653 pharmacokinetic properties, 53 pharyngitis, 192 pneumonia, 237, 238, 781 preparations, 52, 56 spectrum of activity, 55, 59 syphilis, 313 urethritis, 324 Eschar cutaneous anthrax, 827 Escherichia coli bacteremia, 178 chorioamnionitis, 652 diabetic foot infection, 589 diarrhea, 439, 441, 448, 756 endometritis, 652 enterohemorrhagic (0157-H7) diagnosis, 111 diarrhea, 437 hemolytic uremic syndrome, 441, 444 toxins, 439 treatment, 443, 448 enterohemorrhagic (EHEC), 441 enteroinvasive (EIEC), 441 enterotoxigenic (ETEC), 441, 448, 449 necrotizing fasciitis, 26, 30 neutropenic fever, 36 orchitis, 345 primary peritonitis, 483 prostatitis, 338 secondary peritonitis, 483 toxins, 439 traveler’s diarrhea, 756 urinary tract infections, 280, 650 vertebral osteomyelitis, 566 Esophagitis aphthous, 530 Candida, 508, 515, 530 diagnosis, 517, 519 presentation, 517, 519 therapy, 517, 519 cytomegalovirus, 522 human immunodeficiency virus, 530 E-test, 113

Index Ethambutol Mycobacterium avium, 520 Mycobacterium tuberculosis, 262, 781, 783 Exanthem subitum, 142, 143 Famciclovir cutaneous herpes simplex, 407 genital herpes simplex, 312, 332 hepatitis B virus, 464 herpes keratitis, 425 herpes zoster, 777 herpes zoster ophthalmicus, 426 oral varicella zoster, 223, 408 Fasciola hepatica, 634–636 Fatigue, 723–734 chronic fatigue syndrome, 727– 734 forms, 726 human immune deficiency virus, 499 key points, 724 Lyme disease, 606 Fecal leukocytes, 445, 446 Fever, 1–15 acute retroviral syndrome, 500 animal bite infection, 711 animal contact, 166 anthrax, 829, 830, 833 appendicitis, 48 approach to patient, 161–162 arthritis, 542, 543 babesiosis, 612 bacteremia, 172 bacterial meningitis, 17 bursitis, 554 causes by age, 166 cholangitis, 480 cholecystitis, 479 coccidioidomycosis, 626 collagen vascular disease, 156– 158 cryptococcus, 627 decubitus ulcers, 776 dengue, 765 diverticulitis, 482 drug, 5, 49, 151–153 endocarditis, 349, 350 endogenous pyrogens, 2 epididymitis, 342 fever of unknown origin, 162– 167 heart rate, 5, 762, 848 hemodialysis access infection, 696 hepatic abscess, 486

[Fever] hepatitis, 764 herpes simplex encephalitis, 24 herpes simplex genital ulcers, 311 histoplasmosis, 625 historical questions, 164 history, 1 human immunodeficiency virus, 499 humoral theory of, 1 infectious mononucleosis, 738– 739 influenza, 273 international travel, 757–765 intraabdominal infection, 473 laboratory clues, 167 Lyme disease, 605 malaria, 33, 761 malignancy, 154–156 metabolic demand, 14 Mycobacterium avium, 519 nephric abscess, 488 neutropenic, 34 non-focal presentation, 153 noninfectious, 151–168 orchitis, 344 pancreatic abscess, 487 patterns, 5, 761 pelvic inflammatory disease, 308, 653 peritonitis, 478 pharyngitis, 190 plague, 842 Pneumocystis carinii pneumonia, 516 pneumonia, 227 postpartum, 653 prostatitis, 337 prosthetic joint infection, 549 pyelonephritis, 282, 299, 650 pyoderma, 376, 379 rash, 129–150 relapsing, 617 renal abscess, 282 risk-benefit, 11–12 rocky mountain spotted fever, 31, 613 septic shock, 38 smallpox, 838 splenectomy, 663 splenic abscess, 487 syphilis, 312 toxoplasmosis, 520 treatment, 13–15 tuberculosis, 253 tularemia, 617, 846 typhoid fever, 764

Index [Fever] urinary tract infection, 282 vaccine toxicity, 808 vasculitis, 157–158 vertebral osteomyelitis, 562 viral encephalitis, 630 viral hemorrhagic fever, 848 zoonosis, 712–713 Fever and rash, 129–150 acute antiretroviral syndrome, 500 coccidioidomycosis, 626 Colorado tick fever, 715 disseminated gonococcal infection, 543 ehrlichiosis, 715 infectious mononucleosis, 739 Lyme disease, 715 rat bite fever, 715 rickettsial pox, 715 rocky mountain spotted fever, 613, 714 smallpox, 838–839 typhus, 715 viral hemorrhagic fever, 848 zoonosis, 715 Fever of unknown origin (FUO), 162–167 Fifth disease (also see parvovirus B-19), 142, 143 Filariasis, 634–636 diagnosis, 101 lymphadenopathy, 720 Fitz-Hugh-Curtis syndrome, 317 Fleas, 397 key points, 394 Flora, normal gastrointestinal tract, 376 oral cavity, 209 vaginal, 376, 645 Floxin Otic, 197 Fluconazole candida vaginitis, 304, 305, 629 coccidioidomycosis, 627 costs, 125 cryptococcus, 628 cryptococcus meningitis, 519 dermatophyte infection, 400 dose, 125 dose in renal disease, 89 drug interactions, 94 esophageal candidiasis, 517, 519 onychomycosis, 401 outpatient parenteral antibiotic therapy, 125 oral candidiasis, 220, 629

869 [Fluconazole] peritoneal dialysis dose, 702 tinea capitis, 401 urinary tract candidiasis, 297– 298 Flucytosine peritoneal dialysis dose, 702 Fluorescent antibody absorbed test (FTA-ab), 313, 330 Fluoroquinolones, 65–67 concentration dependent, 82 drug interactions, 94 pneumonia, 239 post-antibiotic effect, 83 tissue penetration, 93 urinary tract infection, 287 Folliculitis, 374, 384–385 key points, 384 treatment, 385 Food poisoning, 438, 439–441, 446 botulism, 843 incubation periods, 439 symptoms, 439 toxins, 439 Fournier’s gangrene, 28 Foscarnet cytomegalovirus infection, 521 outpatient parenteral antibiotic therapy, 122 Fosfomycin tromethamine urinary tract infections, 288 Francisella tularensis, (also see tularemia) 617, 845 serological diagnosis, 107 skin lesions, 383 Fungal infections, 621–630 aspergillosis, 628 blastomycosis, 625–626 candidiasis, 629–630, 666 coccidioidomycosis, 626–627 cryptococcus, 627 cultures, 111–112 histoplasmosis, 621–625 mucormycosis, 629 neutropenia, 666 peritoneal dialysis infection, 703 skin testing, 398–402 candida sp., 400–401 pityriasis versicolor, 401–402 sporotrichosis, 628 susceptibility testing, 113 Fungemia, 182 Aspergillus sp., 182 Candida sp., 182 Cryptococcus neoformans, 182 Histoplasma capsulatum, 182

Furuncles, 385–386 cutaneous anthrax, 829 key points, 384 recurrent, 673–674 Fusarium sp. keratitis, 427 Fusobacterium sp. animal bites, 711 bacteremia, 178 human bites, 388 Lemierre’s disease, 178 intraabdominal infection, 483 pneumonia, 236 submandibular abscess, 225 Gallbladder (see cholecystitis, cholangitis) gangrenous, 480 Gallium scan vertebral osteomyelitis, 564, 565, 567 Gallstones, 479 Ganciclovir cytomegalovirus, 517, 521 outpatient parenteral antibiotic therapy, 122, 125 Gangrene (see Clostridium perfringens) bacterial synergistic, 382 streptococcal, 382 Gardnerella vaginalis bacterial vaginosis, 302 endometritis, 652 Gastric carcinoma, 489 Gastritis, 489 Gatifloxacin, 65 costs, 56 decubitus ulcers, 776 dose, 56 dose in renal disease, 54 pharmacokinetics properties, 53 pneumonia, 238, 782 spectrum, 59 Gastroenteritis (also see diarrhea), 437, 446 approach, 443 malaria, 761 Genital ulcers approach to diagnosis, 310 female, 309–314 key points, 309 male, 325–333 Gentamicin costs, 125 chorioamnionitis, 652 dosing, 84, 125, 699, 702 endocarditis, 362, 363, 364, 365, 367, 370

870 [Gentamicin] endometritis, 653 hemodialysis infections, 699– 700 intraabdominal infection, 476, 484, 485 neutropenic fever, 36–37 outpatient parenteral antibiotic therapy, 125 peritoneal dialysis infections, 702 pharmacokinetics, 78, 80 septic shock, 39 surgical prophylaxis, 490 synergy, 81 tularemia, 846 Gentamicin sulfate cream, 385 Genital ulcers (male) causes, 327, 328 chancroid, 325, 331 clinical evaluation, 326 donovanosis, 326 herpes simplex, 325, 330 key points, 326 laboratory evaluation, 329–331 lymphogranuloma venereum, 326 syphilis, 325, 330, 329 German measles (see Rubella virus) Ghon focus, 258 Giardia lamblia, 639 achlorhydria, 664 diagnosis, 639, 445, 446 diarrhea, 442, 454, 639, 712 human immunodeficiency virus, 454, 639 humoral defects, 664 ova & parasite examination, 101, 445 nucleic acid antigen test, 106 treatment, 448, 449, 638 Gingivitis, 214–215 acute necrotizing ulcerative (ANUG), 211, 215 human immunodeficiency virus infection, 505 key points, 214 Gingivostomatitis acute herpetic, 222 Glanders, 829 Glaucoma, 410 differential diagnosis, 412 Glomerulonephritis endocarditis, 352 focal segmental glomerulonephritis, 706 hepatitis B virus, 704

Index [Glomerulonephritis] hepatitis C virus, 466, 705 impetigo, 377 Streptococcus pyogenes, 376 Glucocorticoids cell-mediated immune defect, 669 Glucose-6-phosphate dehydrogenase, (G-6PD) drug fever, 152 Gnathostoma sp., 636 Gonorrhea (see Neisseria gonorrhoeae) Gout, 161, 543 Gram-negative diplococci, 181 Gram-negative rods antibiotic therapy, 184 bacteremia, 177–179 blood culture result, 175, 177– 179 decubitus ulcers, 387 diabetic foot ulcers, 588 endophthalmitis, 434 epididymitis, 342, 344 epiglottitis, 206 hemodialysis access infection, 696 hepatic abscess, 485 intraabdominal infection, 484 keratitis, 426 lactose fermenter, 178 lactose non-fermenter, 178 necrotizing fasciitis, 382 neutropenia, 666 otitis media, 193 pancreatic abscess, 487 peritoneal dialysis infection, 703 pneumonia in nursing homes, 780 primary peritonitis, 477, 483– 484 renal abscess, 488 secondary peritonitis, 478, 483–484 septic arthritis, 537, 543 splenic abscess, 487 surgical site, 389 urinary tract infection, 281, 283, 294, 296 vertebral osteomyelitis, 566 Yersinia pestis, 841 Gram-positive cocci antibiotic therapy, 184 blood culture result, 174–177 Gram-positive rods Bacillus anthracis, 824 blood culture result, 179–181

[Gram-positive rods] Clostridium botulinum, 843 endophthalmitis, 434 Gram stain, 100 blood culture, 174–182 bursitis, 554 cellulitis, 380 cervicitis, 306 chorioamnionitis, 652 CLIA, 100 contamination, 97 epididymitis, 343 inhalation anthrax, 828 keratitis, 426 Legionella pneumonia, 235 meningitis, 23 necrotizing fasciitis, 382 peritoneal dialysis fluid, 701 pneumonia, 237, 828 semi-quantitation, 100 sensitivity, 100 stool, 445 synovial fluid, 544, 549 urethral discharge, 322, 343 urine, 283 tularemia, 846 vertebral osteomyelitis, 564 Yersinia pestis, 843 Granulocytic colony-stimulating factor neutropenic fever, 36 Granuloma inguinale (see donovanosis), 9 Grepafloxacin, 65 decubitus ulcers, 776 Griseofulvin dermatophyte infection, 400 Groshong catheter outpatient parenteral antibiotic therapy, 118–120 Guillain-Barre´ syndrome botulism, 844 Epstein-Barr virus infection, 743 Human immunodeficiency virus, 515 influenza, 273 Gynecological infections, 301– 318 acute urethral syndrome, 316 bacterial vaginosis, 301–303 bartholinitis, 316 cervicitis, 306 Fitz-Hugh-Curtis syndrome, 317 human papillomavirus, 314 intrauterine devices, 317

Index [Gynecological infections] pelvic inflammatory disease, 306–309 trichomonal vaginitis, 304 ulcer disease, 309–314 vulvovaginal candidiasis, 303– 304 HACEK organisms, 171 diagnosis, 108 endocarditis, 354, 360 treatment, 365 Haemophilus aphrophilus diagnosis, 108 endocarditis, 360 Haemophilus ducreyi chancroid, 314, 325, 331, 333– 335 Haemophilus influenzae bronchitis, 243, 245 complicating influenza, 274 culture, 105 epiglottis, 206 meningitis, 22 otitis media, 193 pneumonia, 233, 235, 683, 780 sinusitis, 201 splenectomy, 663 vaccine, 22 Haemophilus parainfluenzae bronchitis, 245 conjunctivitis, 418 injection drug use, 683 Half-life drug, 78–79, 86 Halofantrine Plasmodium falciparum, 34 Hand infections, 375, 381 Hantavirus diagnosis, 112 pulmonary syndrome, 631–632 Head and neck infection deep space infection, 204–205, 206, 224–226 key points, 224 Headache acquired immune deficiency syndrome, 517, 526–527, 528 bacterial meningitis, 17 chronic fatigue syndrome, 727 ehrlichiosis, 609 endocarditis, 352, 353 erythema migrans, 602 histoplasmosis, 622 herpes simplex virus encephalitis, 24 infectious mononucleosis, 739

871 [Headache] influenza, 273 malaria, 33 malignant otitis externa, 575 relapsing fever, 617 rocky mountain spotted fever, 31 sinusitis, 201 syphilis, 312 temporal arteritis, 158 toxoplasmosis, 520 viral encephalitis, 630 Health care workers Bioterrorism, 849 hepatitis B virus, 459, 471 hepatitis C virus, 471 viral hepatitis, 470–471 Heart murmur endocarditis, 350–351 Helicobacter pylori, 489 gastrointestinal disease, 489, 491–492 key points, 489 testing, 102–103, 492 treatment, 491 Hemagglutinin influenza virus, 272 Hematuria endocarditis, 352 fever, 156 fever of unknown origin, 167 prostatitis, 338 tuberculosis, 254 urinalysis, 283, 284, 650 Hemodialysis infections, 695–700 antibiotic dosing, 699–700 bacteremia, 698, 699 hepatitis B virus, 459, 704–705 hepatitis C virus, 705–706 key points, 696 vaccination, 706 vascular access, 695–698 Hemolysis babesiosis, 612 drug induced, 152 Epstein-Barr virus infection, 743 malaria, 32 mycoplasma pneumonia, 234 systemic lupus erythematosus, 156 Hemolytic uremic syndrome, 441, 444 Hemoptysis endocarditis, 352 pneumonia, 229 pneumonic plague, 835

[Hemoptysis] tuberculosis, 254 vasculitis, 157 Hepatic abscess, 484–487 key points, 486 Hepatic failure antibiotic dosage, 85, 87, 92 Hepatic metastasis fever, 155 Hepatitis, 455–471 cholecystitis, 479 cytomegalovirus, 143 diagnosis, 112 Fitz-Hugh-Curtis syndrome, 317 hepatitis A virus, 457–459, 686 hepatitis B virus, 459–464, 685 hepatitis C virus, 464–468, 685 hepatitis D virus, 468–469, 685 hepatitis E virus, 469–470 hepatitis F virus, 470 hepatitis G virus, 470 injection drug use, 685–687 isoniazid, 782 key points, 456, 457, 460, 465, 468 liver test abnormalities, 455– 457 mycoplasma pneumoniae, 234 occupational exposure, 470– 471 SEN virus, 470 syphilis, 312 TT virus, 470 Hepatitis A virus, 457–459 clinical presentation, 458 diagnosis, 458–459 fever, 764 injection drug use, 686 international travel, 764 key points, 457 vaccinations, 459, 507, 687, 754, 810, 813 Hepatitis B virus, 459 arthritis, 552 dialysis patient, 704–705 glomerulonephritis, 704 hepatitis, 459–464 acute, 461, 462 chronic, 463 clinical presentation, 461–462 diagnosis, 462 key points, 460 natural history, 461 serological markers, 462 treatment, 463–464 vaccination, 464, 507, 658, 686 human immunodeficiency virus infection, 505

872 [Hepatitis B virus] injection drug use, 685, 800 nucleic acid tests, 106 occupational exposure, 470– 471, 799–800 perinatal screening, 653, 654 postexposure prophylaxis, 471, 799–802 approach to patient, 802, 804 non-occupational, 801–802 occupational, 800–801 risk groups, 800, 813 vaccination, 464, 507, 810, 812–813 dialysis patients, 705 injection drug use, 686 international travel, 754 postexposure prophylaxis, 800, 802 pregnancy, 658 vasculitis, 157 Hepatitis C virus, 464 arthritis, 552 glomerulonephritis, 705 hemodialysis, 705–706 hepatitis, 464–468 clinical presentation, 466 diagnosis, 466 epidemiology, 465 genotypes, 467 key points, 465 natural history, 466 treatment, 467 human immunodeficiency virus, 499, 505, 513, 524– 525 injection drug use, 685, 802 nucleic acid test, 106 occupational exposure, 470– 471, 803 perinatal infection, 655, 802 postexposure prophylaxis, 802– 804 approach to patient, 804 risk groups, 802 transmission, 802–803 vasculitis, 157, 466 Hepatitis D virus, 468 hepatitis, 468–469 injection drug use, 686 key points, 468 Hepatitis E virus, 469 fever, 764 hepatitis, 469 international travel, 764 key points, 468 Hepatitis F virus, 470 Hepatitis G virus, 470

Index Hepatocellular carcinoma fever, 155 hepatitis B virus, 463 hepatitis C virus, 466, 802 Herpes labialis, 222 Herpes simplex virus, 311, 405 acute retinal necrosis, 432 anterior uveitis, 431 blepharitis, 419 conjunctivitis, 413, 415, 417 counseling, 333 diagnosis, 112, 311, 406 eczema herpeticum, 406 genital ulcers, 309, 311–312, 325–331 gingivostomatitis, 211, 221– 223, 405–406 key points, 221 hepatitis, 470 herpetic whitlow, 406 human immunodeficiency virus, 499 prophylaxis, 508 initial non-primary, 329 keratitis, 424–425 meningitis, 332 nucleic acid antigen detection, 106 partner notification, 333 perinatal infection, 655 peritoneal infection, 655 pharyngitis, 189 primary infection, 327, 329, 405 recurrent cutaneous, 406, 407 recurrent genital, 329 serological testing, 311 treatment, 332, 406–407 type specific testing, 330 Tzanck test, 311, 331, 406 Herpes simplex virus type I (HSV-1) acute retinal necrosis, 432 anterior uveitis, 431 encephalitis, 23–25, 784 genital ulcers, 311, 325 treatment, 311–312, 332 gingivostomatitis, 221–223, 311, 405 hepatitis, 470 recurrent oral, 405, 221–222 Herpes simplex virus type II (HSV-2) acute retinal necrosis, 432 genital ulcers, 311, 325–333, 405 treatment, 312, 332

[Herpes simplex virus type II] gingivostomatitis, 221, 405 hepatitis, 470 Herpetic whitlow, 406 Heterophile antibody test, 103, 740 Hickman catheters outpatient parenteral antibiotic therapy, 118–120 Highly active antiretroviral therapy (HAART) (see also antiretroviral therapy), 495, 513 agents, 511 immune reconstitution syndrome, 524 lipodystrophy, 524 Histoplasma capsulation, 621 fungemia, 182 histoplasmosis, 621–625 diagnosis, 623, 624 disseminated, 624 geographic distribution, 623 key points, 622 major syndromes, 627 pulmonary, 622, 624 therapy, 623 urine antigen test, 624 human immunodeficiency virus infection, 515 prophylaxis, 508 lysis centrifugation, 108 nucleic acid antigen test, 106 prostatitis, 341 serology, 107, 623 Histoplasmosis (see Histoplasma capsulatum) Hookworm infections, 633, 635 clinical syndromes, 636, 643 cutaneous lesion, 636, 637 eosinophilia, 635 risk, 636, 643 therapy, 643 Hordeolum, 419 Human granulocytic ehrlichiosis (also see ehrlichiosis), 608– 612 Human herpesvirus-6 (HHV-6) (also see roseola infantum) infectious mononucleosis, 745 nucleic acid test, 106 rash, 142, 143 Human herpes-8 (HHV-8), 522 Human immunodeficiency virus (HIV), 496 abdominal pain, 530 acute necrotizing ulcerative gingivitis, 215 acute retroviral syndrome, 144, 500–502

Index [Human immunodeficiency virus] anemia, 531 antiretroviral agents 511 indications, 510 Bartonella infection, 720 blastomycosis, 625 cat scratch disease, 720 cell-mediated immunity, 667, 668 chest x-ray, 528–529 clues for recognition, 231 coccidioidomycosis, 626 complications of by CD4 count, 515, 527–528 cough, 529 cryptococcal meningitis, 519, 628 cryptosporidiosis, 520–521 cytomegalovirus, 521 cytomegalovirus retinitis, 432 dementia, 522 diarrhea, 452–454, 530–531 approach to diagnosis, 453 epidemic, 495 esophageal candidiasis, 519, 629 genital ulcers, 310, 327 gynecological warts, 315 headache, 526 hepatitis C virus, 524 histoplasmosis, 625 human papillomavirus in women, 315, 402 immune reconstitution syndromes, 524 infectious mononucleosis, 746 initial management, 503–509 history, 503 immunizations, 507 laboratory studies, 505 physical exam, 505 injection drug use, 231, 495, 497, 498, 500, 683, 687 Kaposi’s sarcoma, 522 key points, 497, 504, 518, 521, 523, 525 lactic acidemia, 532 lipodystrophy, 524 lymphadenopathy, 720 lymphoma, 523 maculopapular rash, 144 microsporidiosis, 520–521 molluscum contagiosum, 405 Mycobacterium avium infection, 519 natural history, 502–503, 514 nucleic acid antigen test, 106

873 [Human immunodeficiency virus] occupational exposure, 470, 787–796 odynophagia, 530 oral candidiasis, 218–219, 629 perinatal screening, 653, 654, 657 pharyngitis, 189 Pneumocystis carinii pneumonia, 516–519 pneumonia, 231, 527–530 postexposure prophylaxis non-occupational, 796–799 occupational, 787–796 pregnancy, 656–658 key points, 657 perinatal transmission, 657 progressive multifocal leukoencephalopathy, 522 prophylaxis for opportunistic infections, 508–509 recognition, 497 renal disease, 532, 706 risk behavior, 497 risk reduction, 497 sporotrichosis, 628 testing indications, 499, 502 pre/post counseling, 499–500 rapid, 102, 104 techniques, 502 toxoplasmosis, 520 transmission, 496, 498, 683, 787–788, 797 tuberculosis, 250, 251, 254, 256, 683 urethritis, 322 vertebral osteomyelitis, 561, 569 viral load, 502, 503, 505 virology, 496 wasting, 523 Human monocytic ehrlichiosis (also see ehrlichiosis), 608– 612 Human papilloma virus (HPV), 314 conjunctivitis, 415 gynecological lesions, 314–316 diagnosis, 315 key points, 315 treatment, 315–316 human immunodeficiency virus, 505 male, 333–336 diagnosis, 334 key points, 334 treatment, 334–336

[Human papilloma virus] mouth lesions, 211, 224 nucleic acid tests, 106 warts, 314–316, 333–336, 402–404 Human polyoma virus, 522 Human T-cell lymphotrophic virus (HTLV) diagnosis, 112 injection drug use, 687–688 tropical spastic paraparesis, 688 Humoral immunity, 661, 662 defects, 664–666 Hydradenitis suppurativa, 674 Hyperbaric oxygen necrotizing fasciitis, 29 Hyperimmunoglobulin E syndrome, 665 Hyperthermia, 6 heat stroke, 6 malignant, 7, 152 neuroleptic malignant syndrome, 7 Hyperthyroidism fever, 161 Hypogammaglobulinemia, 664– 665 acquired, 665 common variable, 664 pneumococcal meningitis, 21 Hypopyon, 410, 412, 426, 434, 691 Id reaction, 398 Imipenem–cisplatin anthrax, 830 cost, 125 dose, 89, 125 dose in renal disease, 89 diabetic foot infection, 596 half life, 125 intraabdominal infection, 476, 484 neutropenic fever, 36–37 outpatient parenteral antibiotic therapy, 125 post-antibiotic effect, 83 Imiquimod cream, 316, 335 cutaneous warts, 403, 404 molluscum contagiosum, 405 Immune compromised host, 661– 675 approach to the patient, 670– 673 aspergillosis, 628 babesiosis, 612 blastomycosis, 625

874 [Immune compromised host] Capnocytophaga sp., 388 Clostridium difficile colitis, 449 coccidioidomycosis, 626 cryptococcosis, 627 dermatophyte infection, 398 fever, 673 hepatitis B virus, 461 histoplasmosis, 624 humoral defect and pneumococcal meningitis, 21 immune defects, 661–662 anatomic defects, 663–664 cell-mediated defects, 667– 670 humoral defects, 664–666 phagocytic defects, 666–667 key points, 663, 671 meningitis, 20, 672 mucormycosis, 430, 629 Norwegian scabies, 396 outpatient parenteral antibiotic therapy, 121 oral candidiasis, 218 oral herpes, 222, 223 presentations, 672 prophylaxis, 672–673 sinusitis, 201 skin infections, 375, 381 tuberculosis, 251–252, 256 vaccination, 819 varicella, 407 vertebral osteomyelitis, 561 warts, 402 Immune reconstitution syndrome Human immunodeficiency virus, 524 Immunization (see vaccine) Immunoglobulin E hyperimmunoglobulin E syndrome, 665 Immunoglobulin G deficiency, 663, 664–665 Streptococcus pneumoniae infection, 662, 670, 672 Immunoglobulin therapy hepatitis A virus, 359, 753 hepatitis B virus, 464, 471 international traveler, 753 postexposure prophylaxis, 800, 802 toxic shock syndrome, 391 Impetigo, 373, 376, 377–379 bullous, 377 Indinavir, 511 dose, 794 postexposure prophylaxis, 794, 799

Index [Indinavir] toxicity, 527, 794 Infection control measures, 849 bioterrorism, 849–850 Infectious mononucleosis (also see Epstein-Barr virus) acute retroviral syndrome, 746 Arcanobacterium sp., 746 cytomegalovirus, 143, 744– 745 differential diagnosis, 745 diagnosis, 103 Epstein-Barr virus infection, 738–743 fever of unknown origin, 166 genital ulceration, 327 human herpes-6, 745 key points, 736, 744 petechiae, 136 rash, 144, 738 Rubella, 746 toxoplasmosis, 745 viral hepatitis, 746 Inflammatory bowel disease fever, 160 genital ulcers, 310 intraabdominal infection, 474, 482 oral ulcers, 211 Influenza virus, 271–278 bacterial pneumonia, 274, 779 bronchitis, 243 clinical manifestations, 273– 274 common cold, 266, 267 complications, 273 conjunctivitis, 415 diagnosis, 274, 779 elderly, 778 inhalation anthrax, 827, 830 key points, 271 nomenclature, 272 nucleic acid antigen test, 106 pathogenesis, 272 pharyngitis, 189 pneumonia, 233, 235, 779 prevention, 276–278 rapid testing, 102, 103, 274 risks for severe illness, 273 sinusitis, 201 treatment, 240, 244, 274, 779 vaccine, 276–277, 810, 812 international travel, 752, 753 pregnancy, 658 target groups, 276, 507, 706, 810 Infus-a-port catheters outpatient parenteral antibiotic therapy, 119–120

Infusion devices (for outpatient parenteral antibiotic therapy), 199–120 Injection drug user, 697–693 botulism, 691 brain abscess, 690 cellulitis, 678 cerebritis, 690 endocarditis, 348, 350, 355, 680–682 endophthalmitis, 691 fever, 677 hepatitis, 685–687 hepatitis A virus, 686 hepatitis B virus, 459, 685 hepatitis C virus, 465, 685 hepatitis D virus, 468, 685 human immunodeficiency virus infection, 231, 495, 497, 498, 500 key points, 678, 681, 683, 686, 688 meningitis, 690 mycotic aneurysm, 682 necrotizing fasciitis, 679, 690 needle exchange program, 692 osteomyelitis, 564, 569–570, 689 pneumonia, 231, 683 safer injection practices, 692– 693 septic arthritis, 538, 539, 688 sexually transmitted diseases, 689 splenic abscess, 682 tetanus, 691 tuberculosis, 252, 256, 683, 684–685 vaccination, 684 vertebral osteomyelitis, 560, 689, 691 Interferon common cold, 268, 270 fever, 9 hepatitis B virus, 363 hepatitis C virus, 467, 705 hepatitis D virus, 469 Kaposi’s sarcoma, 523 Intra-abdominal infections, 473– 493 approach to patient, 473–475, 476 Helicobacter pylori, 48–492 intra-abdominal abscess pancreatic, 487 renal, 488

Index [Intra-abdominal infections] splenic, 487 intraparenchymal abscess, 484– 488 hepatic, 484–487 key points, 477, 479, 486, 489 peritonitis, 475 antimicrobial therapy, 483– 484 localized, 478–483 primary, 477–478 secondary, 478 septic shock, 39 surgical prophylaxis, 488 Intrauterine device infections, 317 Intravenous catheter neutropenic fever, 34–35 Involucra osteomyelitis, 558 Iodoquinol amebiasis, 638 Iridocyclitis (anterior uveitis) (also see iritis), 431 Iritis (also see uveitis), 413, 430 key points, 431 relapsing fever, 617 Isolation meningococcal meningitis, 21 tuberculosis, 263 Bioterrorism, 851 Isoniazid (isonicotinic acid, INH) injection drug user, 684 Mycobacterium tuberculosis latent infection, 255, 684 Myobacterium tuberculosis treatment, 261, 262 nursing home patient, 781, 783 Isospora belli, 641 acquired immune deficiency virus, 454, 531, 641 diagnostic tests, 446, 641 diarrhea, 446, 454, 641 stool examination, 445 treatment, 448, 638, 641 Itraconazole Aspergillosis, 629 blastomycosis, 625 candida vaginitis, 304 coccidioidomycosis, 627 dermatophyte infection, 400 histoplasmosis, 624 onychomycosis, 401 oral candidiasis, 220 sporotrichosis, 628 tinea capitis, 401 Ivermectin scabies, 396 strongyloidiasis, 643

875 Ixodes ticks Babesia microti, 32, 612 Lyme disease, 32, 600, 602 Powassan viral encephalitis, 618

[KOH preparation] pityriasis versicolor, 402 scabies, 395 vaginitis, 304, 629 Koplik’s spots, 141

Janeway lesions endocarditis, 352, 389 Japanese encephalitis vaccine, 753, 754, 816 Jarisch-Herxheimer reaction drug reaction, 152, 331, 605 JC virus nucleic acid antigen test, 106 Job’s syndrome (see hyperimmunoglobulin E syndrome) Jones criteria, 159

Laboratory, 97–114 cultures, 105–111 key points, 98 rapid on site tests, 101–104 sample collection and transport, 97 Lacerations infections, 387 LaCrosse encephalitis, 630–631 Lactic acidemia Human immunodeficiency virus infection, 532 Lactobacillus sp. bacteremia, 180 vaginal flora, 285, 302 Lactoferrin testing, 445 Lamivudine (3TC), 511 dosage, 794 hepatitis B virus, 463 postexposure prophylaxis, 791, 798 toxicities, 794 Larval migrans cutaneous, 633, 752, 769 visceral, 633 Laryngitis pharyngitis, 190 Lassa fever virus (also viral hemorrhagic fever), 848 Legionella sp. human immunodeficiency infection, 528 lysis centrifugation, 108 pneumonia, 233 serological diagnosis, 107 Legionella pneumophila antibiotic penetration, 93 cell-mediated immune defect, 668 endocarditis, 354 nucleic acid antigen test, 106 pneumonia, 235, 668, 780 pulse temperature deficit, 5 rapid testing, 102, 104 urinary antigen test, 235 Legionnaire’s disease (see Legionella pneumophila) Leishmaniasis clinical syndromes, 637 diagnosis, 101 exposure risk, 637 genital ulcer, 309

Kaposi’s sarcoma, 504, 505, 515, 522–523 Kawasaki disease, 133, 140 Keratitis, 410, 413, 423–427 bacterial, 426–427 blepharitis, 419 differential diagnosis, 412 fungal, 427 key points, 423 Lyme disease, 605 Microsporidia, 520 smallpox, 840 viral, 424–426 herpes simplex, 424–425 herpes zoster ophthalmitis, 426 zoster, 408 Keratoconjunctivitis sicca (dry eye syndrome), 423 Kernig’s sign, 18 Ketoconazole blastomycosis, 625 candida vaginitis, 304 pityriasis versicolor, 402 Kingella kingae diagnosis, 108 endocarditis, 360 Kinyoun stain, 100 Klebsiella sp. bacteremia, 178 diabetic foot infections, 589 necrotizing fasciitis, 26, 30 neutropenic fever, 36 primary peritonitis, 477 secondary peritonitis, 477 urinary tract infections, 281, 283, 650 KOH preparation bacterial vaginosis, 302 candida skin infection, 400 dermatophyte infection, 398

876 [Leishmaniasis] geographic locale, 637 tropical ulcer, 769 Lemierre’s disease, 178 Leptospirosis fever of unknown origin, 166 rash, 145, 713 serological diagnosis, 107, 713 sterile pyuria, 284 zoonosis, 713 Leukemia fever, 155 neutropenia, 662, 666 pathogens, 662 Leukocyte adhesion defect, 662, 667 Leukocyte esterase urinalysis, 110 Leukocytosis appendicitis, 481 bursitis, 554 cholangitis, 480 cholecystitis, 479 Clostridium difficile colitis, 450 decubitus ulcers, 776 diverticulitis, 482 drug fever, 153 endometritis, 652 hepatic abscess, 486 malaria, 34 plague, 843 pyelonephritis, 282 renal abscess, 282 secondary peritonitis, 478 septic shock, 38 Still’s disease, 156 tuberculosis, 254 vertebral osteomyelitis, 562, 698 viral hemorrhagic fever, 848 Leukopenia babesiosis, 612 drug reaction, 126 ehrlichiosis, 32, 609 fever of unknown origin, 167 histoplasmosis, 624 human immunodeficiency virus, 499 malaria, 34 peritonitis, 478 Rocky Mountain spotted fever, 32 septic shock, 38 systemic lupus erythematosus, 156 Levofloxacin, 64 costs, 56, 125 dose, 56, 89, 125

Index [Levofloxacin] dose in renal disease, 54, 89 drug interactions, 94 outpatient parenteral antibiotic therapy, 125 pharmacokinetic properties, 53 plague, 843 pneumonia, 238, 239 prostatitis, 341 sinusitis, 202 Lice, 393–395 body, 393 head, 394 key points, 394 pubic, 395 relapsing fever, 617 Lindane lice, 394, 395 scabies, 396 Linezolid, 73–74 methicillin-resistant Staphylococcus aureus, 785 skin infections, 378 Lipodystrophy Human immunodeficiency virus infection, 524 Lipopolysaccharide, 38 Listeria monocytogenes, 668 bacteremia, 179, 180 cell-mediated immune defect, 668, 669, 671–672 endocarditis, 360 meningitis, 20, 22, 656, 783 pregnancy, 656 Liver biochemical tests acute retroviral syndrome, 500 approach to diagnosis, 455– 457 babesiosis, 612 cholangitis, 480 cholecystitis, 479 cytomegalovirus, 143 drug reaction, 126 ehrlichiosis, 32 fever of unknown origin, 167 hepatitis A virus, 458 hepatitis B virus, 461, 463 hepatitis C virus, 466 human immunodeficiency virus infection, 532 infectious mononucleosis, 739 intraabdominal pain, 475 lactic acidemia, 532 leptospirosis, 713 plague, 843 rocky mountain spotted fever, 614 tuberculosis, 254

Liver function tests (LFT) (see liver biochemical tests) Loa loa, 637 Localized osteitis, 210, 213–214 Loeffler’s syndrome, 643 Lomefloxacin, 65–67 adverse reactions, 66 costs, 56 dose, 56 spectrum, 65 Long-term non-progressors, 502 Lopinavir/ritonavir, 511 toxicities, 527 Loracarbef, 49 cost, 42 dose, 42 dose in renal disease, 45 pharmacokinetics, 44 Ludwig’s angina, 225 Lumbar puncture bacterial meningitis, 18–19, 690 cryptococcus meningitis, 519 encephalitis, 24 injection drug user, 690 neurosyphilis, 330 Lyme disease (see Borrelia burgdorferi), 599–608 arthritis, 538, 551–552 conjunctivitis, 413 early, 604, 605, 606, 607 epidemiological characteristics, 600–601 erythema chronicum migrans, 145, 391, 602–604, 715 key points, 600 late, 605, 606, 607 prevention, 607–608 serological diagnosis, 604, 606 tick vectors, 600–601 treatment, 605–607 vaccine, 608, 811, 814 Lymphadenopathy acute retroviral syndrome, 500 bubonic plague, 714, 720 cat scratch disease, 714, 719, 720 cytomegalovirus, 143 differential diagnosis, 747 filariasis, 720 genital ulcers, 325–333 hepatitis A, 458 human immunodeficiency virus, 144, 499, 720 infectious mononucleosis, 738– 739 international traveler, 762 Lyme disease, 604

Index [Lymphadenopathy] leishmaniasis, 720 plague, 842 pharyngitis, 190 sexually transmitted disease, 325, 720 sporotrichosis, 383 syphilis, 312, 720 tularemia, 617, 714, 720, 846 zoonosis, 714–715, 719, 720 Lymphangitis, 380, 383 Lymphocytosis fever of unknown origin, 167 Lymphocytosis, atypical differential diagnosis, 741 fever of unknown origin, 167 infectious mononucleosis, 735, 738, 740 Lymphogranuloma venereum genital ulcer (female), 309 genital ulcer (male), 326 Lymphoma Burkitt’s, 735, 744 fever, 154–155 human immunodeficiency virus, 499, 515, 523, 668 central nervous system, 515, 526, 528 human T-lymphotrophic virus, 688 immune defects, 662, 668 mucosa-associated lymphoid tissue, 489 pathogens, 662, 668 primary central nervous system, 743 Lymphopenia fever of unknown origin, 167 human immunodeficiency virus infection, 231 sarcoidosis, 160 Lysis centrifugation system, 107 endocarditis, 354 histoplasmosis, 624 Legionella sp., 354 Mycobacterium avium, 520 Mycobacterium tuberculosis, 259 MacConkey’s Agar, 105, 178 Macrodantin for urinary tract infection, 286, 287 Macrolides 51–58 adverse reactions, 57 bacterial resistance, 52, 234 clinical indications, 55 drug interactions, 94

877 [Macrolides] mechanism of action, 51 pharmacologic properties, 52 pneumonia, 237 pregnancy, 647 spectrum of activity, 55 tissue penetration, 93 Maculopapular rash, 140–146 acute retroviral syndrome, 500 coccidioidomycosis, 626 drug fever, 153 key points, 141 pediculosis, 393, 395 pityriasis versicolor, 401 rocky mountain spotted fever, 613 scabies, 395 Magic mouthwash oral herpes, 222 Magnetic resonance imaging (MRI), 546 acquired immune deficiency syndrome, 526, 528 dementia, 522 bacterial meningitis, 18 cavernous sinus thrombosis, 430 decubitus ulcers, 387 diabetic foot infection, 588, 589 herpes simples virus-1 encephalitis, 24 necrotizing fascitis, 382 progressive multifocal leukoencephalopathy, 522 septic arthritis, 546 septic bursitis, 555 submandibular abscess, 225 toxoplasmosis, 520 vertebral osteomyelitis, 563, 564, 565, 567, 698 Malaria 33–34, 755, 761–764 diagnosis, 34, 101, 613, 763 pathophysiology, 33 presentation, 33–34 prophylaxis, 755–756 risks, 34 treatment, 34, 763–764 Malarone malaria prophylaxis, 755 Malassezia furfur (see Pityrosporum ovale) Malathion lotion (Ovide), 394 Malignancy and fever, 153–156 and fever of unknown origin, 165

Malignant otitis externa (see otitis externa) Marburg virus, 848 (also see viral hemorrhagic fever) Mastoiditis, 195 key points, 193, 572–573 Measles (see rubeola virus) Measles, mumps, rubella, vaccine 815–816 indications, 811 during pregnancy, 658 Mebendazole ascariasis, 643 enterobiasis, 643 hookworm, 643 trichuris sp., 643 Mefloquine malaria prophylaxis, 34, 755 malaria treatment, 763 toxicity, 34, 755 Meibomian gland, 419 Melioidosis, 829 Men who have sex with men (MSM), 495, 497, 498 Mendelson’s syndrome, 236 Meningitis acute retroviral syndrome, 500 aseptic coccidioidomycosis, 626 cryptococcal, 668, 783 ehrlichiosis, 609 herpes simplex virus, 327 human immunodeficiency virus, 499, 515 Lyme disease, 603, 605, 607 Mycoplasma pneumoniae, 234 relapsing fever, 617 bacterial, 17–23 anthrax, 828 bacteriology, 20–22 clinical presentation, 17 corticosteroids, 22 diagnosis, 18, 108–109 elderly, 783 endocarditis, 353 Haemophilus influenzae, 22 injection drug use, 690 key points, 18 Listeria monocytogenes, 20, 22, 656, 668, 783 Lumbar puncture, 18–19 Mycobacterium tuberculosis, 254, 259, 783 Neisseria meningitides, 20–21 sinusitis, 201 Streptococcus pneumonia, 21– 22, 783 therapy, 22–23

878 Meningococcemia (also see Neisseria meningitidis), 136 exposure risk, 132 rash, 132 treatment, 132 Mental status acquired immune deficiency syndrome, 528 dementia, 522 bacterial meningitis, 17 cryptococcal meningitis, 519 encephalitis, 24, 630 malaria, 33 rocky mountain spotted fever, 31 sepsis syndrome, 36 septic shock, 38 toxoplasmosis, 520 Meropenem cost, 125 diabetic foot infections, 596 dose, 125 half life, 125 post antibiotic effect, 83 neutropenic fever, 36–37 septic shock, 39 Metronidazole, 71–73 adverse reactions, 72–73 amebiasis, 638 bacterial vaginosis, 303, 647 clinical indications, 72 clostridium difficile colitis, 451–452 costs, 56 dosage in hepatic failure, 92 dose, 56, 89 dose in renal disease, 54, 89 drug interactions, 94 giardiasis, 638 Helicobacter pylori, 491 intraabdominal infection, 476, 484, 485 mechanism of action, 71 necrotizing fasciitis, 30 neutropenic fever, 37 pelvic inflammatory disease, 308 peritonitis, 484 pharmacokinetic properties, 53 pharmacological properties, 71 pregnancy, 646 resistance, 71 spectrum, 72, 59 splenic abscess, 487 surgical prophylaxis, 490 urethritis, 324 Miconazole candida vaginitis, 305

Index Microhemagglutination–T. pallidum (MHA-TP), 330 Microsporidian sp., 641 and acquired immune deficiency syndrome, 641, 454, 530–521 diagnosis, 517, 520–521, 642 therapy, 517, 521, 638 presentation, 517, 520 diarrhea, 446, 454, 641 Microsporum sp. skin infections, 398–400 Midline catheter, for outpatient parenteral antibiotic therapy, 118, 120 Minimal inhibitory concentration (MIC), 80 break points, 113 penicillin break points, 233 streptococcal endocarditis, 361 Minocycline costs, 56 dose, 56 meningococcal prophylaxis, 21 Mites, 396–397 chiggers, 397 fleas, 397 Mitral valve prolapse and endocarditis, 348 MMR Vaccine (see measles, mumps, rubella vaccine) Mobiluncus sp. and bacterial vaginitis, 302 Molds (see fungal infections) Molluscum contagiosum, 224, 334, 404–405 blepharitis, 419 conjunctivitis, 413 key points, 403 Monocytosis and fever of unknown origin, 167 Mononeuritis multiplex and human immunodeficiency virus, 515 and lyme disease, 605 Mononucleosis (see infectious mononucleosis) Monospot slide test, 103, 740 Moraxella catarrhalis bacteremia, 181 blepharitis, 423 bronchitis 234, 245 conjunctivitis, 413 otitis media, 193 pneumonia, 780 sinusitis, 201

Morganella sp. bacteremia, 178 Morulae, 611 Mouth pain, 210 lesions, 211 Moxifloxacin 65 costs, 56 decubitus ulcer, 776 dose, 56 pharmacokinetic properties, 53 pneumonia, 238, 782 sinusitis, 202 Mucorales sp., 629 Mucormycosis cerebral, 690 infection drug use, 690 orbital cellulitis, 429, 430 sinusitis, 201, 629 Mumps virus arthritis, 553 conjunctivitis, 415 vaccine, 811, 815 for international travel, 752, 753 Mupirocin, 385, 674 Murphy’s sign, 479 sonographic, 480 Mycobacterium sp. lysis centrifugation, 108, 259 nontuberculous, 252 skin lesions, 829 Mycobacterium avium complex, 252, 259 computerized axial tomography scan, 260 diagnosis, 517 human immunodeficiency virus infection, 502, 514, 515 immune reconstitution syndrome, 524 presentation, 517, 519–520 prophylaxis for, 508, 509 therapy, 517 Mycobacterium marinum skin lesions, 383 Mycobacterium tuberculosis (also see tuberculosis) acid fast bacillus (AFB) smear, 101 arthritis, 535, 538, 550 cutaneous ulceration, 829 diagnosis, 258–260 and human immunodeficiency virus, 502, 520 infection vs. disease, 252–253 nucleic acid antigen defection, 106 prevention, 263

Index [Mycobacterium tuberculosis] prostatitis, 341 retinitis, 433 testing, 254–258 treatment, 261–263 tuberculosis, 251–264 vertebral osteomyelitis, 566, 567, 569 and bacterial vaginosis, 302 prostatitis, 339 urinary tract infection, 292 Mycobacterium ulcerans cutaneous ulcer, 829 Mycoplasma pneumoniae bronchitis, 243, 245 extra pulmonary complications, 234 pharyngitis, 189 pneumonia, 230, 233, 234 serological diagnosis, 107 Mycotic aneurysm, 682, 6900 Myelitis Epstein Barr virus, 743 influenza, 273 Lyme disease, 605 Myelopathy human immunodeficiency virus infection, 531 Myiasis, 769 Myocarditis ehrlichiosis, 609 endocarditis, 351 influenza, 273 Lyme disease, 603, 605, 607 Mycoplasma pneumoniae, 234 relapsing fever, 617 rocky mountain spotted fever, 617 Myopathy human immunodeficiency virus, 515, 531 Myositis 375, 376, 392 clostridial, 28, 392 injection drug use, 680 non-clostridial, 28 Staphylococcus aureus, 392 Nafcillin, 46 dosage in hepatic failure, 92 dose, 89, 125 dose in renal disease, 80 endocarditis, 364, 367 half life, 125 outpatient parenteral antibiotic therapy, 125 septic arthritis, 538 skin infections, 378

879 [Nafcillin] vertebral osteomyelitis, 567, 568 Naftifine, 400 Nalidixic acid, 64 costs, 56 dose, 56 Necator sp. (see Hookworm) Necrotizing soft tissue infections, 25–79, 375 antibiotic therapy, 29, 30 bacterial synergistic gangrene, 382 clostridial cellulitis, 26 diagnosis, 26–27 injection drug use, 680 key points, 25 management, 27, 29 myonecrosis, 28 pathophysiology, 25 streptococcal fasciitis, 26, 147, 680 gangrene, 382 Nedocromil common cold therapy, 269 Needle exchange program, 692 Needle stick injury (see Health Care Worker) Neisseria gonorrhoeae arthritis, 535, 538, 543, 544 bacteremia, 181 cervicitis, 306, 307 complement deficiency, 666 conjunctivitis, 413 culture, 322 diagnosis, 110 diarrhea, 445 disseminated, 321, 390, 543 endocarditis, 349, 360 epididymitis, 342 Fitz-Hugh-Curtis syndrome, 317 keratitis, 426 nucleic acid antigen detection, 106, 322 pelvic inflammatory disease, 308, 653 pharyngitis, 321 proctitis 321, 446 skin lesions, 390 tenosynovitis, 543 urethritis (female), 304, 316 urethritis (male), 319–325 Neisseria meningitidis bacteremia, 181, 390 complement deficiencies, 666 conjunctivitis, 418

[Neisseria meningitidis] meningitis, 20 petechiae, 135, 390 prophylaxis, 21 rash, 21, 132 vaccine, 21, 754, 753, 811, 815 Nelfinavir, 511 dose, 794 postexposure prophylaxis, 794, 799 toxicities, 527, 794 Neuraminidase influenza virus, 272 Neurasthenia, 725 Neuropathy diabetes, 581–582, 583 human immunodeficiency virus, 499, 515, 531 Neurosyphilis, 330, 331 Neutropenia 666 absolute neutrophil count, 666 beta-lactams, 50 causes of, 662 chest x-ray, 230 Epstein Barr virus infection, 743 fungal infections, 666 pathogens, 662 skin infections, 374, 390 Neutropenia fever, 34–36, 666, 662 anaerobic infection, 35–37 causes of, 662 diagnosis, 34–35 ecthyma gangrenosum, 390 key points, 35 outpatient parenteral antibiotic therapy, 121 outpatient management, 36, 666 pathogens, 662 treatment, 36–37 Neutrophil defect, 667 causes of, 662 pathogens of, 662 Nevirapine 511 toxicities 527 New Castle’s disease conjunctivitis, 415 Nitrate reductase, 110 Nitrofurantoin complication of, 294 for urinary tract infections, 287, 650, 651 Nits (see lice) Nocardia sp., 668 cell mediated immune defect, 668, 662

880 [Nocardia sp.] and human immunodeficiency virus infection, 528 modified AFB stain, 101, 259 Nodules, 148–149, 383 coccidioidomycosis, 626 Kaposi’s sarcoma, 522 rheumatic fever, 159 sporotrichosis, 628 vasculitis, 157 Nonsteroidal anti-inflammatory drugs (NSAID) antipyretic therapy, 13 common cold, 268, 269 cox inhibition, 13–14 Norfloxacin, 64–65 costs, 56 dose, 56 drug interactions, 94 primary peritonitis, 478 for urinary tract infections, 286 Norwalk virus diarrhea, 441, 445 Nuclear scintigraphy arthritis, 547 vertebral osteomyelitis, 564 Nucleic acid detection tests, 104, 106 Nucleic acid sequence based analysis (NASBA) human immunodeficiency virus testing, 502 Nursing home, infections in encephalitis, 783 influenza, 778–779 key points, 773, 775, 778 malignant otitis externa meningitis, 783 methicillin resistant Staphylococcus aureus, 784 pneumonia, 779–781 pressure sores, 774–776 scabies, 777–778 shingles, 777 tuberculosis, 781–783 urinary tract infection, 773–774 Nystatin candida skin infection, 400 for candida vaginitis, 305 oral candidiasis, 220 Occupational exposure (see Health Care Worker) Ocular infections, 409–435 anatomic characteristics, 411 blepharitis, 419, 423 conjunctivitis, 410–419 corticosteroid use, 417

Index [Ocular infections] endophthalmitis, 433–434 keratitis, 423–427 key points, 412, 414, 422, 423, 428, 431, 439 periocular infection, 427–430 red eye, 409–410 smallpox, 838 uveitis, 431–433 Odynophagia human immunodeficiency virus infection, 530, 517 Ofloxacin, 64–65 cervicitis, 307 cost, 56 dose, 56 epididymitis, 344 pelvic inflammatory disease, 308 prostatitis, 341 urethritis, 324 urinary tract infection, 286 Onchocerca sp., 634, 635, 637 (also see Filariasis) Onychomycosis, 398 treatment, 401 Oral candidiasis, 218–219 acute retroviral syndrome, 500 cell mediated immune defect, 668 human immunodeficiency virus, 499, 505 treatment, 219–220 Oral hairy leukoplakia, 219 human immunodeficiency virus, 505, 515 Oral infections, 209–226 acute retroviral syndrome, 144 anatomy, 209, 212 candidiasis, 218–219, 499 dental cavities, 210–213 gingivitis, 214–215 hairy leukoplakia, 219 and herpes simplex, 221–222 human papilloma virus, 224 Kaposi’s sarcoma, 522 lesions, 211 neutropenic fever, 35, 37 osteomyelitis, 571 pain, 210 periodontitis, 215–216 systemic lupus erythematosus, 156 smallpox, 838 tongue lesions, 216–219 ulcers, 219–224 varicella zoster, 223

Oral rehydration solution, 447, 756, 757 Oral sex and human immunodeficiencies, 498 Oral ulceration, 219–224 acute retroviral syndrome, 500 Orbital cellulitis, 429–430 Orchitis, 344–345 blastomycosis, 625 Orf, 829 Organ transplantation cell mediated immune defect, 669 cytomegalovirus, 669–670 pathogens, 669–670 Orthomyxoviridae (see influenza virus) Orthopox virus, 836 Oseltamivir, 240, 275 in the elderly, 779 for prophylaxis, 278 Osler nodes and endocarditis, 352 Osteomyelitis, 557–579 animal bites, 574, 575 blastomycosis, 625 coccidioidomycosis, 626 contiguous focus, 572 endocarditis, 353 human bites, 574, 575 in injection drug use, 569–570 malignant otitis externa, 572, 573 odontogenic, 571, 573 outpatient parenteral antibiotic therapy, 121 otitis media, 571, 573 pathogenesis, 557–558 post surgical, 577 pressure sores, 574, 575 prosthetic joint, 576–578 puncture wounds, 573, 575 and septic arthritis, 547 in sickle cell disease, 570 sinusitis, 571, 573 tuberculosis, 254 vertebral, 558–569 clinical presentation, 562 diagnosis approach, 564, 565 hemodialysis, 698 key points, 559 laboratory tests, 562 microbiology, 564–566 pathophysiology, 559–560 radiographic studies, 563 radiological studies, 563–564, 561

Index [Osteomyelitis] risk factors, 560, 561 treatment, 566–567, 568 Otic antibiotics, 197 Otitis externa, 192–198 key points, 193 malignant, 194, 572–573, 571, 784–785 otic antibiotics, 197 otic antifungals, 198 Otitis media, 192–198 diagnosis, 195 and dry socket, 214 influenza, 273 key points, 193 and pneumococcal meningitis, 22 and pressure equalization tubes, 196 osteomyelitis, 571 otic antibiotics, 197 Outpatient parenteral antibiotic therapy (OPAT), 115–128 adverse reactions, 127 antibiotics for , 122, 125 approach to, 117 catheters for, 118–119 clinical candidates for, 118 contraindications, 118, 116 infections for, 121 infusion devices, 119–120 key points, 116 location 120–121 monitoring, 123, 126 Ova and parasite amebiasis, 639 cryptosporidiosis, 517 cyclosporiasis, 641 examination of stool, 101, 445 isosporiasis, 641 Ovarian vein thrombophlebitis, 653 Oxacillin, 46 (also see Nafcillin) Septic arthritis, 538 Oxazolidinones, 73–74 adverse reactions, 74 clinical indications, 74 mechanism of action, 73 pharmacological properties, 73 spectrum, 74 Pancreatic abscess, 487–488 key points, 486 Pancreatic pseudocyst, 488 Pancreatitis antiretroviral medications, 530 cytomegalovirus, 530

881 Pap smear (see Papanicolaou smear) Papanicolaou smear gynecological warts, 315 human immunodeficiency virus infection, 505 human papilloma virus, 314, 336 trichomonal vaginitis, 304 Paracentesis, 478 Parainfluenza virus common cold, 266 nucleic acid antigen test, 106 sinusitis, 201 pneumonia, 233 Paralysis and botulism, 843 Paramyxoviridae common cold, 266 Parasitic infections, 633–644 classifications of, 635 diarrhea, 637–642 eosinophilia and, 633–634, 635 key points, 634, 638, 642 treatment of intestinal protozoa, 638 worms in stool, 642–644 Parasitosis, hysterical, 644 Paromomycin amebiasis, 638 cryptosporidiosis, 638 giardiasis, 638 trichomonal vaginitis, 305 Paronychia 386 key point, 384 Pars-planitis, 430 (also see uveitis) key points, 431 Parvovirus B19 arthritis, 552 diagnosis, 112 fifth disease, 142, 143 and human immunodeficiency virus infection, 532 perinatal infection, 655 rash, 142 Pasteurella canis animal bite, 711 Pasteurella multocida animal bites, 388, 711, 716 bacteremia, 178, 181 septic arthritis, 538 and skin infections, 374, 380 Pastia’s lines, 139 Pediculosus 393–395 (also see lice) key points, 394

Pediculus humanus (see lice) P. humanus VAR capitis, 393 P. humanus var corporis, 393 Pelvic inflammatory disease, 306–309, 653 criteria for diagnosis, 308 treatment, 308 Penciclovir cream (Denavir) cutaneous herpes simplex virus, 407 oral herpes simplex virus, 222 Penicillin Benzathine syphilis, 313, 331 Penicillin G dose, 89 dose, 125 dose in renal disease, 89 endocarditis, 362, 363 human bites, 575 infusion pump for, 120 lyme disease, 606 for meningitis, 22–23 for necrotizing fasciitis, 29–30 pharyngitis, 192 outpatient parenteral antibiotic therapy, 125 resistance, 233, 234 skin infections, 378 vertebral osteomyelitis, 568 Penicillin V, 43 costs, 42 dose, 42 dose with renal disease, 45 indications, 46 pharmokinetic properties, 44 pharyngitis, 190, 192 resistance, 233, 234 skin infections, 378 spectrum, 47 Penicillium sp. keratitis, 427 Penile discharge, 319 Penile lymphangitis, 321 Penlac (topical) onychomycosis, 401 Pentamidine outpatient parenteral antibiotic therapy, 126 pancreatitis, 530 Pneumoocystis carinii, 517, 518 Peptic ulcer disease, 489 Peptostreptococcus sp. bacteremia, 176 diabetic foot infection, 589 human bites, 388 myonecrosis, 28, 30 necrotizing fascitis, 382

882 [Peptostreptococcus sp.] pneumonia, 236 submandibular abscess, 225 Pericarditis influenza, 273 septic, 351 Pericoronitis, 216 Perinatal infections, 653–656 Parinaud’s oculoglandular syndrome, 720 Periodontal abscess, 216 Periodontitis, 215–216 Peripheral vascular disease and diabetic foot infection, 592–598 Peripherally inserted central catheter (PICC), 118–120 Peritoneal dialysis infections, 700–704 antibiotic dosage, 702 catheter infections, 703–704 key points, 700 peritonitis, 700–703 vaccination, 706 Peritonitis, 475–484 antimicrobial therapy for, 483– 484 diffuse key points, 477 localized, 478–483 secondary, 478 eosinophilic, 701 localized, 478–483 peritoneal dialysis, 700–703 primary, 477–478 Permethrin cream 1% (NIX), 394, 395, 396 Permethrin cream 5% (Elimite), 396 lice, 394, 395 scabies, 390 Petechiae approach to patient, 137 endocarditis, 351 infection causes, 136 key points, 135 neisseria meningitis, 390 non-infectious causes, 138 viral hemorrhagic fever, 848 Phagocytic immunity, 661, 662 defects in, 666–667 Pharmacodynamics, 77, 80–85 concentration dependent, 82 concentration independent, 82 drug interactions, 91 key points, 77 post antibiotics effect, 83–84

Index Pharmacokinetics, 77–80 clearance, 78 drug interactions, 87 first order elimination, 79 half life, 78–79 key points, 77 steady stats, 79 volume of distribution, 78 Pharyngitis, 187–192 acute retroviral syndrome, 500 anthrax, 830, 827, 833, Arcanobacterium haemolyticum, 140 common cold, 267 cytomegalovirus, 143 epiglottitis, 206 herpes simplex, 327 human immunodeficiency virus, 144 infectious mononucleosis, 738– 739, 746 influenza, 273 key points, 188 Neisseria gonorrhoeae, 321 rheumatic fever, 158 Streptococci pyogenes, 102, 189–192 syphilis, 312 tularemia, 846 Pharyngoconjunctival fever (PCF), 415 Phenytoin (see Dilantin) Photophobia, 410, 412, 424, 431 Phthirus pubis, 393 (also see lice and crabs) and blepharitis, 423 Phycomycosis (see mucormycosis) Picornaviridae common cold, 266 Pinworm (see Enterobiasis sp.) Pinguecula, 410 Piperacillin dose, 89 dose in renal disease, 89 neutropenic fever, 36 septic arthritis, 538 Piperacillin–tazobactam cost, 125 decubitus ulcers, 776 diabetic foot infections, 596 dose, 89, 125 dose in renal disease, 89 intraabdominal infections, 476, 484, 485 outpatient parenteral antibiotic therapy, 125 osteomyelitis, 575

[Piperacillin–tazobactam] pneumonia, 782 septic shock, 39 Pityriasis versicolor, 401–402 treatment, 402 Pityrosporum ovale skin infection, 398, 402–402 Plague (also see Yersinia Pestis) bioterrorism, 841–843 bubonic, 714, 720, 841–842 diagnosis, 835, 843 differential diagnosis, 842 infection control, 851, 843 management, 843 pneumonic, 712, 842–843, 835, 852 septicemic, 714, 842 transmission, 841, 851 vaccine, 843 Plasmodium sp. (Also see malaria) diagnosis, 34, 101, 613, 763 falciparum, 34, 755 fever, 5 key points, 33 prophylaxis, 755–756 risks, 34 treatment, 34, 763–764 types, 33–34, 755 Pleconaril, 268, 270 Plesiomonas sp. diagnosis 111 Pleural effusion and human immunodeficiency virus infection, 529 pneumonia, 214 Pneumaturia, 282 Pneumococcal vaccine 809 splenectomy, 663 Pneumococcus (see Streptococcus pneumoniae) Pneumocystis carinii, 516 cell mediated immune defect, 668, 669, 671, 672 chest x-ray, 230 human immunodeficiency virus infection, 502 pneumonia, 231, 514, 515, 516–519, 528–529 diagnosis, 517, 518 presentation, 517 therapy, 517, 518 prophylaxis for, 508, 509 Pneumonia, 227–242 abnormal vital signs, 228–229, 231 anaerobic bacteria, 236 anthrax, 827, 833

Index [Pneumonia] antibiotic failure, 241 approach to patient with, 228 aspiration, 236 bacterial, 232–236 blastomycosis, 625 Chlamydia pneumoniae, 234 and cholecystitis, 479 Coccidioidomycosis, 626 Coxiella burnetii, 712 Francisella tularensis, 617, 846 hantavirus pulmonary syndrome, 631–632 Haemophilus influenzae, 233, 235, 683, 780 Histoplasmosis, 622–624 human immunodeficiency virus, 527–530 influenza, 236, 273 injection drug use, 683 Legionella pneumophila, 235 meningitis, 22 Moraxella catarrhalis, 780 mortality, 232 Mycoplasma pneumoniae, 230, 233, 234, 236 Nocardia sp., 668 Nursing home, 779–781 outpatient parenteral antibiotic therapy, 116 plague, 842 Pneumoocystis carinii, 516–519 and septic shock, 39 site of care, 231–232, 241, 683 Streptococcus pneumoniae, 22, 231, 233, 683, 780 tuberculosis, 253, 258, 261 viral, 235–236, 780 zoonotic, 712 Pneumothorax and Pneumocystis carinii pneumonia, 518 Podofilox, 216, 335 Podophyllin resin, 316, 335 Polio virus vaccine oral, 818 pregnancy, 658 inactivated, 818 international travel, 752, 753 Polyarteritis nodosa and Hepatitis B virus, 704 Polymerase chain reaction (PCR) human immunodeficiency virus testing, 502 Polymyalgia rheumatica (PMR), 158 (see temporal arthritis) Polymyxin B–Neomycin-Bacitracin (Neosporin), 385

883 Polyradiculopathy and human immunodeficiency virus, 515, 531 Post-antibiotic effect, 83–84 Postexposure prophylaxis, 787– 805 anthrax, 830, 836 approach to the patient, 804 botulism, 845 hepatitis B virus 471, 799–802 hepatitis C virus 802–804, 471 human immunodeficiency virus costs, 797 injection drug use 687 non-occupational, 796–798 occupational, 687, 787–796 mucous membrane exposure, 793 percutaneous, 792 approach to patient, 804 plague, 843 smallpox, 840 tularemia, 847 key points, 788, 799 Post-herpetic neuralgia cutaneous, 408 in the elderly, 777 oral, 223 Pott puffy tumor, 201 Potts disease (see tuberculosis, vertebral) Powassan viral encephalitis, 618 Pregnancy, 645–659 antibiotic selection, 646–649 arthritis, 539 bacterial vaginosis, 303 congenital infections, 653–656 general principles, 646 hepatitis B virus, 464 human immunodeficiency virus, 499, 656–658 pelvic infections, 652–653 perinatal infections, 653–656 smallpox, 838 syphilis, 313 urinary tract infections, 649– 652 asymptomatic, 649–651 approach, 651 treatment, 650 cystitis, 650 key points, 649 pyelonephritis, 650–651 vaccination, 658, 819 vaginitis, 303 Preseptal cellulitis, 427–429 key points 428 Pressure equalization tubes, 198

Pressure sores (see decubitus ulcers) Prevotella sp. bacterial vaginitis, 302 endometritis, 653 pneumonia, 236 Primaquine and malaria, 763 and Pneumocystis carinii, 519 Proctitis Chlamydia trachomatis, 321 Neisseria gonorrhoeae, 321 Progressive multifocal leukoencephalopathy (PML) human immunodeficiency virus infection, 515, 522 Proguanil for malaria prophylaxis, 755 Prophylaxis for endocarditis, 368–371 surgical, 488–489, 490 Propionibacterium acnes endophthalmitis, 434 Prostaglandins fever, 10–11 Prostatitis, 336–342 acute, 337, 338 blastomycosis, 625 chronic, 337–339 chronic granulomatous, 341 classification, 337, 338 clinical evaluation, 336–339 diagnosis, 339–340 key points, 336 nonbacterial, 339, 338 sterile pyuria, 284 treatment, 340–342 Prosthetic valve endocarditis, 366–367, 348 echocardiography and, 357 pathogens, 360 treatment, 366 Proteus sp. bacteremia, 178 diabetic foot infections, 589 primary peritonitis, 477 prostatitis, 338 secondary peritonitis, 483 urinary tract infection, 281, 283, 285, 650 Providencia sp. prostatitis, 338 Prozone phenomenon, 313 Pruritus dermatophyte infection, 398 fleas, 397

884 [Pruritus] pediculosis, 394–395 scabies, 395 Pseudogout and fever, 161 from septic arthritis, 543 Pseudomembranous colitis, 450 (also see Clostridium difficile) Pseudomonas aeruginosa antibiotic synergy, 81 bacteremia, 175, 177–178 bronchitis, 245, 246 burn infections, 389 conjunctivitis, 418 diabetic foot infections, 589 endocarditis, 681 folliculitis, 385 ecthyma gangrenosum, 38, 148 injection drug use, 681, 683, 689 intraabdominal infection, 528 and human immunodeficiency virus infection, 528 keratitis, 426 lacerations, 387 necrotizing fasciitis, 28, 30 neutropenia, 666 neutropenia fever, 36 orchitis, 345 osteomyelitis, 569, 575 otitis externa, 193, 572, 789 paronychia, 386 peritoneal dialysis infection, 703–704 pneumonia, 242 prostatitis, 338 prosthetic valve endocarditis, 366 puncture wounds, 389 septic arthritis, 538 surgery for endocarditis, 368 urinary tract infection, 281 vertebral osteomyelitis, 564, 568 Psittacosis (see Chlamydia psittaci) Pterygium, 410 Pulex irritans (see fleas) Pulmonary embolism and fever, 160 Puncture wound infection with, 387 Purified protein derivative (PPD), 254–258 false negative, 257 and human immunodeficiency virus infection, 505, 684 injection drug user, 684

Index [Purified protein derivative] nursing home patient, 781 perinatal screening, 653 and spinal tuberculosis, 569 sequential, 257–258 Purpura (also see petechiae) vasculitis, 157 Pyarthritis (see arthritis) Pyelonephritis, 282, 299 and cholecystitis, 479 pregnancy, 650 unrecognized, 289 white cell casts, 283 Pyoderma, 376–382 key points, 377 Pyomyositis (also see myonecrosis) 392 Pyrazinamide Mycobacterium tuberculosis, 261, 262, 684, 781, 783 Pyridium (phenazopyridine hydrochloride) for urinary tract infections, 288 Pyrimethamine for toxoplasmosis, 517 Pyrinate liquid (RID), 394 Pyuria in the elderly, 773 infectious mononucleosis, 739 end stage renal disease, 706 nephritis, 284 pyelonephritis, 650 sterile, 254, 284 tuberculosis, 254 urinary tract infection, 283, 290, 280 Q fever (also see Coxiella burnetii) and fever of unknown origin, 166 pneumonia, 712 zoonosis, 713 Quinine babesiosis, 613 malaria, 34, 763 Quinolones, 63–67 ehrlichiosis, 612 drug interactions, 287 mechanism of action, 64 pharmacodynamics, 82–83 pharmacological properties, 64 resistance, 64 urinary tract infections, 287 Quinupristin-dalfopristin methicillin resistant Staphylococcus aureus, 785

Rabbit fever (see tularemia) Rabies immune globulin, 719 and travel, 752 Rabies vaccine, 717, 719, 814 indications, 811 and travel, 752, 753, 754 Rabies virus prophylaxis for, 716–719 Ramsey hunt syndrome, 408 Ranke complex, 258 Rapid plasma reagin (RPR) test, 313, 330 false negative, 313 false positive, 313, 689 Rash bacteremia, 171 candida infection, 400–401 dermatophyte infection, 398– 700 discoid, 156 drug, 49 ehrlichiosis, 36, 136 erythema chronicum migrans, 602–604 and fever, 129–150 infectious mononucleosis, 739 international travel, 766–769 Kawasaki disease, 133 malar, 156 meningococcemia, 21, 132 neutropenic fever, 35 noninfectious, 151–168 pediculosis, 393–395 pharyngitis, 190 pityriasis versicolor, 401–402 scabies, 395–396 smallpox, 838–839 staphylococcal scalded skin syndrome, 133 staphylococcal toxic skin, 38, 390 streptococcal toxic skin, 38 syphilis, 312, 329, 382 toxic epidermal necrolysis, 133 viral hemorrhagic fever, 848 Rat-bite fever from cutaneous anthrax, 829 rash, 145, 715 Rectal infection neutropenic fever, 35 Red eye, 409–410 differential diagnosis, 412 hyperemia, 411–412 circumlimbal, 410 diffuse, 410 focal, 410 unilateral, 410

Index Redman syndrome vancomycin and, 124 Reiter’s syndrome Campylobacter sp., 440 genital ulcers, 327 mouth ulcers, 211 Relapsing fever, 617 and lice, 393 Renal abscess 282, 488 key points, 486 Renal calculi, 285, 284, 474 and cholecystitis, 479 indinavir, 527 urinary tract infections, 651, 289 Renal cell carcinoma and fever, 155 Renal disease antibiotic dosage, 85, 89 and endocarditis, 352–353 drug related, 127 and human immunodeficiency virus infection, 532, 706 leptospirosis, 713 malaria, 33 plague, 843 viral hemorrhagic fever, 848 Respiratory syncytial virus common cold, 266 nucleic acid antigen test, 106 otitis media, 193 pneumonia, 233, 780 Respiratory tract infections bronchitis, 242–249 pneumonia, 227–242 upper, 187–207 Retinal necrosis, 432 Retinitis, 430–433, (also see uveitis) Cytomegalovirus, 123, 432 key points, 431 toxoplasmosis, 432 Reye’s syndrome influenza, 273–274 Rheumatic fever, 158–159 exposure risk, 132 rash, 145 and Streptococcus pyogenes, 376 Rheumatic heart disease endocarditis, 347 Rhinitis allergic, 267 common cold, 265 symptomatic treatment, 244 Rhinosinusitis (also see sinusitis) and cough, 246

885 Rhinovirus common cold, 266 otitis media, 193 sinusitis, 201 Ribavirin and end stage renal disease, 706 hepatitis C virus, 467, 706 viral hemorrhagic fever, 848 Rickettsia Akari 715 Skin ulcer, 829 Rickettsia coronia rash, 767 Rickettsia prowazekii, 145 Rickettsia rickettsii (see rocky mountain spotted fever) Rickettsia tsutsugamushi Rash, 767 Rickettsia typhi, 145 murine typhus, 712 Rickettsial pox 715 differing from cutaneous anthrax, 829 Rickettsiosis serological diagnosis, 107 Rifabutin drug interactions, 94, 684 Mycobacterium avium, 520 Mycobacterium tuberculosis, 684 Rifampin anthrax, 830 dosage in hepatic failure, 92 drug interactions, 94, 684 ehrlichiosis, 612 endocarditis, 367 meningococcal prophylaxis, 21 Mycobacterium tuberculosis 261, 262 Rift Valley fever virus, 848 (also see viral hemorrhagic fever) Rimantadine, 240, 274, 275 in the elderly, 779 for prophylaxis, 277 Ringworm (see dermatophytic infection) Ritonavir, 511, 527 Rocky Mountain Spotted Fever, 613–517 clinical manifestations, 29, 137, 613 diagnosis, 32, 616 epidemiology, 613 geographic distribution, 615 key points, 31, 614 leukopenia, 32 prevention, 617 petechiae, 135

[Rocky Mountain Spotted Fever] rash, 132, 138, 144, 715 risk exposure, 132, 138 spot less, 31 thrombocytopenia, 32 treatment, 32, 616 zoonosis, 715 Rosacea blepharitis, 419, 422 Roseola infantum, 142, 143 Rotavirus diarrhea, 441 nucleic acid antigen test, 106 Roth spot and endocarditis, 352 Round worms, 635, 644 Rubella virus, 143 arthritis, 553 diagnosis, 112 infectious mononucleosis, 746 international travel, 752, 753 perinatal screening for, 653, 654 rash, 142, 746 vaccination, 811, 816 Rubeola virus atypical, 136, 141 conjunctivitis, 415 rash, 141, 142 travel, 752, 753 Salicylic acid for cutaneous warts, 404 Salivary gland infection, 226 key points, 224 Salmonella enteritidis diarrhea, 440, 712 Salmonella paratyphi (also see typhoid fever) paratyphoid fever 764 Salmonella sp., 440 acquired immune deficiency syndrome, 454 antibiotic resistance, 444 bacteremia, 178 chronic carrier, 440, 444, 454 diagnosis, 111, 444–445, 446 diarrhea, 440, 446 reactive arthritis, 541 septic arthritis, 539 stool culture, 444 toxins, 439 travelers diarrhea, 756 treatment, 440, 448 Salmonella typhi (see typhoid fever) Salmonella typhimurium diarrhea, 440

886 Salpingitis (also see pelvis inflammatory disease), 653 Saquinavir, 511, 527 Sarcoidosis, 159 prostatitis, 342 Sarcoptes scabiei var hominis (see scabies) Scabies, 395–396 in the elderly, 777–778 international travel, 769 key points, 394 Norwegian, 396 Scarlet fever, 138, 190, 376, 391, rash, 142 Schistosoma sp., 633 avian, 633, 636 classification, 635 clinical syndromes, 636 eosinophilia, 635 risks, 636 Seizures bacterial meningitis, 17 Herpes simplex virus-1 encephalitis, 24 endocarditis, 353 Selenium 2.5% (Selsun), 400 SEN virus, 470 Sepsis syndrome, 36 ecthyma gangrenosum, 132 Septata intestinalis (also see microsporidia) and acquired immune deficiency virus, 515, 520 Septicemia definition, 36 Septic shock, 36–40 definition, 38 clinical presentation, 38 ehrlichiosis, 609 hantavirus pulmonary syndrome, 632 intra-abdominal infection, 474 key points, 36 pathophysiology, 38 splenectomy, 663 treatment, 38 viral hemorrhagic fever, 848 Sequestra diabetic foot infection, 587 osteomyelitis, 558 Serological diagnosis, 105, 107 Sexually transmitted disease (STD), 282, 290 cervicitis, 306 chancroid, 314, 326 (see Chlamydia trachomatis) counseling, 333 diarrhea, 454,

Index [Sexually transmitted disease] (see donovanosis) epididymitis, 342, 344 Fitz-Hugh Curtis syndrome 317 genital ulcer disease (female), 309–314 genital ulcer disease (male), 325–333 hepatitis, 455, 459 Herpes simplex virus, 311–312, 330–333 human immunodeficiency virus, 310, 315, 331, 343, 499, 505 human papilloma virus (female), 314–316 human papilloma virus (male), 333–336 injection drug user, 689 international traveler, 751 (see lymphogranuloma venereum) (see Neisseria gonorrhoeae) partner notification, 333 pelvic inflammatory disease, 306–309, 653 pharyngitis, 321 proctitis, 321 prostatitis, 339 septic arthritis, 538, 543 syphilis, 312–314, 325–330, 343 Trichomonas vaginitis, 304– 305 urethritis (female), 304, 316 urethritis (male), 319–325 Shigella boydii, 441 Shigella dysenteriae, 441 Shigella flexneri, 441 Shigella sonnei, 441 Shigella sp., 441 achlorhydria, 664 acquired immune deficiency syndrome, 454 diagnosis, 111, 444, 446 diarrhea, 756, 454, 441, 445, 446 reactive arthritis, 541 toxins, 439 travelers diarrhea, 756 treatment, 441, 448 Shingles (see zoster) Shock (see septic shock) Sickle cell disease pneumococcal meningitis, 21 osteomyelitis, 570 septic arthritis, 539 vertebral osteomyelitis, 560 Simon foci, 258

Sin Nombre virus, 631 Sinusitis, 198–203 anatomy, 200 chronic, 22, 203, 664, 670, 672, 662 common cold, 267 influenza, 273 key points, 199 Mucormycosis, 629, 201 osteomyelitis, 571 sphenoid, 201 vasculitis, 157 Sixth disease (see exanthem subitum) Skin infection candidemia, 390 outpatient parenteral antibiotic therapy, 121 parasitic, 637 rash, 129–150 bacterial, 373–392 anatomic structures, 373 animal bites, 388 bacteremia, 389–390 bacterial toxins, 390 blastomycosis, 625 burns, 389 carbuncles, 385–386 cellulitis, 379–382 chancriform lesions, 382 decubitus ulcers, 387 erysipelas, 379 folliculitis, 384–385 furuncles, 385–386 human bites, 388 hyper IgE syndrome, 670 impetigo, 377–379 key points, 379, 377, 383, 384, 386 lacerations, 387 muscle infections, 392 organisms, 374 paronychia, 386 pathogens, 375–376 puncture wounds, 387 pyoderma, 376–382 recurrent, 670 severity, 374–375 spirochete infections, 391 staphylococcal furuncles, 673 subcutaneous infection, 382 surgical bite, 388–389 non-bacterial, 393–408 infestations, 393–397 lice, 393–395 mites, 396–397 scabies, 395–396 key points, 394, 397, 403

Index [Skin infection] fungal infections, 398–402 dermatophyte, 398–400 pityriasis versicolor, 401–402 yeast candida, 400–401 viral infections, 402–408 herpes simplex virus, 405– 407 molluscum contagiosum, 404– 405 varicella zoster, 407–408 warts, 402–704 Smallpox, 836–841 from chickenpox, 840 clinical illness, 838–840, 835, 852 diagnosis, 835, 839 differential diagnosis, 839, 840 differentiating from varicella, 147 hemorrhagic, 838 infection control, 851 malignant, 838 management, 840–841 transmission, 836, 840, 851 vaccine, 840–841 Sore throat (see pharyngitis) Sparfloxacin, 65–66 costs, 56 decubitus ulcers, 776 dose, 56 Spectinomycin urethritis, 324 Spider bite, 829 Spirillum minor rat bite fever, 715 Splenectomy, 662, 663–664 causes of, 662 infectious related to, 662, 711 Splenic abscess, 487, 682 key points, 486 Splenomegaly babesiosis, 612 endocarditis, 354 hepatitis A virus, 458 human immunodeficiency virus infection, 505, 530 infectious mononucleosis, 739, 743 in international traveler, 762 Splinter hemorrhage and endocarditis, 352 Spontaneous bacterial peritonitis (SBP) (see peritonitis, primary) Sporothrix schenckii 628 Sporotrichosis Skin lesions, 383

887 Sporotrichosis (see Sporothrix schenckii) Squamous intraepithelial lesions, 516 cervical, 314, 315 penile, 333 SSKI, 628 St. Louis encephalitis, 630–631 Staphylococcal aureus arthritis, 535, 537, 528 bacteremia, 176–177 blepharitis, 419 blood culture, 175, 176 burn infections, 389 bursitis, 553 carbuncles, 385 conjunctivitis, 418 decubitus ulcers, 387, 776 diabetic foot infections, 588 diarrhea, 439, 449 endocarditis, 349, 353, 355 native valve, 360, 681 treatment, 364–367 prosthetic valve, 366 endophthalmitis, 434 epiglottitis, 206 erysipelas, 379 folliculitis, 385 furuncles, 385 hemodialysis access, 696, 698 hepatic abscess, 486 human immunodeficiency virus infection, 528 human bites, 388 hype immunoglobulin E syndrome, 665 impetigo, 377 influenza, complication of, 274, 779 keratitis, 426 lacerations, 387 methicillin resistant endocarditis, 364, 367 injection drug user, 681 nursing home, 784 surgery for, 368 myositis, 392, 680 nasal carriage, 699, 704 nasal colonization, 389 necrotizing fasciitis, 26 neutropenia, 666 nursing home pneumonia, 780 osteomyelitis, 569, 570 otitis media, 193 petechiae, 136 peritoneal dialysis infection, 701 preseptal cellulitis, 428

[Staphylococcal aureus] primary peritonitis, 478 prosthetic joint, 549 puncture wounds, 387 renal abscess, 488 skin infections, 374, 375, 673– 674, 670 splenic abscess, 487 submandibular abscess, 226 surgical site, 389 toxic shock syndrome, 139, 390 urinary tract infection, 281 vertebral osteomyelitis, 564, 566 Staphylococcal scalded skin syndrome, 391 rash, 133 Staphylococcal toxic shock syndrome, 139, 140, 325, 390– 391 Staphylococcus coagulase negative bacteremia, 175 conjunctivitis, 418 contaminant in blood culture, 174 diabetic foot infection, 589 endocarditis, 360, 366 hemodialysis access infection, 696 keratitis, 426 peritoneal dialysis infection, 701 prosthetic joint infection, 549 urinary tract infections, 281 vertebral osteomyelitis, 564, 566 Staphylococcus coagulase positive (see Staphylococcus aureus) Staphylococcus saprophyticus and urinary tract infections, 281, 289 Staphylococcus sp. blepharitis, 419 chicken pox superinfection, 407 coagulase test, 174 conjunctivitis, 418 endocarditis, 360 endophthalmitis, 434 orchitis, 345 Stavudine (D4T), 511 dosage, 794 lipodystrophy, 524 pancreatitis, 530 post exposure prophylaxis, 791–798 toxicities, 527–794

888 Steady state drug, 79 Sternal wound infection, 577 Stevens Johnson Syndrome, 49, 145 conjunctivitis, 413 genital ulceration, 327 Still’s disease, 156 Stomatitis aphthous, 223 herpetic, 222 syphilis, 329 varicella zoster, 223 Streptobacillus moniliformis rat bite fever, 715 Streptococcal toxic shock syndrome, 139 Streptococcus agalactiae (Group B) bacteremia, 176 cellulitis, 376 chorioamnionitis, 652 endocarditis, 359 perinatal screening for, 653, 654, 656 skin infections, 324 surgical site, 389 urinary tract infection, 281, 650 Streptococcus bovis endocarditis, 359 gastrointestinal carcinoma, 359 Streptococcus group C pharyngitis, 189 Streptococcus group G cellulitis, 376 pharyngitis, 189 Streptococcus milleri muscle infection, 392 Streptococcus, nutritionally variant (see Abiotrophia) Streptococcus pneumoniae antibiotic resistance, 233 bacteriemia, 176 bronchitis, 243, 245 complicating influenza, 274, 779 conjunctivitis, 418 endocarditis, 349, 359 epiglottitis, 206 human immunodeficiency virus infection, 231, 502 hypogammaglobulinemia, 662, 664, 670, 672 injection drug use, 683 keratitis, 426 meningitis, 21–22 nursing home acquired, 780 otitis media, 193

Index [Streptococcus pneumoniae] pneumonia, 22, 683, 231, 233, 780 preseptal cellulitis, 428 primary peritonitis, 478 sinusitis, 201 splenectomy, 663 vaccination, 684, 706, 809, 810 international travel, 752, 753 Streptococcus pyogenes (Group A) bacteremia, 176 bursitis, 553 common cold, 266, 267 conjunctivitis, 413 diabetic foot infection, 589 endocarditis, 349, 359 erysipelas, 379 fasciitis, 25–26, 30 glomerulonephritis, 376 human bites, 388 impetigo, 377 lacerations, 387 myositis, 392 nucleic acid antigen test, 106 pharyngitis, 102, 189–192 preseptal cellulitis, 428 puncture wound, 387 rapid antigen testing, 102, 190 rheumatic fever, 158–159, 376 scarlet fever, 376, 138, 190, 142 serological diagnosis, 107 sinusitis, 201 skin infections, 374, 375, 142 surgical site, 389 toxic shock, 38, 139, 376, 391 Streptomycin for tularemia, 846 Strongyloides sp. achlorhydria, 664 cell mediated immune defect, 669 classification, 634 clinical syndromes, 630, 643, 644 eosinophilia, 633, 634, 766 risks and exposure, 636, 643 serological diagnosis, 107 skin lesions, 637, 769 therapy, 643 Stye, 419 Submandibular abscess, 225 Subperiosteal abscess, 429–430 Sulfadiazine for toxoplasmosis, 517 Sulfamethoxazole urinary tract infections, 286

Sulfisoxazole urinary tract infections, 650 Sulfonamides, 68–71 mechanism of action, 68 pharmacological properties, 68 resistance, 68 Surgical site infection, 388–389 prophylaxis for, 488–489, 490 surgical procedures, 488 Suspicious powder anthrax, 834 Sweats bacteremia, 1723 endocarditis, 352 night time, 4 pathophysiology, 4, 6 Swimmer’s Itch, 633, 767 (also see Schistosoma sp.) Synercid (see quinupristin-dalfopristin) Syphilis (also see Treponema pallidum) counseling, 333 neurosyphilis, 330, 331 partner notification, 333 proctitis, 446 genital ulcer disease, 309, 312– 314, 325–333 human immunodeficiency virus infection, 505–506 latent, 312, 329 primary, 312 secondary, 312, 391 serological tests, 313, 310, 330, 391 skin lesions, 382, 312, 329 tertiary, 312, 329, 330, 331 treatment, 313, 321 Systemic lupus erythematosus, 156 mouth ulcers, 211 T-helper cell (see CD4) Taenia sp., 634 classification, 635 worms in stool, 642 Temafloxacin, 65 decubitus ulcers, 776 Temperature antipyretic therapy, 13–15 diurnal variation, 4 measurement, 7 normal, 4, 6 pulse-temperature deficit, 5 thermoregulation, 7–11, 9 cytokine, 8, 10–11 exogenous pyrogen, 8, 10

Index Temporal arteritis, 157–158 Terazosin, 341 Terbinafine dermatophyte infection, 400 onychomycosis, 401 tinea capitis, 401 topical, 400 Testicular torsion, 343 Tetanus injection drug use, 691 Tetanus toxoid, 813–814 animal bites, 717 indications, 810 injection drug use, 691 international travel, 752, 753 pregnancy, 658 Tetracycline, 60–63 adverse reactions, 62 categories, 61 clinical indication, 61–62 cost, 56 dose, 56 dose in renal disease, 54 Helicobacter pylori, 491 mechanism of action, 60 pharmacological properties, 61, 53 resistance, 61 rock mountain spotted fever, 616 spectrum, 61–62, 59 syphilis, 313 tissue penetration, 93 Thermometer history, 2 types, 7 Threadworm (see Strongyloides sp.) Thrombocytopenia dengue hemorrhagic fever, 765 ehrlichiosis, 32 endocarditis, 354 Epstein Barr virus infection, 743 fever of unknown origin, 167 hantavirus pulmonary syndrome, 632 histoplasmosis, 624 human immunodeficiency virus infection, 499, 515 rocky mountain spotted fever, 614 septic shock, 38 systemic lupus erythematosus, 156 viral hemorrhagic fever, 848

889 Thromboembolic disease and fever, 160 prevention of in traveler, 750 and pulmonary emboli, 683 Thrombophlebitis ovarian vein, 653 septic, 682 Thrush, 218–219, 508, 515, 629, 662, 668 (also see oral candidiasis) and immune deficiency, 670, 672 Ticarcillin-clavulanate cost, 125 decubitus ulcers, 776 dose, 125 outpatient parenteral antibiotic therapy, 125 pneumonia, 782 Ticks Amblyomma sp., 601, 610, 617 Dermacentor sp., 613, 616, 617, 618 Ixodes sp., 600–601, 602, 608, 612, 618 Ornithodoros sp. 617 Tick borne illnesses, 29–32, 599– 619 babesiosis, 612–613 coinfection, 608, 612 colorado tick fever, 618 ehrlichiosis, 32, 145, 608–612 key points, 31, 600, 609, 614 lyme disease, 145, 599–608 Powassan viral encephalitis, 618 relapsing fever, 617 rocky mountain spotted fever, 29, 144, 613–617 serological diagnosis, 112, 604–606, 612, 616 tick paralysis, 618 tularemia, 617–618 Tick paralysis, 618 Tinea (see dermatophyte infection) Tinea versicolor (see pityriasis versicolor) Tinidazole Trichomonal vaginitis 305 Tobramycin cost, 125 dose, 125, 699, 702 hemodialysis infections, 699– 700 neutropenia fever, 36–37 outpatient parenteral antibiotic therapy, 125

[Tobramycin] peritoneal dialysis infections, 702 septic shock, 39 Tolnaftate, 400 Tongue lesions, 216–218 coated, 218 geographic, 217 key points, 217 red strawberry, 139 ulcerations, 216–217 Toxic epidermal necrolysis (TEN) rash, 133, 391 risk, 133 Toxic shock syndrome (TSS), 38 staphylococcal, 139, 390 criteria for diagnosis 139 rash, 390 treatment, 390–391 streptococcal, 139, 391 Toxocara sp. classification, 635 clinical syndromes, 636 eosinophilia, 634 retinitis, 433 risk exposure, 636 serological diagnosis, 107 visceral larva migrans, 634 Toxoid, 808 Toxoplasma gondii cell mediated immune defect, 669 diagnosis, 517, 714 human immunodeficiency virus infection, 502, 505, 514, 515 infectious mononucleosis, 745 perinatal infection, 655 presentation, 617, 520, 526 prophylaxis for, 508 retinitis, 432 serological testing, 506 therapy, 517 zoonosis, 714 Trachoma, 418 Traveler, 749–770 counseling and prevention, 749–756 diarrhea, 441, 765–766 eosinophilia, 766 fever, 757–765 causes 759, 760 immunizations, 752–754 internet resources, 749, 752, 754 key points, 750, 758, 765 malaria prophylaxis, 755–756 malaria risks, 34 rash, 766–769

890 [Traveler] systemic illness, 767 type of lesions, 768 Tremacamra common cold, 268, 270 Trench fever lice, 393 Trench mouth, 215 Treponema Pallidum (also see syphilis) anterior uveitis, 433 dark field examination, 101 genital ulcer disease, 309, 312– 314 Jarisch-Herxheimer reaction, 152 perinatal screening for, 653, 654 rash, 166 retinitis, 433 serological diagnosis, 107 skin lesions, 382, 312, 329 Treponemal Pallidum Hemagglutination Assay (TPHA), 319 Trichinella sp., 634–636 serological diagnosis, 107 Trichloroacetic acid (TCA), 316, 335 Trichomonas vaginitis cervicitis, 306 treatment, 307 genital ulcer, 327 urethritis, 322, 325 vaginitis, 304, 305 treatment, 305 wet mount, 101 Trichophyton sp. skin infections, 398–400 Trichuris sp. classification, 635 clinical syndrome, 636, 643 exposure risk, 636, 643 therapy, 643 Tricuspid valve and endocarditis, 350 Trifluridine (Viroptic) herpes keratitis, 425 Trimethoprim, 68–71 mechanism of action, 68 pharmacological properties, 68 resistance, 68 urinary tract infections, 286 Trimethoprim–sulfamethoxazole (see co-trimoxazole) Trizivir, 511 postexposure prophylaxis 794 Tropheryma whippelii endocarditis, 354

Index Trovafloxacin, 65 dosage in hepatic failure, 92 dose, 89 dose in renal disease, 89 drug interactions, 94 Trypanosoma sp. African sleeping sickness, 719 Chagas disease, 719 diagnosis, 101 lymphadenopathy, 719 TT virus, 470 Tuberculosis (also see Mycobacterium tuberculosis), 251– 264 active, 258–261, 251, 255 approach to patient, 255 diagnosis, 258–260 extra-pulmonary, 254, 260 human immunodeficiency virus, 499, 504, 506, 520, 515 immune reconstitution syndrome, 524 key points, 252, 260 latent, 251, 253, 254–258, 261 multidrug resistant, 262 in nursing home patient, 781– 783 surveillance, 782 perinatal screening, 653 prevention, 263 primary infection, 253 pulmonary, 253–254, 258–260 risk groups, 252, 499 septic arthritis, 550, 551 sterile pyuria, 284 testing, 254–258 treatment, 261–263, 782–783 vertebral osteomyelitis, 566, 567, 569 Tubo-ovarian abscess, 308 Tularemia, 617–618 (also see Francisella tularensis) Bioterrorism, 845–847 diagnosis, 846, 835 fever, 713, 846 and fever of unknown origin, 166 infection control, 851 lymphadenopathy, 714, 720 pneumonia, 712, 846, 852 postexposure prophylaxis, 847 skin lesions, 383, 846 transmission, 851 typhoidal, 846 ulceroglandular, 714, 829, 846 vaccine, 847 Tungiasis, 752, 769

Typhilitis neutropenic fever, 36 Typhoid fever diagnosis, 764 diarrhea, 440 exposure risk, 132 fever, 764 international travel, 764 pulse-temperature deficit, 5, 762 rash, 132, 145, 764 treatment, 764–765 Typhoid vaccine international travel, 753, 754, 817 pregnancy, 658 Typhus louse-borne, 145, 393, 712, 715 tick-borne, 145 Tzanck test cutaneous herpes simplex, 406 genital herpes simplex, 311, 331 varicella zoster virus, 400 Ulcerations cutaneous anthrax, 827, 828 differentiation from cutaneous anthrax, 829 decubitus, 387 due to injection drug use, 679 foot (see diabetic foot infections) genital, 325–333, 309–314 key points, 309, 326 mouth, 211 aphthous stomatitis, 223 herpes simplex virus, 219 key points, 211 traumatic, 219 varicella zoster 223 tularemia, 617, 829, 846 Ulcerative colitis (see inflammatory bowel disease) Upper respiratory tract infection, 187–207 symptomatic treatment, 244 Ureaplasma sp. prostatitis, 339 urethritis, 322, 325 urinary tract infection, 292 Urethritis, 290 acute urethral syndrome, 316 causes, 320 evaluation of, 323 female, 304, 316 gonococcal, 319, 321, 324 gram stain for, 322, 323

Index [Urethritis] key points, 320 laboratory diagnosis, 321–322 male, 319–325 nongonococcal, 319, 321, 324 post-gonococcal, 325 recurrent, 325 treatment, 322, 324 trichomonas vaginitis, 322 urinary tract infection, difference from, 321, 650 Urinalysis contamination, 284 dipstick, 284 endocarditis, 354 end stage renal disease, 706 fever of unknown origin, 167 infectious mononucleosis, 739 leukocytes esterase, 284 nitrite test, 283 renal abscess, 488 tuberculosis, 254 urinary tract infection, 110, 283–284, 650 vasculitis, 157 Urinary tract catheter culture collection, 283 in the elderly, 774 and infection, 279, 282, 774 Urinary tract culture, 284–285 collection, 283 contamination, 284 clean catch, 283 transport, 283 Urinary tract infections, 279–299 acidification for, 288 antibiotics for, 285–288 asymptomatic, 282, 298–299, 649 bacteriology, 281 clinical manifestations, 282 complicated, 290, 296 bacteriology, 281 key points, 292 contamination, 107 culture, 289 diagnosis, 109 dialysis patient, 706–707 elderly, 773–774, 279, 282 fungus, 296–298 imaging, 285, 290 key points, 297, 298, 289, 292, 649 laboratory diagnosis, 282–285 in men, 280 nonspecific measures for, 288 pathophysiology, 279–281 pregnancy, 649–652

891 [Urinary tract infections] prophylaxis for, 290, 294– 295 prostatitis, 343 pyelonephritis, 282, 299, 707 reconnect, 292–296, 339 recurrent, key points, 292 reinfection, 293–294 relapse, 292, 290 risk factors, 293 treatment, 293 renal cyst infection, 707 septic shock, 39 quantitative cultures, 109 uncomplicated, 289–290 antibiotic therapy, 291, 289 bacteriology, 281 key points, 289 single dose therapy, 291, 289 Urological (male) infections, 319–345 epididymitis, 342–344 genital ulcers disease, 325–333 genital warts, 333–336 orchitis, 344–345 prostatitis, 336–342 urethritis, 319–325 Urticaria, 149 chiggers, 397 fleas, 397 papular urticaria, 397 pediculosis, 393 vasculitis, 157 Uveitis, 410, 430, 431–433 differential diagnosis, 412 key points, 431 lyme disease, 605 zoster, 408 Vaccine, 807–819 active, 808 adverse reactions, 808–809 anthrax, 836 conjugate, 808 contraindications, 809 costs, 809–810 diphtheria–tetanus (dt), 507, 684 Haemophilus influenzae, 22, 808 healthcare worker, 818–819 hepatitis A virus, 459, 507, 684, 813 hepatitis B virus, 464, 507, 684, 812 and human immunodeficiency virus infection, 507

[Vaccine] immune compromised host, 819 inactivated, 808 indications, 809–810 influenza, 276–277, 684, 507, 812 injection drug use, 684 for international travel, 752– 754, 816–818 japanese encephalitis virus, 816 live, 808 lyme disease, 608, 814 meningococcal, 21, 811, 815, 817 measles, mumps and rubella, 507, 811, 815 passive, 808 pneumococcal, 684, 809, 810 polio, 507, 818 pregnancy, 658, 819 smallpox, 840–841 typhoid, 753, 754, 817 varicella, 811, 815 varicella zoster virus, 407, 507, 811, 815 yellow fever, 658, 753, 817 Vaccinia virus, 836, 840–841 Vaginal candidiasis, 303–304 human immunodeficiency virus infection 499, 508, 515 Vaginal discharge bacterial vaginosis, 301 candida, 303, 499 key points, 302 noninfectious, 304 trichomonal, 304 types, 302 Vaginitis, 290, 301–306 candida, 303–304 treatment, 304, 305 KOH wet mount 100–101 trichomonas, 304–305 Vaginosis (see bacterial vaginosis) Valacyclovir cutaneous herpes simplex, 407 for genital herpes simplex, 312, 332 for oral herpes simplex, 222 for varicella Zoster, 223, 408, 777 Valganciclovir for CMV infection, 521 Valley fever (see Coccidioides immitis) Vancomycin anthrax, 830

892 [Vancomycin] Clostridium difficile colitis, 451–452 cost, 125 dosage, 92, 125 endocarditis, 363, 362, 364, 367, 370, 681 during hemodialysis, 699–700 hepatic abscess, 487 intraabdominal infections, 484 meningitis, 22–23 methicillin resistant Staphylococcus aureus, 785 necrotizing fasciitis, 30 neutropenic fever, 36 outpatient parenteral antibiotic therapy, 122, 125 orchitis, 345 during peritoneal dialysis, 702– 703 pharmacokinetics, 80 primary peritonitis, 478 redman syndrome, 124 secondary peritonitis, 484 septic shock, 39 skin infections, 378 splenic abscess, 487 surgical prophylaxis, 490 vertebral osteomyelitis, 568 Varicella Zoster Virus (also see Zoster) acute retinal necrosis, 432 cell mediated immune defect, 668, 671 chickenpox, 407 conjunctivitis, 415 direct fluorescent antibody, 147 hepatitis, 470 keratitis, 426 mouth ulcers, 211, 223 nucleic acid antigen test, 106 perinatal infection, 655 rash, 147, 407 shingles, 407 from small pox, 839, 840 vaccine, 407, 507, 752, 753, 811, 815 Variola virus (also see smallpox) major, 836 minor, 839 Vasculitis, 157–158 and fever of unknown origin, 165 Venereal disease research laboratory test (VDRL), 313, 330 false negative, 313 false positive, 313, 156, 330, 742

Index Veillonella sp. bacteremia, 181 Vegetations and endocarditis, 349, 355, 358 Vesicles, 146–148 small pox, 838 varicella, 407 Vibrio cholerae achlorhydria, 664 diagnosis, 111, 446 toxins, 439 treatment, 448 Vibrio parahaemolyticus And acquired immune deficiency syndrome, 454 diagnosis, 111 diarrhea, 445, 454 Vibrio vulnificus, 148 and skin infections, 376 Vidarabine herpes keratitis, 425 Vincent’s angina, 189 Vincent’s infection, 215 Viral hemorrhagic fever Bioterrorism, 847–849 clinical manifestations, 848, 835, 852 diagnosis, 848, 835 exposure risk, 851 infection control, 851 management, 848 petechiae, 136, 138 rash, 132 transmission, 847, 851 types, 848 Viral infection arthritis, 535, 552–553 bronchitis, 227, 243, 247 colorado tick fever, 518 common cold, 265–271 conjunctivitis, 414 cough, 248 cultures, 111 cystitis, 284 cytomegalovirus, 521 encephalitis, 23–25, 630–632 Epstein Barr virus, 735–744 gynecological infection, 311, 314 human herpes 6, 106, 143 human herpes 8, 522 see herpes simplex infections, 223 see human immunodeficiency virus human polyoma virus, 522 influenza, 271–278

[Viral infection] keratitis, 424–426 laboratory diagnosis, 103–106, 111–112 molluscum contagiosum, 404– 405 oral, 211, 221–223, 224 orchitis, 344 otitis media, 193 pharyngitis, 102, 189 pneumonia, 230, 235, 236, 780 Powassan viral encephalitis, 618 and rash, 138, 141–144, 146, 149 sinusitis, 198, 201 susceptibility, 113 urethritis, 320 variola virus, 836–841 viral hemorrhagic fever, 847 warts, 333–336, 314–316, 211, 224, 402–404 Viral load antiretroviral therapy and, 510 and human immunodeficiency virus infection, 502, 503, 506 Viridian’s streptococcus bacteremia, 176 endocarditis, 358–359, 399 treatment 361–362 epiglottitis, 206 Vitamin C common cold, 268, 270, 271 Volume of distribution drug, 78, 86 Vulvovaginitis (see vaginitis) Warts anogenital, 333, 334 cutaneous, 402–404 key points, 403 treatment, 403–404 types, 403–404 Wasting and human immunodeficiency virus infection, 515, 523– 524 Wegener’s Granulomatosis, 157, 156 West Nile virus encephalitis, 631, 709, 783 Western Equine encephalitis, 630–631 Wet mounts, 100 vaginitis, 100 Whipworm (see Trichuris sp.)

Index White blood cell scan (also see nuclear scintigraphy) diabetic foot infections, 587, 588, 589 osteomyelitis, 564 Whooping cough (see Bordetella pertussis) Woolsorter’s disease, 825 Wucheria bancrofti, 635–637 (also see filariasis) Xanthomonas sp. peritoneal dialysis infection, 703 Yeast (also see candida infection) blood culture, 175 Yellow fever virus vaccine, 817 international travel, 753 pregnancy, 658 Yersinia enterocolitica diagnosis, 111, 446 diarrhea, 445 hepatic abscess, 486 pharyngitis, 189

893 [Yersinia enterocolitica] reactive arthritis, 541 stool culture, 444 treatment, 448 Yersinia pestis 841 bioterrorism, 823, 841–843 lymphadenopathy, 714, 720 plague, 210, 214 serological diagnosis, 107 Zalcitabine, 511 pancreatitis, 530 toxicities, 527 Zanamivir 240, 275 in the elderly, 779 for prophylaxis, 278 Zidovudine, 511 anemia, 532 dosage, 794 postexposure prophylaxis, 791, 798 pregnancy, 656–658 toxicities, 527, 794 Ziehl-Nielsen stain, 100 Zinc common cold 268, 270

Zoonosis, 709–722 animal bites, 710–712, 716– 719 cat scratch disease, 719–722 exposure history, 712 fever of unknown origin, 166 key points, 710 lymphadenopathy and, 714– 715, 719, 720 pathogens, 716 plague, 841 rabies prophylaxis, 716–719 tularemia, 845 viral hemorrhagic fever, 847 Zoster (also see Varicella Zoster virus) bell’s palsy, 408 cutaneous, 407–408 in the elderly, 777 human immunodeficiency virus, 499 ophthalmic, 408, 426 post herpetic neuralgia, 408, 777 oral, 223 treatment, 408, 777 Zyvox (see Linezolid)

About the Editor

CHRISTOPHER GRACE is Director of the Infectious Diseases Unit and Associate Professor of Medicine, Fletcher Allen Health Care, University of Vermont, Burlington. The author or coauthor of more than 35 professional publications, he is a member of the Infectious Disease Society of America and the American Society of Microbiology, and is the Vermont representative for the New England Chapter of the American Academy of HIV Medicine. Dr. Grace received the B.S. degree (1975) from the University of Notre Dame, Indiana, and the M.D. degree (1979) from New York Medical College, Valhalla, New York.